register interest

Emeritus Professor Helen Chapel

Research Area: Immunology
Scientific Themes: Immunology & Infectious Disease
Keywords: immunology, common variable immunodeficiency disorders, primary immune deficiencies and therapies

Primary immunodeficiencies (PIDs) in adults and children are rare disorders due to failure of the immune system - sometimes inherited as a single gene defect in infants but without evidence of inheritance in adults.
Oxford hosts the largest clinic for adult patients with common variable immunodeficiency disorders [CVIDs], which constitute the commonest forms of symptomatic immunodeficiency. These antibody failure syndromes are of unknown aetiology and likely to be polygenic in nature.

Clinical and laboratory research over the last 25 years has resulted in data enabling the definition of four distinct clinical phenotypes leading to improved prognosis and outcome prediction. Genetic studies are ongoing in these different phenotypes as well as functional studies of blood and bone marrow, to determine pathogenesis, so that improved treatments can be used for the wide ranging complications seen in CVID patients. Current therapy depends on replacing missing antibodies that protect against bacterial infections; details of optimal dosing have been published and are being incorporated into guidelines world-wide.

Name Department Institution Country
Professor Julian C Knight Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Anna Katharina (Katja) A Simon Experimental Medicine Division Oxford University, Weatherall Institute of Molecular Medicine United Kingdom
Professor Paul Klenerman Experimental Medicine Division Oxford University, Peter Medawar Building United Kingdom
Professor Jacques van Dongen Dept of Immunology, Erasmus MC Faculty, University of Rotterdam Netherlands
Dr Mirjam Van Der Burg Erasmus Medical Centre Netherlands
Professor Jiri Liztmann University of Brno Czech Republic
Professor Eric Oksenhendler Hôpital Saint-Louis Paris France
Professor Charlotte Cunningham-Rundles Medical Centre Mount Sinai United States
Professor Klaus Warnatz University of Freiburg Germany
de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla FA, Kanariou M et al. 2017. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol, 139 (4), pp. 1282-1292. | Show Abstract | Read more

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Friman V, Winqvist O, Blimark C, Langerbeins P, Chapel H, Dhalla F. 2016. Secondary immunodeficiency in lymphoproliferative malignancies. Hematol Oncol, 34 (3), pp. 121-132. | Show Abstract | Read more

Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti-inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections. The pathogenesis of immune deficiency secondary to lymphoproliferative malignancy is multifactorial including disease- and treatment-related factors. Supportive treatment, including early vaccination, anti-infective prophylaxis, and replacement immunoglobulin, plays a key role in preventing infections in MM and CLL. This article provides an overview of the basic immunology necessary to understand the pathogenesis of secondary immunodeficiency and the infectious complications in MM and CLL. We also discuss the evidence supporting the role of prophylactic replacement immunoglobulin treatment in patients with antibody failure secondary to MM and CLL and the indications for its use. Copyright © 2016 John Wiley & Sons, Ltd.

Dhalla F, Fox H, Davenport EE, Sadler R, Anzilotti C, van Schouwenburg PA, Ferry B, Chapel H, Knight JC, Patel SY. 2016. Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility. Clin Exp Immunol, 184 (2), pp. 216-227. | Show Abstract | Read more

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6⁺ CXCR3⁻ CCR4⁺ CD161⁺ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6⁺ CXCR3⁻ CD4⁺ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.

Schwerd T, Pandey S, Yang H-T, Bagola K, Jameson E, Jung J, Lachmann RH, Shah N, Patel SY, Booth C et al. 2017. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut, 66 (6), pp. 1060-1073. | Show Abstract | Read more

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.

Kienzler A-K, van Schouwenburg PA, Taylor J, Marwah I, Sharma RU, Noakes C, Thomson K, Sadler R, Segal S, Ferry B et al. 2016. Hypomorphic function and somatic reversion of DOCK8 cause combined immunodeficiency without hyper-IgE. Clin Immunol, 163 pp. 17-21. | Show Abstract | Read more

Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral infections, food allergies and elevated serum IgE. Although patients may present with a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability in patients are poorly defined. Here we characterized a novel compound heterozygous mutation in DOCK8 in a patient diagnosed with primary combined immunodeficiency which was not typical of classical DOCK8 deficiency. In contrast to previously identified mutations in DOCK8 which result in complete loss of function, the newly identified single nucleotide insertion results in expression of a truncated DOCK8 protein. Functional evaluation of the truncated DOCK8 protein revealed its hypomorphic function. In addition we found somatic reversion of DOCK8 predominantly in T cells. The combination of somatic reversion and hypomorphic DOCK8 function explains the milder and atypical phenotype of the patient and further broadens the spectrum of DOCK8-associated disease.

Sánchez-Ramón S, Dhalla F, Chapel H. 2016. Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy. Front Immunol, 7 (AUG), pp. 317. | Show Abstract | Read more

Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are prone to present with antibody production deficits associated with recurrent or severe bacterial infections that might benefit from human immunoglobulin (Ig) (IVIg/SCIg) replacement therapy. However, the original IVIg trial data were done before modern therapies were available, and the current indications do not take into account the shift in the immune situation of current treatment combinations and changes in the spectrum of infections. Besides, patients affected by other B cell malignancies present with similar immunodeficiency and manifestations while they are not covered by the current IVIg indications. A potential beneficial strategy could be to vaccinate patients at monoclonal B lymphocytosis and monoclonal gammopathy of undetermined significance stages (for CLL and MM, respectively) or at B-cell malignancy diagnosis, when better antibody responses are attained. We have to re-emphasize the need for assessing and monitoring specific antibody responses; these are warranted to select adequately those patients for whom early intervention with prophylactic anti-infective therapy and/or IVIg is preferred. This review provides an overview of the current scenario, with a focus on prevention of infection in patients with hematological malignancies and the role of Ig replacement therapy.

Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, Espinosa-Rosales FJ, Hammarström L, Nonoyama S, Quinti I et al. 2016. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract, 4 (1), pp. 38-59. | Read more

Li YR, Zhao SD, Li J, Bradfield JP, Mohebnasab M, Steel L, Kobie J, Abrams DJ, Mentch FD, Glessner JT et al. 2015. Genetic sharing and heritability of paediatric age of onset autoimmune diseases. Nat Commun, 6 pp. 8442. | Show Abstract | Read more

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Li YR, Li J, Zhao SD, Bradfield JP, Mentch FD, Maggadottir SM, Hou C, Abrams DJ, Chang D, Gao F et al. 2015. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med, 21 (9), pp. 1018-1027. | Show Abstract | Read more

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Lucas M, Lee M, Oksenhendler E, Chapel H. 2015. The ratio of mean daily IgG increment/mean daily dose in immunoglobulin replacement therapy in primary antibody deficiencies. J Allergy Clin Immunol Pract, 3 (6), pp. 998-1000.e2. | Read more

van Schouwenburg PA, Davenport EE, Kienzler A-K, Marwah I, Wright B, Lucas M, Malinauskas T, Martin HC, WGS500 Consortium, Lockstone HE et al. 2015. Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders. Clin Immunol, 160 (2), pp. 301-314. | Show Abstract | Read more

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

Maggadottir SM, Li J, Glessner JT, Li YR, Wei Z, Chang X, Mentch FD, Thomas KA, Kim CE, Zhao Y et al. 2015. Rare variants at 16p11.2 are associated with common variable immunodeficiency Journal of Allergy and Clinical Immunology, 135 (6), pp. 1569-1577. | Show Abstract | Read more

© 2015 American Academy of Allergy, Asthma & Immunology. Background Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. Objective We sought to seek novel associations of genes and genetic variants with CVID. Methods We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. Results We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10 -9 ), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10 -5 ) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. Conclusion We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier J-B, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C et al. 2015. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet, 47 (7), pp. 717-726. | Show Abstract | Read more

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Hodkinson JP, Lucas M, Lee M, Harrison M, Lunn MP, Chapel H. 2015. Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients. Clin Exp Immunol, 181 (1), pp. 179-187. | Show Abstract | Read more

There are currently no data to support the suggestion that the dose of therapeutic immunoglobulin (Ig) should be capped in obese patients for pharmacokinetic (PK), safety and economic reasons. We compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically equivalent lean patient across a range of indications, including primary antibody deficiency or autoimmune peripheral neuropathy. Comprehensive matching was carried out using ongoing research databases at two centres in which the dose of Ig was based on clinical outcome, whether infection prevention or documented clinical neurological stability. The IgG trough or steady state levels, IgG increments and Ig efficiencies at times of clinical stability were compared between the obese and lean cohorts and within the matched pairs. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight-adjusted dose compared with the lean patients. However at an individual patient level there were significant exceptions to this correlation, and upon sub-group analysis no significant difference was found between obese and lean patients receiving replacement therapy. Across all dose regimens a high body mass index (BMI) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate.

Maggadottir SM, Li J, Glessner JT, Li YR, Wei Z, Chang X, Mentch FD, Thomas KA, Kim CE, Zhao Y et al. 2015. Rare variants at 16p11.2 are associated with common variable immunodeficiency. J Allergy Clin Immunol, 135 (6), pp. 1569-1577. | Show Abstract | Read more

BACKGROUND: Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients. OBJECTIVE: We sought to seek novel associations of genes and genetic variants with CVID. METHODS: We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis. RESULTS: We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10(-9)), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10(-5)) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts. CONCLUSION: We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.

Lucas M, Lee M, Oksenhendler E, Chapel H. 2015. The ratio of mean daily IgG increment/mean daily dose in immunoglobulin replacement therapy in primary antibody deficiencies Journal of Allergy and Clinical Immunology: In Practice, 3 (6), pp. 998-1000.e2. | Read more

Anzilotti C, Kienzler AK, Lopez-Granados E, Gooding S, Davies B, Pandit H, Lucas M, Price A, Littlewood T, Van Der Burg M et al. 2015. Key stages of bone marrow B-cell maturation are defective in patients with common variable immunodeficiency disorders Journal of Allergy and Clinical Immunology, 136 (2), pp. 487-490. | Read more

Hodkinson JP, Lucas M, Lee M, Harrison M, Lunn MP, Chapel H. 2015. Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients Clinical and Experimental Immunology, 181 (1), pp. 179-187. | Show Abstract | Read more

© 2015 British Society for Immunology. There are currently no data to support the suggestion that the dose of therapeutic immunoglobulin (Ig) should be capped in obese patients for pharmacokinetic (PK), safety and economic reasons. We compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically equivalent lean patient across a range of indications, including primary antibody deficiency or autoimmune peripheral neuropathy. Comprehensive matching was carried out using ongoing research databases at two centres in which the dose of Ig was based on clinical outcome, whether infection prevention or documented clinical neurological stability. The IgG trough or steady state levels, IgG increments and Ig efficiencies at times of clinical stability were compared between the obese and lean cohorts and within the matched pairs. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight-adjusted dose compared with the lean patients. However at an individual patient level there were significant exceptions to this correlation, and upon sub-group analysis no significant difference was found between obese and lean patients receiving replacement therapy. Across all dose regimens a high body mass index (BMI) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate.

Dhalla F, Murray S, Sadler R, Chaigne-Delalande B, Sadaoka T, Soilleux E, Uzel G, Miller J, Collins GP, Hatton CSR et al. 2015. Identification of a Novel Mutation in MAGT1 and Progressive Multifocal Leucoencephalopathy in a 58-Year-Old Man with XMEN Disease Journal of Clinical Immunology, 35 (2), pp. 112-118. | Show Abstract | Read more

© 2014, Springer Science+Business Media New York. XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1] , and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1–3] . We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.

Li J, Jørgensen SF, Maggadottir SM, Bakay M, Warnatz K, Glessner J, Pandey R, Salzer U, Schmidt RE, Perez E et al. 2015. Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. Nat Commun, 6 pp. 6804. | Show Abstract | Read more

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

Anzilotti C, Kienzler A-K, Lopez-Granados E, Gooding S, Davies B, Pandit H, Lucas M, Price A, Littlewood T, van der Burg M et al. 2015. Key stages of bone marrow B-cell maturation are defective in patients with common variable immunodeficiency disorders. J Allergy Clin Immunol, 136 (2), pp. 487-90.e2. | Read more

Dhalla F, Murray S, Sadler R, Chaigne-Delalande B, Sadaoka T, Soilleux E, Uzel G, Miller J, Collins GP, Hatton CSR et al. 2015. Identification of a novel mutation in MAGT1 and progressive multifocal leucoencephalopathy in a 58-year-old man with XMEN disease. J Clin Immunol, 35 (2), pp. 112-118. | Show Abstract | Read more

XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.

Šedivá A, Chapel H, Gardulf A, European Immunoglobulin Map Group (35 European Countries) for European Society for Immunodeficiencies (ESID) Primary Immunodeficiencies Care in Development Working Party. 2014. Europe immunoglobulin map. Clin Exp Immunol, 178 Suppl 1 (S1), pp. 141-143. | Read more

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Aguilar C, Lenoir C, Lambert N, Bègue B, Brousse N, Canioni D, Berrebi D, Roy M, Gérart S, Chapel H et al. 2014. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers Journal of Allergy and Clinical Immunology, 134 (5), pp. 1131-1141.e9. | Show Abstract | Read more

© 2014 American Academy of Allergy, Asthma & Immunology. Background Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. Objective We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. Methods We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Results Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. Conclusion IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.

Lopez-Granados E, Stacey M, Kienzler A-K, Sierro S, Willberg CB, Fox CP, Rigaud S, Long HM, Hislop AD, Rickinson AB et al. 2014. A mutation in X-linked inhibitor of apoptosis (G466X) leads to memory inflation of Epstein-Barr virus-specific T cells. Clin Exp Immunol, 178 (3), pp. 470-482. | Show Abstract | Read more

Mutations in the X-linked inhibitor of apoptosis (XIAP) gene have been associated with XLP-like disease, including recurrent Epstein-Barr virus (EBV)-related haemophagocytic lymphohystiocytosis (HLH), but the immunopathogenic bases of EBV-related disease in XIAP deficiency is unknown. We present the first analysis of EBV-specific T cell responses in functional XIAP deficiency. In a family of patients with a novel mutation in XIAP (G466X) leading to a late-truncated protein and varying clinical features, we identified gradual hypogammaglobulinaemia and large expansions of T cell subsets, including a prominent CD4(+) CD8(+) population. Extensive ex-vivo analyses showed that the expanded T cell subsets were dominated by EBV-specific cells with conserved cytotoxic, proliferative and interferon (IFN)-γ secretion capacity. The EBV load in blood fluctuated and was occasionally very high, indicating that the XIAP(G466X) mutation could impact upon EBV latency. XIAP deficiency may unravel a new immunopathogenic mechanism in EBV-associated disease.

Peter JG, Chapel H. 2014. Immunoglobulin replacement therapy for primary immunodeficiencies. Immunotherapy, 6 (7), pp. 853-869. | Show Abstract | Read more

Exogenous antibody therapy to protect patients against infections and toxins is over 100 years old, yet progress continues to be made in the manufacture, administration and application of this type of immunotherapy, known as therapeutic human immunoglobulin. For the majority of patients with primary immunodeficiencies, immunoglobulin replacement is the only life-saving therapy and treatment is life-long, since the vast majority of primary immunodeficiency patients have primary antibody failure. Successful treatment depends on multiple factors: the availability of products, the type of immunodeficiency and any comorbidities of the individual patient. Essential components include long-term follow-up, regular monitoring and a close relationship between the patient and the multidisciplinary clinical immunology team. In this article, we describe the current immunoglobulin products and the types of adverse reactions. We provide evidence for clinical decision-making regarding dosing, route of administration and location of therapy, highlighting current 'best practice' recommendations.

Keller M, Glessner J, Resnick E, Perez E, Chapel H, Lucas M, Sullivan KE, Cunningham-Rundles C, Orange JS, Hakonarson H. 2014. Burden of copy number variation in common variable immunodeficiency Clinical and Experimental Immunology, 177 (1), pp. 269-271. | Show Abstract | Read more

Common variable immunodeficiency (CVID) has been associated recently with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to explore further the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy or other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease. © 2013 British Society for Immunology.

Keller M, Glessner J, Resnick E, Perez E, Chapel H, Lucas M, Sullivan KE, Cunningham-Rundles C, Orange JS, Hakonarson H. 2014. Burden of copy number variation in common variable immunodeficiency. Clin Exp Immunol, 177 (1), pp. 269-271. | Show Abstract | Read more

Common variable immunodeficiency (CVID) has been associated recently with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to explore further the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy or other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease.

Aguilar C, Lenoir C, Lambert N, Bègue B, Brousse N, Canioni D, Berrebi D, Roy M, Gérart S, Chapel H et al. 2014. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol, 134 (5), pp. 1131-41.e9. | Show Abstract | Read more

BACKGROUND: Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. OBJECTIVE: We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. METHODS: We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. RESULTS: Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. CONCLUSION: IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.

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Dhalla F, Lucas MM, Schuh AA, Bhole MM, Jain RR, Patel SY, Misbah S, Chapel H. 2014. Antibody deficiency secondary to chronic lymphocytic leukemia: Should patients be treated with prophylactic replacement immunoglobulin? Journal of Clinical Immunology, 34 (3), pp. 277-282. | Show Abstract | Read more

Hypogammaglobulinemia is a common finding in chronic lymphocytic leukemia (CLL). Its incidence increases with disease duration and stage such that it is present in up to 85 % of patients at some point in their disease course. It is therefore important to monitor patients for the development of an antibody deficiency. However, not all patients with antibody deficiency secondary to CLL are symptomatic with bacterial infections. In addition patients ar e susceptible to viral, fungal and opportunistic infections as a result of iatrogenic immunosuppression and through a variety of disease-related mechanisms, which affect cellular immunity and phagocytes. Published guidelines suggest that patients with a history of recurrent bacterial infections and a documented failure of antibody production should be treated with antibiotic prophylaxis in the first instance, with replacement immunoglobulin reserved for those who continue to suffer with significant bacterial infections. Here we present a review of the existing literature in order to provide a practical approach, based on best available evidence, to the investigation, monitoring and treatment of patients with antibody failure secondary to CLL; and we highlight areas in which further studies are needed. © 2014 Springer Science+Business Media New York.

Dhalla F, Lucas M, Schuh A, Bhole M, Jain R, Patel SY, Misbah S, Chapel H. 2014. Antibody deficiency secondary to chronic lymphocytic leukemia: Should patients be treated with prophylactic replacement immunoglobulin? J Clin Immunol, 34 (3), pp. 277-282. | Show Abstract | Read more

Hypogammaglobulinemia is a common finding in chronic lymphocytic leukemia (CLL). Its incidence increases with disease duration and stage such that it is present in up to 85 % of patients at some point in their disease course. It is therefore important to monitor patients for the development of an antibody deficiency. However, not all patients with antibody deficiency secondary to CLL are symptomatic with bacterial infections. In addition patients are susceptible to viral, fungal and opportunistic infections as a result of iatrogenic immunosuppression and through a variety of disease-related mechanisms, which affect cellular immunity and phagocytes. Published guidelines suggest that patients with a history of recurrent bacterial infections and a documented failure of antibody production should be treated with antibiotic prophylaxis in the first instance, with replacement immunoglobulin reserved for those who continue to suffer with significant bacterial infections. Here we present a review of the existing literature in order to provide a practical approach, based on best available evidence, to the investigation, monitoring and treatment of patients with antibody failure secondary to CLL; and we highlight areas in which further studies are needed.

Chapel H, Prevot J, Gaspar HB, Español T, Bonilla FA, Solis L, Drabwell J, Editorial Board for Working Party on Principles of Care at IPOPI. 2014. Primary immune deficiencies - principles of care. Front Immunol, 5 (DEC), pp. 627. | Show Abstract | Read more

Primary immune deficiencies (PIDs) are a growing group of over 230 different disorders caused by ineffective, absent or an increasing number of gain of function mutations in immune components, mainly cells and proteins. Once recognized, these rare disorders are treatable and in some cases curable. Otherwise untreated PIDs are often chronic, serious, or even fatal. The diagnosis of PIDs can be difficult due to lack of awareness or facilities for diagnosis, and management of PIDs is complex. This document was prepared by a worldwide multi-disciplinary team of specialists; it aims to set out comprehensive principles of care for PIDs. These include the role of specialized centers, the importance of registries, the need for multinational research, the role of patient organizations, management and treatment options, the requirement for sustained access to all treatments including immunoglobulin therapies and hematopoietic stem cell transplantation, important considerations for developing countries and suggestions for implementation. A range of healthcare policies and services have to be put into place by government agencies and healthcare providers, to ensure that PID patients worldwide have access to appropriate and sustainable medical and support services.

Kerr J, Quinti I, Eibl M, Chapel H, Späth PJ, Sewell WAC, Salama A, van Schaik IN, Kuijpers TW, Peter H-H. 2014. Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe. Front Immunol, 5 (DEC), pp. 629. | Show Abstract | Read more

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic "per kg" dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki' disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases.

Chapel H, Gardulf A. 2013. Subcutaneous immunoglobulin replacement therapy: the European experience. Curr Opin Allergy Clin Immunol, 13 (6), pp. 623-629. | Show Abstract | Read more

PURPOSE OF REVIEW: Rapid subcutaneous immunoglobulin (SCIg) infusions have been used as an important method of delivering replacement immunoglobulin (Ig) to patients with primary immune deficiencies (PIDs) in Europe over the last 25 years. This review provides a comprehensive interpretation of the literature relating to the administration of SCIg and the services that have been developed alongside. RECENT FINDINGS: Using rates of at least 20 ml/h per infusion site and simultaneous sites, the infusion time once per week is short (1-2 h in adults) and using small portable pumps, the child or adult is free for other activities during the therapy. The rapid SCIg infusions have been documented as well tolerated, efficacious and acceptable to infants and their parents, children, adults and elderly patients, and more recently to patients with autoimmunity requiring immunomodulatory Ig doses. SUMMARY: As part of PID diagnostic and management services, educational programmes for self-infusion of both intravenous Ig and SCIg at home have been developed throughout Europe, resulting in increased patient compliance and patient empowerment as well as cost-savings for healthcare providers.

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Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, Etzioni A, Fischer A, Franco JL, Geha RS et al. 2013. A phenotypic approach for IUIS PID classification and diagnosis: Guidelines for clinicians at the bedside Journal of Clinical Immunology, 33 (6), pp. 1078-1087. | Show Abstract | Read more

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since. © 2013 Springer Science+Business Media New York.

Wong GK, Goldacker S, Winterhalter C, Grimbacher B, Chapel H, Lucas M, Alecsandru D, McEwen D, Quinti I, Martini H et al. 2013. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients (vol 172, pg 63, 2013) CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 173 (1), pp. 161-161. | Read more

Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, Etzioni A, Fischer A, Franco JL, Geha RS et al. 2013. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol, 33 (6), pp. 1078-1087. | Show Abstract | Read more

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.

Gouilleux-Gruart V, Chapel H, Chevret S, Lucas M, Malphettes M, Fieschi C, Patel S, Boutboul D, Marson M-N, Gérard L et al. 2013. Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor. Clin Exp Immunol, 171 (2), pp. 186-194. | Show Abstract | Read more

Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An 'efficiency' index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig.

Wong GK, Goldacker S, Winterhalter C, Grimbacher B, Chapel H, Lucas M, Alecsandru D, McEwen D, Quinti I, Martini H et al. 2013. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients. Clin Exp Immunol, 172 (1), pp. 63-72. | Show Abstract | Read more

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

Bateman EAL, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, Packwood K, Burden J, Harrison D, Kaenzig N et al. 2012. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol, 170 (2), pp. 202-211. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X-linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four-colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen-driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency.

Chapel H, Lucas M, Patel S, Lee M, Cunningham-Rundles C, Resnick E, Gerard L, Oksenhendler E. 2012. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts. J Allergy Clin Immunol, 130 (5), pp. 1197-1198.e9. | Read more

Hernandez-Trujillo HS, Chapel H, Lo Re V, Notarangelo LD, Gathmann B, Grimbacher B, Boyle JM, Hernandez-Trujillo VP, Scalchunes C, Boyle ML, Orange JS. 2012. Comparison of American and European practices in the management of patients with primary immunodeficiencies. Clin Exp Immunol, 169 (1), pp. 57-69. | Show Abstract | Read more

Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of rare disorders. This study was devised in order to compare management of these diseases in the northern hemisphere, given the variability of practice among clinicians in North America. The members of two international societies for clinical immunologists were asked about their management protocols in relation to their PID practice. An anonymous internet questionnaire, used previously for a survey of the American Academy of Allergy, Asthma and Immunology (AAAAI), was offered to all full members of the European Society for Immunodeficiency (ESID). The replies were analysed in three groups, according to the proportion of PID patients in the practice of each respondent; this resulted in two groups from North America and one from Europe. The 123 responses from ESID members (23·7%) were, in the majority, very similar to those of AAAAI respondents, with > 10% of their practice devoted to primary immunodeficiency. There were major differences between the responses of these two groups and those of the general AAAAI respondents whose clinical practice was composed of < 10% of PID patients. These differences included the routine use of intravenous immunoglobulin therapy (IVIg) for particular types of PIDs, initial levels of IVIg doses, dosing intervals, routine use of prophylactic antibiotics, perceptions of the usefulness of subcutaneous immunoglobulin therapy (SCIg) and of the risk to patients' health of policies adopted by health-care funders. Differences in practice were identified and are discussed in terms of methods of health-care provision, which suggest future studies for ensuring continuation of appropriate levels of immunoglobulin replacement therapies.

Rahman M, Chapel H, Chapman RW, Collier JD. 2012. Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: case report and review of the literature. Int Arch Allergy Immunol, 159 (2), pp. 204-208. | Show Abstract | Read more

A 43-year-old man with a hyper-immunoglobulin M syndrome due to CD40 ligand deficiency presented with insidious onset of recurrent diarrhoea and deranged liver function tests. Standard stool microscopy was repeatedly negative for cryptosporidia but immunofluorescent testing and polymerase chain reaction demonstrated the presence of infection eventually. Despite both paromomycin and nitazoxanide, he developed sclerosing cholangitis secondary to cryptosporidial infection. Whilst being considered for dual bone marrow and liver transplantation, he was found to have cholangiocarcinoma on imaging after three biopsies of a suspicious lesion. This is a rare complication of this combined immune deficiency predominantly in children that has not been reported previously in a long-term survivor with this condition.

Chapel H. 2012. Classification of primary immunodeficiency diseases by the International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency 2011. Clin Exp Immunol, 168 (1), pp. 58-59. | Read more

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Chapel H, Lucas M, Patel S, Lee M, Cunningham-Rundles C, Resnick E, Gerard L, Oksenhendler E. 2012. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts Journal of Allergy and Clinical Immunology, 130 (5), | Read more

da Silva SP, Resnick E, Lucas M, Lortan J, Patel S, Cunningham-Rundles C, Gatter K, Liu Q, Jaffe ES, Chapel H. 2011. Lymphoid proliferations of indeterminate malignant potential arising in adults with common variable immunodeficiency disorders: unusual case studies and immunohistological review in the light of possible causative events. J Clin Immunol, 31 (5), pp. 784-791. | Show Abstract | Read more

Patients with common variable immunodeficiency disorders (CVIDs) who developed B cell lymphoproliferation of indeterminate malignant potential are described in order to raise a discussion of the relationship between infection and lymphoproliferation in infection prone patients. Those with CVID are at risk of developing either polyclonal or monoclonal lymphoproliferation in part due to the dysregulation of their adaptive immune systems. The aetiologies of the lymphoproliferations are unknown but intriguing; the relevance of infection being particularly problematic. The patients described here demonstrate variability in preceding infection, age at presentation, response to antibiotics and other types of therapy as well as outcome. The question of treatment is also controversial; issues include whether antibiotics or chemotherapy are the first line of therapy in all patients and whether transformation to aggressive B cell malignancy is inevitable or depends on other factors and if so, the length of time for such progression.

Rigaud S, Lopez-Granados E, Sibéril S, Gloire G, Lambert N, Lenoir C, Synaeve C, Stacey M, Fugger L, Stephan J-L et al. 2011. Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG. Blood, 118 (2), pp. 252-261. | Show Abstract | Read more

The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.

Dhalla F, da Silva SP, Lucas M, Travis S, Chapel H. 2011. Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme. Clin Exp Immunol, 165 (1), pp. 1-7. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy.

Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, Kanegane H, Lopez-Granados E, Mejstrikova E, Pellier I et al. 2011. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood, 117 (5), pp. 1522-1529. | Show Abstract | Read more

X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.

Eley KA, Golding SJ, Chapel H, Watt-Smith SR. 2011. Polycystic parotid disease in a male child: report of a case and review of the literature. J Oral Maxillofac Surg, 69 (5), pp. 1375-1379. | Read more

Aslam A, Chapel H, Ogg G. 2011. Direct ex-vivo evaluation of pneumococcal specific T-cells in healthy adults. PLoS One, 6 (10), pp. e25367. | Show Abstract | Read more

Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. The nasopharynxes of children are believed to be the natural reservoir of pneumococcus and by adulthood nasopharyngeal carriage is infrequent; such infrequency may be due to demonstrable pneumococcal specific T and B-cell responses. HLA Class 2 tetrameric complexes have been used to characterise antigen specific T-cell responses in a variety of models of infection. We therefore sought to determine the frequency and phenotype of pneumococcal specific T-cells, using a novel HLA-DRB1*1501 tetramer complex incorporating a recently defined T-cell epitope derived from the conserved pneumococcal serine/threonine kinase (StkP). We were able to detect direct ex-vivo StkP(446-60)-tetramer binding in HLA-DRB1*1501 adults. These StkP(446-60)-tetramer binding T-cells had increased CD38 expression and were enriched in CCR7- CD45RA+ expression indicating recent and on-going activation and differentiation. Furthermore, these StkP(446-60)-tetramer binding T-cells demonstrated rapid effector function by secreting interferon-gamma on stimulation with recombinant StkP. This is the first study to directly enumerate and characterise pneumococcal specific T-cells using HLA class 2 tetrameric complexes. We found that ex-vivo pneumococcal-specific T cells were detectable in healthy adults and that they were enriched with cell surface markers associated with recent antigen exposure and later stages of antigen-driven differentiation. It is likely that these activated pneumococcal specific T-cells reflect recent immunostimulatory pneumococcal exposure in the nasopharynx and it is possible that they may be preventing subsequent colonisation and disease.

da Silva SP, Resnick E, Lucas M, Lortan J, Patel S, Cunningham-Rundles C, Gatter K, Liu Q, Jaffe ES, Chapel H. 2011. Lymphoid Proliferations of Indeterminate Malignant Potential arising in Adults with Common Variable Immunodeficiency Disorders: Unusual Case Studies and Immunohistological Review in the Light of Possible Causative Events Journal of Clinical Immunology, pp. 1-8.

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Dhalla F, da Silva SP, Lucas M, Travis S, Chapel H. 2011. Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme Clinical and Experimental Immunology, 165 (1), pp. 1-7. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy. © 2011 The Authors; Clinical and Experimental Immunology © 2011 British Society for Immunology.

Eley KA, Golding SJ, Chapel H, Watt-Smith SR. 2011. Polycystic Parotid disease in a male child: Report of a case and review of the literature Journal of Oral and Maxillofacial Surgery, 69 (5), pp. 1375-1379. | Read more

Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, Heath PT, Steward CG, Smith O, O'Meara A et al. 2011. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood, 117 (1), pp. 53-62. | Show Abstract | Read more

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Al-Herz W, Bousfiha A, Casanova J-L, Chapel H, Conley ME, Cunningham-Rundles C, Etzioni A, Fischer A, Franco JL, Geha RS et al. 2011. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol, 2 (NOV), pp. 54. | Show Abstract | Read more

We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases.

Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, Kim CE, Hou C, Wang F, Chiavacci R et al. 2011. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol, 127 (6), pp. 1360-7.e6. | Show Abstract | Read more

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities. OBJECTIVE: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. METHODS: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. RESULTS: Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10(-7)) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10(-16)), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. CONCLUSION: Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model.

Cited:

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Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, Kim CE, Hou C, Wang F, Chiavacci R et al. 2011. Genome-wide association identifies diverse causes of common variable immunodeficiency Journal of Allergy and Clinical Immunology, 127 (6), | Show Abstract | Read more

Background: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities. Objective: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. Methods: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. Results: Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10 -7 ) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10 -16 ), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. Conclusion: Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model. © 2011 American Academy of Allergy, Asthma & Immunology.

Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonald D, Geha RS, Takada H, Krause JC et al. 2010. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore), 89 (6), pp. 403-425. | Show Abstract | Read more

Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.

Aslam A, Mason A, Zemenides S, Chan H, Nováková L, Branny P, Finn A, Chapel H, Ogg GS. 2010. Rapid effector function of circulating CD4+ T cells specific for immunodominant regions of the conserved serine/threonine kinase found in Streptococcus pneumoniae (StkP) in healthy adults. FEMS Immunol Med Microbiol, 60 (2), pp. 113-122. | Show Abstract | Read more

Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. There is emerging evidence that T cells contribute to the immunity that protects humans from S. pneumoniae-associated disease. However, no T-cell epitopes have been identified as yet in this bacterium and there are no data that address the functional nature of T cells specific for pneumococcal-derived epitopes. We sought to define T-cell epitopes in the conserved serine/threonine kinase, found in S. pneumoniae (StkP) and to investigate specific interferon γ (IFN-γ) production resulting from such T-cell activation in healthy donors. We were able to detect the activation of T cells in response to pneumococcal whole-cell antigen or StkP-derived peptides in all 15 individuals. We found that the majority of the T-cell responses were directed against the extracellular, penicillin-binding protein and serine/threonine kinase-associated domains. We proceeded to characterize the immunodominant epitope in detail and observed HLA-DRB1(*) 1501 restriction. This is the first study that has identified T-cell responses to peptides derived from a protein from S. pneumoniae and has shown that in healthy adults, specific T cells have rapid IFN-γ production compatible with effector cell differentiation. The use of such T-cell epitopes will aid in the future monitoring of T-cell responses to both S. pneumoniae infection and vaccination in humans.

Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. 2010. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol, 125 (6), pp. 1354-1360.e4. | Show Abstract | Read more

BACKGROUND: Common variable immunodeficiency disorders (CVIDs) are the most common forms of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment, although there are few consistent data on optimal dosages and target trough IgG levels required for infection prevention. OBJECTIVE: To provide data to support the hypothesis that each patient requires an individual dose of therapeutic immunoglobulin to prevent breakthrough infections and that efficacious trough IgG levels vary between patients. METHODS: Data, collected prospectively from a cohort of 90 patients with confirmed CVIDs from 1 center over a follow-up period of 22 years, was validated and analyzed. Immunoglobulin doses had been adjusted in accordance with infections rather than to achieve a particular trough IgG level. Doses to achieve infection-free periods were determined and resultant trough levels analyzed. A smaller group of patients with X-linked agammaglobulinemia was analyzed for comparison. RESULTS: Patients with a CVID had a range of trough IgG levels that prevented breakthrough bacterial infections (5-17 g/L); viral and fungal infections were rare. Doses of replacement immunoglobulin to prevent breakthrough infections ranged from 0.2 to 1.2 g/kg/mo. Those with proven bronchiectasis or particular clinical phenotypes required higher replacement doses. Patients with X-linked agammaglobulinemia showed a similar range of IgG levels to stay infection-free (8-13 g/L). CONCLUSION: These data offer guidance regarding optimal doses and target trough IgG levels in individual patients with CVIDs with or without bronchiectasis and for particular clinical phenotypes. The goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level.

Lucas M, Hugh-Jones K, Welby A, Misbah S, Spaeth P, Chapel H. 2010. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol, 30 Suppl 1 (S1), pp. S84-S89. | Show Abstract | Read more

INTRODUCTION: The Oxford Programme for Immunomodulatory Immunoglobulin Therapy has been operating since 1992 at Oxford Radcliffe Hospitals in the UK. Initially, this program was set up for patients with multifocal motor neuropathy or chronic inflammatory demyelinating poly-neuropathy to receive reduced doses of intravenous immunoglobulin (IVIG) in clinic on a regular basis (usually every 3 weeks). The program then rapidly expanded to include self-infusion at home, which monitoring showed to be safe and effective. It has been since extended to the treatment of other autoimmune diseases in which IVIG has been shown to be efficacious. METHODS: This review includes details of the program such as the training of patients, dosing with immunoglobulin, and monitoring and compliance for self-infusion at home, with cases to illustrate these points. RESULTS: In addition, the Evidence for efficacy and the effects of confounding morbidities will be are included described. More recently, subcutaneous immunoglobulin therapy (SCIG) has been used in several chronic autoimmune peripheral neuropathies and in epidermolysis bullosa acquisita, with equally good effect. Trials of SCIG in other autoimmune diseases are planned.

Deniz G, Chapel H, Barlan I, de Vries E, Jaraquemada D. 2010. Women advancing science. Eur J Immunol, 40 (3), pp. 589-592. | Read more

van Bruggen R, Drewniak A, Tool ATJ, Jansen M, van Houdt M, Geissler J, van den Berg TK, Chapel H, Kuijpers TW. 2010. Toll-like receptor responses in IRAK-4-deficient neutrophils. J Innate Immun, 2 (3), pp. 280-287. | Show Abstract | Read more

Human neutrophils were found to express all known Toll-like receptors (TLRs) except TLR3 and TLR7. IRAK-4-deficient neutrophils were tested for their responsiveness to various TLR ligands. Essentially all TLR responses in neutrophils, including the induction of reactive oxygen species generation, adhesion, chemotaxis and IL-8 secretion, were found to be dependent on IRAK-4. Surprisingly, the reactivity towards certain established TLR ligands, imiquimod and ODN-CpG, was unaffected by IRAK-4 deficiency, demonstrating their activity is independent of TLR. TLR-4-dependent signaling in neutrophils was totally dependent on IRAK-4 without any major TRIF-mediated contribution. We did not observe any defects in killing capacity of IRAK-4-deficient neutrophils for Staphylococcus aureus, Escherichia coli and Candida albicans, suggesting that microbial killing is primarily TLR independent.

Packwood K, Drewe E, Staples E, Webster D, Witte T, Litzman J, Egner W, Sargur R, Sewell W, Lopez-Granados E et al. 2010. NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders. Clin Exp Immunol, 161 (3), pp. 536-541. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.

International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies, Notarangelo LD, Fischer A, Geha RS, Casanova J-L, Chapel H, Conley ME, Cunningham-Rundles C, Etzioni A, Hammartröm L et al. 2009. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol, 124 (6), pp. 1161-1178. | Show Abstract | Read more

More than 50 years after Ogdeon Bruton's discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern development and function of the human immune system. This report provides the updated classification of PIDs that has been compiled by the International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies after its biannual meeting in Dublin, Ireland, in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in human beings have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs.

van Bruggen R, Drewniak A, Jansen M, van Houdt M, Roos D, Chapel H, Verhoeven AJ, Kuijpers TW. 2009. Complement receptor 3, not Dectin-1, is the major receptor on human neutrophils for beta-glucan-bearing particles. Mol Immunol, 47 (2-3), pp. 575-581. | Show Abstract | Read more

We investigated the role of the beta-glucan receptor, Dectin-1, in the response of human neutrophils to unopsonized Saccharomyces cerevisiae and its major beta-glucan-containing capsular constituent, zymosan. Although reported to be indispensable for yeast phagocytosis in murine phagocytes, human Dectin-1 was not involved in the phagocytosis of S. cerevisiae or zymosan by human neutrophils. Phagocytosis of yeast particles proved to be completely dependent on CD11b/CD18, also known as complement receptor 3 (CR3). The findings were supported by data with neutrophils from a patient suffering from Leukocyte-Adhesion Deficiency type-1 (LAD-1) syndrome lacking CD11b/CD18. In addition, neither the priming by zymosan of the fMLP-induced NADPH-oxidase activity in human neutrophils nor the secretion of IL-8 by human neutrophils in response to zymosan preparations was affected by blocking anti-Dectin-1 antibodies or laminarin as a monovalent inhibitor. As shown by neutrophils from an IRAK-4-deficient patient, the zymosan-induced IL-8 release was also independent of TLR2. In summary, our data show that Dectin-1, although indispensable for recognition of beta-glucan-bearing particles in mice, is not the major receptor for yeast particles in human neutrophils.

Aslam A, Chapel H. 2009. Dissecting the group of common variable immunodeficiency disorders. Clin Infect Dis, 49 (9), pp. 1339-1340. | Read more

Arnold DF, Roberts AG, Thomas A, Ferry B, Morgan BP, Chapel H. 2009. A novel mutation in a patient with a deficiency of the eighth component of complement associated with recurrent meningococcal meningitis. J Clin Immunol, 29 (5), pp. 691-695. | Show Abstract | Read more

INTRODUCTION: Complement component C8 is one of the five terminal complement components required for the formation of the membrane attack complex. Complete absence of C8 results in increased susceptibility to gram-negative bacteria such as Neisseria species. MATERIALS AND METHODS: Two functionally distinct C8 deficiency states have been described: C8 alpha-gamma deficiency has been predominantly reported amongst Afro-Caribbeans, Hispanics, and Japanese and C8beta mainly in Caucasians. RESULTS: We report a case of functional and immunochemical deficiency of the complement component C8, diagnosed in a Caucasian adult following three episodes of meningitis. Western blotting and hemolytic assay demonstrated absence of C8beta. In genetic studies, the common exon 9 C > T transition responsible for 85% of C8beta deficiencies was not found. Two mutations were identified: a novel duplication mutation, c.1047_1053 dupGGCTGTG in exon 7 that introduces a frame shift, resulting in the addition of seven novel amino acid residues and a premature stop codon, and a previously reported mutation, c.271C > T in exon 3. The parents each expressed one of these mutations, confirming compound heterozygosity. DISCUSSION: This is the first report of a duplication mutation in C8beta deficiency and extends the molecular heterogeneity of the disorder.

Chapel H, Cunningham-Rundles C. 2009. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol, 145 (6), pp. 709-727. | Show Abstract | Read more

The common variable immunodeficiency disorders are a mixed group of heterogeneous conditions linked by lack of immunoglobulin production and primary antibody failure. This variability results in difficulty in making coherent sense of either immunopathogenesis or the role of various genetic abnormalities reported in the literature. The recent attempt to collate the varied complications in these conditions and to define particular clinical phenotypes has improved our understanding of these diseases. Once refined and confirmed by other studies, these definitions will facilitate improved accuracy of prognosis and better management of clinical complication. They may also provide a method of analysing outcomes as related to new immunopathological and genetic findings.

Salzer U, Bacchelli C, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V, Bergbreiter A, Hagena T, Birmelin J, Plebani A et al. 2009. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood, 113 (9), pp. 1967-1976. | Show Abstract | Read more

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

da Silva SP, Ferreira MB, Chapel H. 2009. Spectrum of lymphoproliferation in common variable immunodeficiency disorders - review of the literature Revista Portuguesa de Imunoalergologia, 17 (5), pp. 403-417. | Show Abstract

Common variable immunodeficiency disorders (CVIDs) represent a group of primary immunodeficiency disorders, characterized by a deficit of antibody production although other aspects of the immune system are frequently altered too. These disorders usually present with recurrent and/or severe infections, affecting mainly the respiratory and gastrointestinal tracts. A considerable proportion of these patients also present non infective complications, including autoimmunity and different manifestations of chronic lymphoid proliferation. Such lymphoid proliferation may affect different organs simultaneously, including spleen, lymph nodes, lung and gut. CVIDs are associated with a higher risk of lymphoma and the pathophysiology is poorly understood. The current therapeutic strategies and management of CVID patients result in longer survival, mainly due to the decrease of infectious complications and has increased awareness of non -infective complications. In this paper, the authors review the literature, in regard to the different presentations of lymphoproliferation, from benign to malignant, and discuss the possible mechanisms underlying this form of disease expression found in subgroups of patients with CVIDs.

Tayal U, Burton J, Dash C, Wojnarowska F, Chapel H. 2008. Subcutaneous immunoglobulin therapy for immunomodulation in a patient with severe epidermolysis bullosa acquisita. Clin Immunol, 129 (3), pp. 518-519. | Read more

Ward C, Lucas M, Piris J, Collier J, Chapel H. 2008. Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia. Clin Exp Immunol, 153 (3), pp. 331-337. | Show Abstract | Read more

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku C-L, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y et al. 2008. Pyogenic bacterial infections in humans with MyD88 deficiency. Science, 321 (5889), pp. 691-696. | Show Abstract | Read more

MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L. 2008. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood, 112 (2), pp. 277-286. | Show Abstract | Read more

The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.

de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, von Bernuth H, Samarina A, Jannière L et al. 2008. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med, 205 (7), pp. 1543-1550. | Show Abstract | Read more

The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.

Arnold DF, Wiggins J, Cunningham-Rundles C, Misbah SA, Chapel HM. 2008. Granulomatous disease: distinguishing primary antibody disease from sarcoidosis. Clin Immunol, 128 (1), pp. 18-22. | Read more

Staples E, Packwood K, Drewe E, Ferry B, Seneviratne S, Chapel H. 2008. Investigation of NOD2 polymorphisms in Common Variable Immunodeficiency (CVID) and its granulomatous and enteropathic manifestations CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 26 (2), pp. 186-186.

Provan D, Chapel HM, Sewell WAC, O'Shaughnessy D. 2008. Prescribing intravenous immunoglobulin: summary of Department of Health guidelines BMJ, 337 (oct20 2), pp. a1831-a1831. | Read more

Bhole MV, Burton J, Chapel HM. 2008. Self-infusion programmes for immunoglobulin replacement at home: feasibility, safety and efficacy. Immunol Allergy Clin North Am, 28 (4), pp. 821-ix. | Show Abstract | Read more

This review of the currently available literature from more than two decades of clinical experience with self-infusions of immunoglobulin at home provides evidence to support the feasibility, safety, and efficacy in all age groups. Self-infusions at home not only increase patient confidence and their understanding of the immune deficiency but also contribute to the improvement of health-related quality of life. Such home therapy programs should be encouraged, and wherever possible, experienced centers should extend their services to include patients who require immunoglobulin therapy for immunomodulation. Home therapy programs play an important role in long-term health outcome.

Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, Vlkova M, Hernandez M, Detkova D, Bos PR et al. 2008. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood, 111 (1), pp. 77-85. | Show Abstract | Read more

The heterogeneity of common variable immunodeficiency (CVID) calls for a classification addressing pathogenic mechanisms as well as clinical relevance. This European multicenter trial was initiated to develop a consensus of 2 existing classification schemes based on flowcytometric B-cell phenotyping and the clinical course. The clinical evaluation of 303 patients with the established diagnosis of CVID demonstrated a significant coincidence of granulomatous disease, autoimmune cytopenia, and splenomegaly. Phenotyping of B-cell subpopulations confirmed a severe reduction of switched memory B cells in most of the patients that was associated with a higher risk for splenomegaly and granulomatous disease. An expansion of CD21(low) B cells marked patients with splenomegaly. Lymphadenopathy was significantly linked with transitional B-cell expansion. Based on these findings and pathogenic consideration of B-cell differentiation, we suggest an improved classification for CVID (EUROclass), separating patients with nearly absent B cells (less than 1%), severely reduced switched memory B cells (less than 2%), and expansion of transitional (more than 9%) or CD21(low) B cells (more than 10%). Whereas the first group contains all patients with severe defects of early B-cell differentiation, severely reduced switched memory B cells indicate a defective germinal center development as found in inducible constimulator (ICOS) or CD40L deficiency. The underlying defects of expanded transitional or CD21(low) B cells remain to be elucidated. This trial is re-gistered at http://www.uniklinik-freiburg.de/zks/live/uklregister/Oeffentlich.html as UKF000308.

Geha RS, Notarangelo LD, Casanova J-L, Chapel H, Conley ME, Fischer A, Hammarström L, Nonoyama S, Ochs HD, Puck JM et al. 2007. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol, 120 (4), pp. 776-794. | Show Abstract | Read more

Primary immunodeficiency diseases (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. More than 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic,immunologic, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international committee of experts has met every 2 years since 1970. In its last meeting in Jackson Hole, Wyo, after 3 days of intense scientific presentations and discussions, the committee has updated the classification of PID, as reported in this article.

Ku C-L, von Bernuth H, Picard C, Zhang S-Y, Chang H-H, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J et al. 2007. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med, 204 (10), pp. 2407-2422. | Show Abstract | Read more

Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4-dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4-dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.

Wood P, Stanworth S, Burton J, Jones A, Peckham DG, Green T, Hyde C, Chapel H, UK Primary Immunodeficiency Network. 2007. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol, 149 (3), pp. 410-423. | Show Abstract | Read more

The primary purpose of this systematic review was to produce an evidence-based review of the literature as a means of informing current clinical practice in the recognition, diagnosis and management of patients with suspected primary antibody deficiency. Randomized controlled trials (RCTs) were identified from a search of MEDLINE, EMBASE, The Cochrane Library, DARE (CRD website) and CINAHL by combining the search strategies with The Cochrane Collaboration's validated RCT filter. In addition, other types of studies were identified in a separate search of MEDLINE and EMBASE. Patients at any age with recurrent infections, especially in the upper and lower respiratory tracts, should be investigated for possible antibody deficiency. Replacement therapy with immunoglobulin in primary antibody deficiencies increases life expectancy and reduces infection frequency and severity. Higher doses of immunoglobulin are associated with reduced infection frequency. Late diagnosis and delayed institution of immunoglobulin replacement therapy results in increased morbidity and mortality. A wide variety of organ-specific complications can occur in primary antibody deficiency syndromes, including respiratory, gastroenterological, hepatic, haematological, neurological, rheumatological and cutaneous. There is an increased risk of malignancy. Some of these complications appear to be related to diagnostic delay and inadequate therapy. High-quality controlled trial data on the therapy of these complications is generally lacking. The present study has identified a number of key areas for further research, but RCT data, while desirable, is not always obtained easily for rare conditions. Few data from registries or large case-series have been published in the past 5 years and a greater focus on international collaboration and pooling of data is needed.

Tchilian EZ, Gil J, Navarro ML, Fernandez-Cruz E, Chapel H, Misbah S, Ferry B, Renz H, Schwinzer R, Beverley PCL. 2006. Unusual case presentations associated with the CD45 C77G polymorphism CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 146 (3), pp. 448-454. | Show Abstract | Read more

CD45, the leucocyte common antigen, is a haematopoietic cell specific tyrosine phosphatase. Human polymorphic CD45 variants are associated with autoimmune and infectious diseases and alter the phenotype and function of lymphocytes, establishing CD45 as an important regulator of immune function. Here we report four patients with diverse diseases with unusual clinical features. All four have the C77G polymorphism of CD45 exon 4, which alters the splicing and CD45RA/CD45R0 phenotype of lymphocytes. We suggest that C77G may be a contributing factor in these unusual cases. © 2006 British Society for Immunology.

von Bernuth H, Ku C-L, Rodriguez-Gallego C, Zhang S, Garty B-Z, Maródi L, Chapel H, Chrabieh M, Miller RL, Picard C et al. 2006. A fast procedure for the detection of defects in Toll-like receptor signaling. Pediatrics, 118 (6), pp. 2498-2503. | Show Abstract | Read more

OBJECTIVES: Inborn defects in Toll-like receptor signaling are recently described primary immunodeficiencies that predispose affected children to life-threatening infections. Patients with interleukin-1 receptor-associated kinase-4 deficiency are prone to invasive pneumococcal disease, and patients with UNC-93B deficiency are prone to herpes simplex virus encephalitis. These genetic disorders are underdiagnosed, partly because diagnosis currently requires expensive and time-consuming techniques available at only a few specialized centers worldwide. We, therefore, aimed to develop a cheap and fast test for the detection of defects in Toll-like receptor signaling. PATIENTS AND METHODS: We used flow cytometry to evaluate the cleavage of membrane-bound L-selectin on granulocytes in 38 healthy controls and in 7 patients with genetically defined Toll-like receptor signaling defects (5 patients with interleukin-1 receptor-associated kinase-4 deficiency and 2 patients with UNC-93B deficiency), on activation with various Toll-like receptor agonists. RESULTS: Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8. All of the healthy controls responded to these stimuli. CONCLUSIONS: The assessment of membrane-bound L-selectin cleavage on granulocytes by flow cytometry may prove useful for the detection of primary immunodeficiencies in the Toll-like receptor pathway, such as interleukin-1 receptor-associated kinase-4 deficiency and UNC-93B deficiency. This procedure is cheap and rapid. It may, therefore, be suitable for routine testing worldwide in children with invasive pneumococcal disease and in patients with herpes simplex encephalitis.

Semmo N, Lucas M, Krashias G, Lauer G, Chapel H, Klenerman P. 2006. Maintenance of HCV-specific T-cell responses in antibody-deficient patients a decade after early therapy. Blood, 107 (11), pp. 4570-4571. | Read more

Notarangelo L, Casanova J-L, Conley ME, Chapel H, Fischer A, Puck J, Roifman C, Seger R, Geha RS, International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. 2006. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol, 117 (4), pp. 883-896. | Show Abstract | Read more

Although relatively rare, primary immunodeficiency diseases (PIDs) provide an excellent window into the functioning of the immune system. In the late 1960s, observations on these diseases, with their associated infections and genetics, bisected the immune system into humoral immunity and cell-mediated immunity. These diseases also represent a challenge in their diagnosis and treatment. Beginning in 1970, a unified nomenclature for the then-known PIDs was created by a committee convoked by the World Health Organization. Since then, and later under the aegis of the International Union of Immunological Societies, an international committee of experts has met every 2 to 3 years to update the classification of PIDs. During the past 15 years, the molecular basis of more than 120 PIDs has been elucidated. This update results from the latest meeting of this committee in Budapest, Hungary, in June 2005, which followed 2 1/2 days of scientific discussions. As a result of this work, new entities have been included, and the nomenclature of some PIDs (specifically of the various forms of class-switch recombination defects, previously known as hyper-IgM syndromes) has been changed.

Yang K, Puel A, Zhang S, Eidenschenk C, Ku C-L, Casrouge A, Picard C, von Bernuth H, Senechal B, Plancoulaine S et al. 2005. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity, 23 (5), pp. 465-478. | Show Abstract | Read more

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.

Conacher M, Callard R, McAulay K, Chapel H, Webster D, Kumararatne D, Chandra A, Spickett G, Hopwood PA, Crawford DH. 2005. Epstein-Barr virus can establish infection in the absence of a classical memory B-cell population. J Virol, 79 (17), pp. 11128-11134. | Show Abstract | Read more

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that persists in the body for life after primary infection. The primary site of EBV persistence is the memory B lymphocyte, but whether the virus initially infects naïve or memory B cells is still disputed. We have analyzed EBV infection in nine cases of X-linked hyper-immunoglobulin M (hyper-IgM) syndrome who, due to a mutation in CD40 ligand gene, do not have a classical, class-switched memory B-cell population (IgD(-) CD27(+)). We found evidence of EBV infection in 67% of cases, which is similar to the infection rate found in the general United Kingdom population (60 to 70% for the relevant age range). We detected EBV DNA in peripheral blood B cells and showed in one case that the infection was restricted to the small population of nonclassical, germinal center-independent memory B cells (IgD(+) CD27(+)). Detection of EBV small RNAs, latent membrane protein 2, and EBV nuclear antigen 3C expression in peripheral blood suggests full latent viral gene expression in this population. Analysis of EBV DNA in serial samples showed variability over time, suggesting cycles of infection and loss. Our results demonstrate that short-term EBV persistence can occur in the absence of a germinal center reaction and a classical memory B-cell population.

Chapel H, Puel A, von Bernuth H, Picard C, Casanova J-L. 2005. Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency. Clin Infect Dis, 40 (9), pp. 1227-1231. | Show Abstract | Read more

BACKGROUND: Inherited interleukin-1-receptor-associated kinase-4 (IRAK-4) deficiency is a recently described immunodeficiency associated with pyogenic bacterial infections and a poor inflammatory response. Shigella sonnei is generally associated with outbreaks of rectocolitis in developed countries, but systemic illnesses have occasionally been reported. An underlying primary immunodeficiency has not been found in such cases before now. METHODS: We report the clinical and immunological features of a patient with IRAK-4 deficiency who has a history of systemic shigellosis in addition to other infections. RESULTS: The patient has a history of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa infections during childhood and an episode of S. sonnei septicemia and meningitis at 10 years of age. This patient's history contrasted with that of other individuals infected concurrently by the same organism. Of note, these episodes were not accompanied by acute phase responses in our patient. Subsequently, the patient has had more episodes of staphylococcal disease, but no systemic illnesses. The patient is now 30 years old and has been doing well since prophylactic antibiotic treatment was stopped 4 years ago. DISCUSSION: To our knowledge, this is the first report of a case of systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency. Thus, immunity mediated by IRAK-4 seems to be crucial for both the containment of and the inflammatory response to S. sonnei infection in the intestinal mucosa. IRAK-4 deficiency and related disorders should be considered in patients with systemic shigellosis.

Chapel HM. 2005. Primary immune deficiencies--improving our understanding of their role in immunological disease. Clin Exp Immunol, 139 (1), pp. 11-12. | Read more

Ferry BL, Jones J, Bateman EA, Woodham N, Warnatz K, Schlesier M, Misbah SA, Peter HH, Chapel HM. 2005. Measurement of peripheral B cell subpopulations in common variable immunodeficiency (CVID) using a whole blood method. Clin Exp Immunol, 140 (3), pp. 532-539. | Show Abstract | Read more

Recent reports have described reduced populations of CD27+ memory B cells and increased percentages of undifferentiated B cells in peripheral blood of patients with common variable immunodeficiency (CVID). This work has prompted two attempts to classify CVID based on rapid flow cytometric quantification of peripheral blood memory B cells and immature B cells. Evidence to support the hypothesis that such in vitro B cell classification systems correlate with clinical subtypes of CVID is being sought. For the classification to be useful in routine diagnosis, it is important that the flow cytometric method can be used without prior separation of peripheral blood mononuclear cells (PBMC). We have examined 23 CVID patients and 24 controls, using both PBMC and whole blood, and find an excellent correlation between these methods. The reproducibility of the method was excellent. We classified the CVID patients by all three of the existing classifications, including secretion of immunoglobulin by B cells in vitro as described by Bryant, as well as the more recent flow cytometric classification methods. Only one patient changed classification as a result of using whole blood.

Booy R, Haworth EA, Ali KA, Chapel HM, Moxon ER. 2005. Immunogenicity of routine vaccination against diphtheria, tetanus, and Haemophilus influenzae type b in Asian infants born in the United Kingdom. Arch Dis Child, 90 (6), pp. 589-591. | Show Abstract | Read more

AIM: To determine the immunogenicity of routine vaccination against diphtheria, tetanus, and Haemophilus influenzae type b (Hib) in Asian infants born in the UK, and whether maternal antibody suppression occurs. METHODS: A cohort study with 80% power, within 95% confidence limits, to show that 80% or fewer Asian infants would respond with an anti-PRP antibody concentration >0.15 microg/ml. Infants of South Asian origin born in Berkshire were enrolled at two general practices in Reading: 41 Asian families sequentially asked to participate within 2 weeks of birth; 36 infants were enrolled and 34 completed the study. Main outcome measures were: antibody concentration against diphtheria, tetanus, and Hib expressed as geometric mean titres (GMT) and proportion of infants about a threshold protective antibody concentration. RESULTS: Median age for completing primary vaccination course was 5 months. All 34 achieved anti-PRP antibody concentration of >0.15 microg/ml, 33 were >1.0 microg/ml, and the GMT was 15.0 microg/ml. All infants developed protective antibody concentration >0.1 IU/ml for tetanus and diphtheria; the respective GMTs were 1.94 and 5.57 IU/ml. Infants with high (>0.25 IU/ml) antibody concentrations against diphtheria and tetanus at 2 months achieved lower antibody concentrations after their three dose course than those with low concentrations (<0.1 IU/ml) (p = 0.06 and 0.03, respectively). CONCLUSIONS: Despite evidence for maternal antibody suppression of the response to tetanus and diphtheria vaccination, excellent antibody responses were achieved by routine vaccination according to the accelerated schedule. High vaccine coverage should be encouraged to provide protection against the possibility of imported infection.

Salzer U, Chapel HM, Webster ADB, Pan-Hammarström Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schäffer AA et al. 2005. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet, 37 (8), pp. 820-828. | Show Abstract | Read more

The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.

Eastwood D, Gilmour KC, Nistala K, Meaney C, Chapel H, Sherrell Z, Webster AD, Davies EG, Jones A, Gaspar HB. 2004. Prevalence of SAP gene defects in male patients diagnosed with common variable immunodeficiency. Clin Exp Immunol, 137 (3), pp. 584-588. | Show Abstract | Read more

The molecular basis of common variable immunodeficiency (CVID) is undefined, and diagnosis requires exclusion of other diseases including X-linked lymphoproliferative disease (XLP). This rare disorder of immunedysregulation presents typically after Epstein-Barr virus infection and results from defects in the SAP (SLAM associated protein) gene. SAP mutations have been found in a few patients diagnosed previously as CVID, suggesting that XLP may mimic CVID, but no large-scale analysis of CVID patients has been undertaken. We therefore analysed 60 male CVID and hypogammaglobulinaemic patients for abnormalities in SAP protein expression and for mutations in the SAP gene. In this study only one individual, who was found later to have an X-linked family history, was found to have a genomic mutation leading to abnormal SAP cDNA and protein expression. These results demonstrate that SAP defects are rarely observed in CVID patients. We suggest that routine screening of SAP may only be necessary in patients with other suggestive clinical features.

Aslam A, Misbah SA, Talbot K, Chapel H. 2004. Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency. Clin Immunol, 112 (1), pp. 24-29. | Show Abstract | Read more

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae.

Ferry BL, Misbah SA, Stephens P, Sherrell Z, Lythgoe H, Bateman E, Banner C, Jones J, Groome N, Chapel HM. 2004. Development of an anti-Salmonella typhi Vi ELISA: assessment of immunocompetence in healthy donors. Clin Exp Immunol, 136 (2), pp. 297-303. | Show Abstract | Read more

We have developed a solid-phase enzyme-linked immunosorbent assay (ELISA) to study the vaccination responses to Vi capsular polysaccharide of Salmonella typhi (S. typhi Vi) vaccine. Purified S. typhi Vi polysaccharide was biotinylated and bound to streptavidin coated microtitre plates. Reproducibility was determined across a range of IgG antibody levels: mean interassay coefficients of variation (CVs) were <11.9% for non-vaccinated sera with low levels and <11.1% for sera with very high levels of anti-S. typhi Vi IgG. Specificity was assessed by inhibition studies using salmonella antigen. We have developed the ELISA based on normal adult serum responses to test immunization with S. typhi Vi vaccine. We also report here anti-S. typhi Vi IgG levels in a group of healthy preschool children. In non-vaccinated adult sera (n = 104), the median value of anti-S. typhi Vi IgG, expressed in S. typhi Vi arbitrary units (AU/ml), was 5.3 AU/ml and in non-vaccinated sera from children (n = 44) the median value was 1.4 AU/ml. The data from immunization of healthy volunteers (n = 23) show that geometric mean levels of anti-S. typhi Vi IgG were significantly higher (P < 0.0001) for post-vaccination subjects (39.2 AU/ml) compared to paired prevaccination (3.9 AU/ml) values. A total of 21/23 vaccine recipients had <8 AU/ml S. typhi Vi IgG in their sera prior to vaccination and of these 20/21 (95%) exhibited threefold increases and 14/21 (67%) fourfold increases in their S. typhi Vi IgG following vaccination. Based on the data in this study, we propose a threefold increase in anti-S. typhi Vi IgG post-vaccination to be considered a positive vaccination response. The ability to demonstrate clearly an antibody rise in response to immunization with S. typhi Vi capsular polysaccharide vaccine suggests that this is likely to be a useful vaccine for the assessment of B cell function in patients with suspected immune deficiency.

Evangelou N, Littlewood T, Anslow P, Chapel H. 2003. Transverse sinus thrombosis and IVIg treatment: a case report and discussion of risk-benefit assessment for immunoglobulin treatment. J Clin Pathol, 56 (4), pp. 308-309. | Show Abstract | Read more

A 54 year old woman presented with symptoms resulting from a thrombosis of the lateral transverse and sagittal sinuses the day after an infusion of intravenous immunoglobulin (IVIg) replacement treatment. She had previously suffered a milder episode after IVIg. Following recurrent bacterial chest infections and sinusitis for more than 40 years, a diagnosis of IgG1 deficiency had been made two years earlier, after exclusion of other causes. She made a good recovery from the thrombosis but high platelet counts were investigated and primary thrombocythaemia was diagnosed. Investigation of humoral immunity revealed protective amounts of IgG antibodies to pathogens, and because the previous IgG1 deficiency had resolved IVIg infusions were not restarted. She made a good response to treatment with hydroxyurea, with improvement of the headaches and lowering of the platelet counts. Prophylactic antibiotics reduced the number of bacterial chest infections and nasal corticosteroids improved the chronic sinusitis. This case is presented to highlight the need to look for other contributing factors for severe recurrent headaches after IVIg treatment, and to consider the risk of thrombosis even when replacement doses of IVIg are used. It is also important to emphasise the need to ensure that an isolated IgG subclass deficiency is not transient; that failure to produce specific IgG antibodies to immunisation and/or exposure antigens is confirmed, thus meeting the criteria for the diagnosis of primary antibody deficiency. A thorough risk-benefit assessment is essential before blood product treatment is started.

Chapel H, Geha R, Rosen F, IUIS PID (Primary Immunodeficiencies) Classification committee. 2003. Primary immunodeficiency diseases: an update. Clin Exp Immunol, 132 (1), pp. 9-15. | Read more

Brennan VM, Salomé-Bentley NJ, Chapel HM, Immunology Nurses Study. 2003. Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin. Clin Exp Immunol, 133 (2), pp. 247-251. | Show Abstract | Read more

Intravenous immunoglobulin (IVIG) is used as the standard replacement therapy for patients with primary antibody deficiencies. A previous study of adverse reactions in patients self-infusing at home over 1 year showed an overall reaction rate of 0.7%. A larger prospective study is reported here, involving a greater number of immunology centres and including children and adults who received infusions from medical or nursing staff as well as those self-infusing. Four hundred and fifty-nine patients were entered into this study and 13 508 infusions were given. The study showed that no severe reactions occurred and the reaction rate was low at 0.8%. This figure could have been lower, 0.5%, if predisposing factors responsible for some reactions had been considered before infusion. In conclusion, the study shows the importance of ongoing training for patients and staff to recognize the predisposing factors to prevent avoidable reactions. Because none of these reactions were graded as severe, the present guidance to prescribe self-injectable adrenaline for patients infusing outside hospital should be reviewed.

Quinti I, Pierdominici M, Marziali M, Giovannetti A, Donnanno S, Chapel H, Bjorkander J, Aiuti F, European Study Group for the Surveillance of Immunoglobulin Safety. 2002. European surveillance of immunoglobulin safety--results of initial survey of 1243 patients with primary immunodeficiencies in 16 countries. Clin Immunol, 104 (3), pp. 231-236. | Show Abstract | Read more

A European multicenter study was conducted to obtain information on the current practices of immunoglobulin administration, the policies in use for the surveillance of the risk of hepatitis C virus (HCV) transmission, and the natural history of HCV infection in patients with hypogammaglobulinemia. Data from 1243 patients with primary immunodeficiencies in 16 countries demonstrated that 90% of patients with antibody deficiencies receive intravenous immunoglobulins in an inpatient setting, and 7% of patients are treated with subcutaneous immunoglobulins, mainly at home. Wide variations have been reported regarding the frequency and the type of tests monitored for the surveillance on the risk of viral hepatitis transmission. Only 60% of patients have been tested at least once for HCV RNA detection. Data from 71 HCV-infected patients demonstrated a rapid progression of HCV infection, with end-stage liver disease, in about 40% of patients. Ten percent of patients spontaneously cleared the virus, and about 30% are asymptomatic. Patients with CVID have a worse prognosis than patients with XLA.

Wiles CM, Brown P, Chapel H, Guerrini R, Hughes RAC, Martin TD, McCrone P, Newsom-Davis J, Palace J, Rees JH et al. 2002. Intravenous immunoglobulin in neurological disease: a specialist review. J Neurol Neurosurg Psychiatry, 72 (4), pp. 440-448. | Show Abstract | Read more

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Sansom ME, Ferry BL, Sherrell ZPMC, Chapel HM. 2002. A preliminary assessment of alpha-1 antitrypsin S and Z deficiency allele frequencies in common variable immunodeficiency patients with and without bronchiectasis. Clin Exp Immunol, 130 (3), pp. 489-494. | Show Abstract | Read more

Common variable immunodeficiency (CVID) is the name given to a clinically heterogeneous group of hypogammaglobulinaemic immunodeficiency states. Bronchiectasis is a feature of this disease and is believed to be the result of recurrent bacterial infection affecting the respiratory tract. Bronchiectasis is also a feature associated with emphysematous changes of the lung in alpha-1 antitrypsin (AAT) deficiency, a serious and relatively common disease, affecting 1 : 2000 in the United Kingdom. This has been demonstrated to result from possession of deficiency alleles, the most clinically important alleles being PI*Z and PI*S. Isolated reports of families with antibody deficiency and AAT deficiency have been published but to date no study has been performed to specifically investigate if AAT deficiency is associated with the lung damage seen in CVID patients. We have developed a PCR genotyping assay that identifies S and Z deficiency alleles and we have used this assay in a preliminary study to investigate the occurrence of these deficiency alleles of AAT in 43 CVID patients. Results of this preliminary study suggest that CVID patients did not have an altered distribution of AAT genes when compared to 70 normal controls. Subgrouping of CVID patients into those with and without bronchiectasis demonstrated a Z allele frequency of 0.077 in those patients with bronchiectasis, which is higher than found in normal controls, namely 0.029 (P < 0.15). Due to the relatively small numbers studied, these results are inconclusive in determining whether AAT deficiency may exacerbate lung damage in some CVID patient, the data does however, indicate that a larger multi-centre study involving many more CVID patients may be useful.

Vorechovsky I, Kralovicova J, Tchilian E, Masterman T, Zhang Z, Ferry B, Misbah S, Chapel H, Webster D, Hellgren D et al. 2001. Does 77C-->G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nat Genet, 29 (1), pp. 22-23. | Show Abstract | Read more

A 77G allele of the gene encoding CD45, also known as the protein tyrosine phosphatase receptor-type C gene (PTPRC), has been associated with multiple sclerosis (MS). Here we determine allele frequencies in large numbers of MS patients, primary immunodeficiencies linked to major histocompatibility complex (MHC) locus and over 1,000 controls to assess whether aberrant splicing of PTPRC caused by the 77C-->G polymorphism results in increased susceptibility to these diseases. Our results show no difference in the frequency of the 77G allele in patients and controls and thus do not support a causative role for the polymorphism in the development of disorders with a strong autoimmune component in etiology.

Weston SA, Prasad ML, Mullighan CG, Chapel H, Benson EM. 2001. Assessment of male CVID patients for mutations in the Btk gene: how many have been misdiagnosed? Clin Exp Immunol, 124 (3), pp. 465-469. | Show Abstract | Read more

The presentation of hypogammaglobulinaemia in young males without a family history of immunodeficiency can pose a diagnostic problem. In the past, the presence of B-cells has suggested a diagnosis of common variable immunodeficiency (CVID), although genotypic analysis has now clarified that individuals with B cells may have mutations in their Btk gene. In order to address the issue of how many male individuals with a clinical diagnosis of CVID do in fact have mutations in the Btk gene, we analysed a group of 24 male patients. Single-strand conformation polymorphism (SSCP) analysis was used to screen the patient cohort for mutations in the Btk gene. Given the size of the Btk gene, the number of patients in the cohort and the amount of available DNA, multiplex PCR reactions were utilized to span the 19 exons and promoter region of the gene. Where abnormal migration patterns were observed with multiplex PCR reactions, in nine of the 24 patients, the individual Btk gene fragments were re-amplified and analysed again by SSCP. Following this analysis, four patients continued to demonstrate abnormal SSCP migration patterns. However, direct sequencing of the relevant Btk gene fragments for these four CVID patients revealed a mutation in only one patient. The mutation was the previously described polymorphism at position 2031 of Btk gene within exon 18. These results indicate that caution should be taken with the application of SSCP analysis to mutation detection. While it has a role to play in screening large patient cohorts, direct sequencing is a necessary adjunct to such analysis. Finally, the clinical diagnosis of CVID in this cohort successfully excluded males with Btk mutations.

Farrell AM, Antrobus P, Simpson D, Powell S, Chapel HM, Ferry BL. 2001. A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy. Br J Dermatol, 144 (1), pp. 24-33. | Show Abstract | Read more

BACKGROUND: The immune response in atopic dermatitis (AD) is thought to be driven by T-helper (Th) 2 cytokines. Using flow cytometry, higher frequencies of peripheral blood CD4+ and CD8+ T cells producing interleukin (IL)-4 and correspondingly lower frequencies of CD4+ T cells producing interferon (IFN)-gamma have been found in patients with AD compared with healthy controls. It would be of interest to know whether other Th1 and Th2 cytokines such as IL-5, IL-13 and tumour necrosis factor (TNF)-alpha are similarly skewed in patients with AD and whether this immune skewing, detected via a simple blood assay, can be correlated with other clinical measurements or treatments in AD. OBJECTIVES: To use a rapid (4-h) flow cytometric assay to study a wide range of Th1 and Th2 cytokine patterns in peripheral blood lymphocytes from patients with AD, comparing them with non-atopic healthy controls. To correlate cytokine patterns with the degree of eosinophilia observed and in the case of one patient with severe disease, to observe the effect of cyclosporin therapy on peripheral blood cytokine patterns. METHODS: Peripheral blood from eight patients with AD and 23 healthy controls was examined for the frequencies of CD4+ and CD8+ T cells expressing IL-2, IL-4, IL-5, IL-13, IFN-gamma and TNF-alpha using flow cytometry. RESULTS: Significantly higher frequencies of CD4+/IL-4+ (P < 0.005) and CD4+/IL-13+ (P < 0.0001) and lower frequencies of CD4+/IFN-gamma+ (P < 0.002) and CD8+/TNF-alpha+ (P < 0.05) T lymphocytes were found in patients with AD compared with controls. There were significant positive correlations with the increased percentages of CD4+/IL-4+ and CD4+/IL-13+ T lymphocytes and the degree of eosinophilia observed (P < 0.05, P < 0.001) and a negative correlation between the percentage of CD4+/IFN-gamma+ T lymphocytes and eosinophilia (P < 0.05). In one patient examined before and 8 days after cyclosporin therapy, 50% or greater reductions were observed in percentages of peripheral blood CD8+/IL-5+, CD8+/IL-13+, CD4+/IL-4+ and CD4+/IL-5+ T lymphocytes following cyclosporin therapy. A smaller reduction of 15% after cyclosporin therapy was found in percentages of CD4+/IL-13+ T cells. CONCLUSIONS: These data strongly support a Th2 predominance in the peripheral blood of AD. The results suggest that administration of cyclosporin therapy in patients with AD may help to restore the Th2 cytokine imbalance seen in these patients.

Bonhomme D, Hammarström L, Webster D, Chapel H, Hermine O, Le Deist F, Lepage E, Romeo PH, Levy Y. 2000. Impaired antibody affinity maturation process characterizes a subset of patients with common variable immunodeficiency. J Immunol, 165 (8), pp. 4725-4730. | Show Abstract

Common variable immunodeficiency (CVID) is an heterogeneous syndrome characterized by decreased levels of serum Ig and recurrent bacterial infection. Here, we were interested to study whether a qualitative defect of the affinity Ab maturation process could be combined to the low level of serum Ig in a cohort of 38 CVID patients. For this, we designed a novel and rapid screening test for the detection of hypomutated V gene expressed by memory B cells. This test delineated a subset of 9/38 (23%) CVID patients with an abnormal pattern of Ig V gene mutation. The mean frequency of V gene mutation of this subset was significantly lower (1.74%) compared with other CVID patients (5.46%) and normal donors (6.5%) (p<0.0001). The mean age of this subgroup was significantly higher than other hypogammaglobulinemic patients with normal levels of V gene mutation (p<0.02), whereas no difference in the duration of symptoms was noted between the two groups. This suggests that hypomutation characterizes patients who began CVID late in life. Recently, it was shown that non-Ig sequences, such as the intronic BCL-6 gene, could be the target of the somatic hypermutation process in normal memory B cells. Our finding of a normal mutation frequency of the BCL-6 gene in two hypomutated CVID point to a defect of the Ig targeting of hypermutation machinery in these cases.

Jayne DR, Chapel H, Adu D, Misbah S, O'Donoghue D, Scott D, Lockwood CM. 2000. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM, 93 (7), pp. 433-439. | Show Abstract | Read more

Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.

Béné MC, Stockinger H, Capel PJ, Chapel H, Knapp W. 2000. Clinical immunology: a unified vision for Europe. Immunol Today, 21 (5), pp. 210-211. | Read more

Cited:

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Scopus

Davies CWH, Juniper MC, Gray W, Gleeson FV, Chapel HM, Davies RJO. 2000. Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A Thorax, 55 (1), pp. 88-90. | Show Abstract | Read more

Lymphoid interstitial pneumonitis (LIP) is a rare clinicopathological entity that may be associated with common variable immune deficiency (CVID) and may lead to respiratory failure and death. Some patients may respond to prolonged corticosteroid treatment. We hypothesised that, in view of the predominant T cell nature of LIP, cyclosporin A would be a more appropriate choice of immunosuppressive agent and report the first case of its successful use in a woman with LIP associated with CVID.

Bjorkander J, Spickett G, Ericson D, Engl W, Eibl M, Chapel H. 2000. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 105 (1), pp. S174-S175. | Read more

Gross BS, Wilde JI, Quek L, Chapel H, Nelson DL, Watson SP. 1999. Regulation and function of WASp in platelets by the collagen receptor, glycoprotein VI. Blood, 94 (12), pp. 4166-4176. | Show Abstract

Wiskott Aldrich syndrome (WAS) is an X-linked recessive disorder associated with abnormalities in platelets and lymphocytes giving rise to thrombocytopenia and immunodeficiency. WAS is caused by a mutation in the gene encoding the cytoskeletal protein (WASp). Despite its importance, the role of WASp in platelet function is not established. WASp was recently shown to undergo tyrosine phosphorylation in platelets after activation by collagen, suggesting that it may play a selective role in activation by the adhesion molecule. In the present study, we show that WASp is heavily tyrosine phosphorylated by a collagen-related peptide (CRP) that binds to the collagen receptor glycoprotein (GP) VI, but not to the integrin alpha2beta1. Tyrosine phosphorylation of WASp was blocked by Src family kinase inhibitors and reduced by treatment with wortmannin and in patients with X-linked agammaglobulinemia (XLA), a condition caused by a lack of functional expression of Btk. This indicates that Src kinases, phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to the regulation of tyrosine phosphorylation of WASp. The functional importance of WASp was investigated in 2 WAS brothers who show no detectable expression of WASp. Platelet aggregation and secretion from dense granules induced by CRP and thrombin was slightly enhanced in the WAS platelets relative to controls. Furthermore, there was no apparent difference in morphology in WAS platelets after stimulation by these agonists. These observations suggest that WASp does not play a critical role in intracellular signaling downstream of tyrosine kinase-linked and G protein-coupled receptors in platelets.

Rieux-Laucat F, Blachère S, Danielan S, De Villartay JP, Oleastro M, Solary E, Bader-Meunier B, Arkwright P, Pondaré C, Bernaudin F et al. 1999. Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations. Blood, 94 (8), pp. 2575-2582. | Show Abstract

Fas (CD95/Apo-1) mutations were previously reported as the genetic defect responsible for human lymphoproliferative syndrome associated with autoimmune manifestations (also known as autoimmune lymphoproliferative syndrome or Canale-Smith syndrome). We have identified 14 new heterozygous Fas mutations. Analysis of patients and families allow us to further dissect this syndrome with regards to the relationship between Fas mutations, inheritance pattern, and phenotype as observed on long-term follow-up. In vitro studies show that lymphocytes from all Fas mutant carriers exhibit a Fas-antibody-induced apoptosis defect. However, among the 8 inherited mutations, 4 of 4 Fas missense mutations were associated with high clinical penetrance, whereas 3 of 4 mutations leading to a truncated Fas product were associated with variable clinical penetrance. This suggests that a second defect, in another yet undefined factor involved in apoptosis and/or lymphoproliferation control, is necessary to induce full clinical expression of the disease. These results also indicate that the currently available antibody-mediated in vitro apoptosis assay does not necessarily reflect the in vivo ability of abnormal Fas molecules to trigger lymphocyte death. In addition, we found that lymphoproliferative manifestations resolved with age, whereas immunological disorders [ie, hypergammaglobulinemia and detection of TcR alphabeta(+) CD4(-) CD8(-) lymphocytes] persisted. This observation suggests that Fas-mediated apoptosis plays a more important role in lymphocyte homeostasis in early childhood than later on in life.

Christie JM, Chapel H, Chapman RW, Rosenberg WM. 1999. Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus. Hepatology, 30 (4), pp. 1037-1044. | Show Abstract | Read more

How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.

Jayne D, Chapel H, Adu J, O'Donoghue D, Misbah S, Scott D, Lockwood CM. 1999. Placebo-controlled trial of intravenous immunoglobulin in ANCA-associated systemic vasculitis. KIDNEY INTERNATIONAL, 55 (6), pp. 2574-2574.

Chapel H, Shaw J, Williams A, Moncrieff G, Moxon ER. 1998. Unclassified immunodeficiency in a boy of five years with restriction of circulating B cells to immature phenotype in association with haemolytic anaemia MOLECULAR IMMUNOLOGY, 35 (11-12), pp. 753-753. | Read more

Ferry B, Antrobus P, Huzicka I, Farrell A, Lane A, Chapel H. 1997. Intracellular cytokine expression in whole blood preparations from normals and patients with atopic dermatitis. Clin Exp Immunol, 110 (3), pp. 410-417. | Show Abstract | Read more

In recent years, the importance of characterizing the role of cytokines in a wide range of clinical conditions has resulted in development of new methods to assess cytokine expression in clinical samples. The use of anti-cytokine MoAbs and flow cytometry to detect cytokines intracellularly at the single-cell level has the potential to quantify cytokine production in different diseases. For this technique to be useful in a clinical setting, rapid throughput of clinical samples and a cheap, reliable assay would be required, therefore the development of the above technique using unseparated whole blood samples would be advantageous. Using this technique, only one study to date (Maino et al., 1996) has used unseparated whole blood as the source of cells for detecting intracellular cytokines. In clinical practice, whole blood may be optimal, since this most closely approximates conditions in vivo: as no purification of blood mononuclear cells is required, very little blood is needed to detect a number of cytokines simultaneously in various lymphocyte subpopulations, and the assay can be applied to samples from infants and children. In this study we describe an intracellular cytokine assay using unseparated whole blood from normals. In activated CD8- T cells, IL-2 and interferon-gamma (IFN-gamma) were optimally induced after 10 h stimulation with phorbol 12-myristate acetate (PMA)/ionomycin, and in CD8+ T cells IL-2 was optimally induced after 10 h and IFN-gamma after 6 h. The levels of IL-2 and IFN-gamma in CD8+ and CD8- T cells in four healthy individuals were consistent on four occasions over a 3-month period. In a large group of 34 normal subjects, there was considerable heterogeneity in CD3/IL-2+ (range 9.7-41.3) and CD3/IFN-gamma+ cells (10.1-44), expressed as a percentage of total lymphocytes. In patients with atopic dermatitis (n = 5) there was a significantly decreased percentage of CD3+/CD8+ peripheral blood T cells expressing IFN-gamma and an increased percentage of CD3+/CD8- T cells expressing IL-4 compared with non-atopic dermatitis controls (n = 5). Possible applications of this technique are discussed.

Christie JM, Healey CJ, Watson J, Wong VS, Duddridge M, Snowden N, Rosenberg WM, Fleming KA, Chapel H, Chapman RW. 1997. Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C: 2 year follow up. Clin Exp Immunol, 110 (1), pp. 4-8. | Show Abstract | Read more

In 1994, an outbreak of hepatitis C virus (HCV) infection, genotype 1a, occurred in 30 hypogammaglobulinaemic patients in the UK from one batch of contaminated anti-HCV screened intravenous immunoglobulin. This study aimed to study prospectively the outcome of HCV in hypogammaglobulinaemic patients, and to assess the response to early treatment with interferon-alpha, 6 million units three times weekly for 6 months. Data were collected using standardized questionnaires. Five patients with secondary hypogammaglobulinaemia due to lymphoid malignancy were not treated and all have died of their primary malignancy. Of 25 patients with primary hypogammaglobulinaemia, one resolved HCV infection before treatment, 17 commenced on treatment, and seven declined or treatment was contra-indicated. Thirteen of 17 patients completed therapy and seven (54%) have a sustained response (normal transaminases, negative serum HCV RNA) at 6 and 12 months after treatment. Two of the 12 patients with primary hypogammaglobulinaemia, who were not treated or failed to complete treatment, have cleared the virus. Liver biopsy was performed in patients not clearing HCV and was abnormal in all. Four patients developed liver failure within 2 years, of whom three have died and one has been successfully transplanted. In conclusion, HCV can cause rapid severe liver disease in hypogammaglobulinaemic patients. Early treatment with high-dose interferon-alpha results in a high clearance of HCV.

Christie J, Healey C, Fleming K, Chapel H, Chapman R, Rosenberg W. 1997. Conservation within cytotoxic T lymphocyte epitopes in hepatitis C virus in chronic infection. GASTROENTEROLOGY, 112 (4), pp. A1243-A1243.

Ferry BL, Welsh KI, Dunn MJ, Law D, Proctor J, Chapel H, Yacoub MH, Rose ML. 1997. Anti-cell surface endothelial antibodies in sera from cardiac and kidney transplant recipients: association with chronic rejection. Transpl Immunol, 5 (1), pp. 17-24. | Show Abstract | Read more

The aetiologies of accelerated or transplant-associated coronary artery disease (TxCAD) following cardiac transplantation and chronic rejection following renal transplantation remain ill-defined. Previous studies have used Western blotting to demonstrate an association between the formation of anti-endothelial (anti-EC) antibodies and TxCAD after heart transplantation. However, Western blotting favours detection of cytosolic proteins. The objectives of this study were to determine whether flow cytometry, a method which detects antigens on the cell surface, could be used to detect anti-EC antibodies and also whether the observations would extend to renal transplant patients with chronic rejection. Flow cytometry was used to look for antibodies reactive with the surface antigens of macrovascular and microvascular endothelial cell lines in sera from 44 cardiac and 35 renal transplant recipients before and after transplantation. In addition, sera from normals (n = 20), patients with nontransplant CAD (n = 50) and patients with unrelated diseases (n = 40) were investigated. Of 23 cardiac recipients who had developed TxCAD at one or two years post-transplant, 61% had IgM and 13% had IgG anti-EC antibodies post-transplantation. In contrast, in 21 cardiac recipients who had not developed TxCAD 14% had IgM and 14% IgG anti-EC antibodies. There was little evidence for the presence of anti-EC antibodies in cardiac recipients before transplantation. Of 26 renal transplant recipients whose transplants failed due to chronic rejection, 42% had IgG and 19% IgM anti-EC antibodies post-transplantation. Of nine renal recipients whose grafts were either functioning normally or who had acutely rejected, none had IgG or IgM anti-EC antibodies either pre- or post-transplantation. The anti-EC antibodies were not found in normals and were rare (less than 4%) in the other disease groups; they do not appear to be autoantibodies. In conclusion, these results suggest the FACS assay could be an informative and rapid test to provide more information on chronic rejection following cardiac and renal transplantation.

Misbah SA, Griffiths H, Mitchell T, Freeland A, Haeney MR, Chapel HM. 1997. Antipolysaccharide antibodies in 450 children with otitis media. Clin Exp Immunol, 109 (1), pp. 67-72. | Show Abstract | Read more

We have measured antibodies to pneumococcal and Haemophilus polysaccharides in a prospective study of 450 children aged 2-16 years with otitis media requiring grommets (ear tubes). Pneumococcal antibody levels were significantly higher in the 2-6 year (P < 0.004) and 7-10 year (P < 0.04) study groups in comparison with age-matched controls. There was no difference in Haemophilus antibody levels between the study and control group children for the age groups 2-6 years and 11-16 years. Haemophilus antibody levels were significantly lower in the 7-10 year (P < 0.003) group in comparison with age-matched controls. Eighty-eight out of 450 (19.6%) children had pneumococcal antibody levels below the 25th percentile. Nineteen out of 88 (21.6%) children with pneumococcal antibody levels below the 25th centile were test immunized with 23 valent Pneumococcal polysaccharide and unconjugated Haemophilus type b capsular polysaccharide. Of these 19 children (aged 4-11 years), five mounted suboptimal responses to both polysaccharide antigens, whilst one child failed to respond to Haemophilus polysaccharide alone. There was no significant difference in the prevalence of IgG subclass deficiency between the normal responders and poor responders to immunization (P = 0.12). We found no evidence of specific polysaccharide antibody deficiency in the vast majority of the 450 children studied. However, the significance of poor antibody responses to test immunization in a small minority of children with otitis media is unclear. Long-term follow up of these children is required to determine whether poor immunization responses herald the development of frank antibody deficiency.

Healey CJ, Chapel H, Simmonds P, Chapman RWG. 1996. Hepatitis G virus in intravenous immunoglobulin - Reply GASTROENTEROLOGY, 111 (5), pp. 1399-1400.

Notarangelo LD, Peitsch MC, Abrahamsen TG, Bachelot C, Bordigoni P, Cant AJ, Chapel H, Clementi M, Deacock S, de Saint Basile G et al. 1996. CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome. Immunol Today, 17 (11), pp. 511-516. | Show Abstract | Read more

X-linked hyper-IgM syndrome (X-HIM) is an immunodeficiency caused by mutations in the gene encoding the CD40 ligand (CD40L). A database (CD40Lbase) of CD40L mutations has now been established, and the resultant information, together with other mutations reported elsewhere in the literature, is presented here.

Litzman J, Jones A, Hann I, Chapel H, Strobel S, Morgan G. 1996. Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome. Arch Dis Child, 75 (5), pp. 436-439. | Show Abstract | Read more

AIM: To assess the results of supportive treatment with intravenous immunoglobulin (IVIG) and antibiotic prophylaxis in combination with splenectomy in patients with Wiskott-Aldrich syndrome. STUDY DESIGN: Retrospective review of case records of 21 patients from March 1984 to February 1996. RESULTS: Thrombocytopenia was cured in 14 of 15 patients who had splenectomy, but it recurred intermittently in three. Mean platelet volume (MPV) was normal transiently in some patients, but all MPV values were subnormal 8-23 months after splenectomy. Antibiotic and IVIG prophylaxis may have contributed to the lack of a detectable increase in the number of severe acute bacterial infections in the 451 months after splenectomy. Four patients died in 2205 months of observation before and after splenectomy (median 82, range 16-248): two of cerebral B cell lymphoma, one of progressive multifocal leucoencephalopathy, and one with severe chronic chest disease of pneumonia. CONCLUSION: Adequate supportive treatment with IVIG and antibiotic prophylaxis together with splenectomy enables good survival and quality of life in the short and medium term in patients with Wiskott-Aldrich syndrome. Persistence of infection, bleeding, and vasculitic and allergic symptoms in a significant minority and the risk of development of lymphoma, however, suggest that bone marrow transplantation may be indicated if an HLA identical donor is available.

Christie J, Healey C, Watson J, Wong S, Durridge M, Snowdon N, Rosenberg W, Fleming K, Chapel H, Chapman R. 1996. Treatment and outcome of acute hepatitis C infection in hypogammaglobulinaemia - 2 year follow-up of the UK Gammagard outbreak. HEPATOLOGY, 24 (4), pp. 1089-1089.

Chapel H. 1996. Intravenous immunoglobulin therapy. QJM, 89 (9), pp. 641-643. | Read more

Healey CJ, Sabharwal NK, Daub J, Davidson F, Yap PL, Fleming KA, Chapman RW, Simmonds P, Chapel H. 1996. Outbreak of acute hepatitis C following the use of anti-hepatitis C virus--screened intravenous immunoglobulin therapy. Gastroenterology, 110 (4), pp. 1120-1126. | Show Abstract | Read more

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has been associated with intravenous (IV) immunoglobulin (Ig), and plasma donations used to prepare IV Ig are now screened to prevent transmission. Thirty-six patients from the United Kingdom received infusions from a batch of anti-HCV antibody-screened intravenous Ig (Gammagard; Baxter Healthcare Ltd., Thetford, Norfolk, England) that was associated with reports of acute hepatitis C outbreak in Europe. The aim of this study was to document the epidemiology of this outbreak. METHODS: Forty-six patients from the United Kingdom treated with Gammagard (34 exposed and 12 unexposed to the batch) returned epidemiological questionnaires. RESULTS: Eighty-two percent of the exposed patients (28 of 34) became positive for HCV RNA. Eighteen percent of the patients (6 of 34) who had infusions with this batch tested negative for HCV RNA, but 2 of the patients had abnormal liver function and subsequently seroconverted to anti-HCV antibody positive. Twenty-seven percent of the patients (9 of 34) developed jaundice, and 79% (27 of 34) had abnormal liver transferase levels. Virus isolates (n=21), including an isolate from the implicated batch, were genotype 1a and virtually identical by sequence analysis of the NS5 region, consistent with transmission from a single source. CONCLUSIONS: Hepatitis C infection can be transmitted by anti-HCV-screened IV Ig. Careful documentation of IV Ig batch numbers and regular biochemical monitoring is recommended for all IV Ig recipients.

Connors MH, Dunger DB, Chapel H, Jefferson I, Jowett TP, Edwards PR. 1996. Diminished thyroxine-binding globulin in pubertal diabetic children. Diabetes Care, 19 (3), pp. 246-248. | Show Abstract | Read more

OBJECTIVE: To determine the effect of diabetes on thyroid hormone and thyroxine-binding globulin (TBG) concentrations during puberty. RESEARCH DESIGN AND METHODS: Total thyroxine (TT4), free thyroxine (FT4), and TBG levels of 171 thyroid microsomal antibody-negative subjects with normal thyroid-stimulating hormone (TSH) levels were measured and compared with those of nondiabetic adolescents. A random subset of 68 diabetic patients (40 boys and 28 girls) and 51 control subjects (24 boys and 27 girls) were analyzed for puberty-related changes. RESULTS: Most TT4 levels of diabetic subjects (80% of girls and 63% of boys) were below the 50th percentile for the normal range. TT4 increased with age in girls (r = 0.25, P < 0.04) but not in boys. FT4 was within normal limits in both sexes. TBG measurements were below the 50th percentile and 20% were below the 95% CI for both sexes; TT4 correlated with TBG in boys (r = 0.54, P < 0.001) and in girls (r = 0.58, P < 0.001). Duration of diabetes had no effect, whereas TT4 and FT4 levels were higher in girls with the lowest HbA1 levels (r = -0.29, P < 0.01 and r = -0.45, P < 0.01). Levels of TBG were reduced for all male pubertal stages (P < 0.01) and for early and late female pubertal stages (P < 0.01). There was no direct relationship between glucose control or the duration of diabetes and levels of TBG. CONCLUSIONS: Because TT4 levels are low and correlate with the low levels of TBG, it is important to measure free thyroid hormone and TSH levels in diabetic adolescents to establish euthyroidism.

Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B. 1996. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology, 47 (3), pp. 678-683. | Show Abstract | Read more

Intravenous immunoglobulin improves many antibody-mediated autoimmune disorders, but its mode of action is unknown. We investigated its effects on muscle strength and on the serum titer of the calcium-channel autoantibodies that are likely to be pathogenic in the Lambert-Eaton myasthenic syndrome (LEMS). In a randomized, double-blind, placebo-controlled crossover trial, serial indices of limb, respiratory, and bulbar muscle strength and the serum titer of calcium-channel antibodies in nine patients were compared over an 8-week period, using the area-under-the-curve approach, following infusion on two consecutive days of immunoglobulin at 1 g/kg body weight/day (total dose 2.0 g/kg body weight) or placebo (equivalent volume of 0.3% albumin). Calcium-channel antibodies were measured by radioimmunoassay using 125I-omega-conotoxin MVIIC. Direct anti-idiotypic actions of immunoglobulin were tested in this assay. Immunoglobulin infusion was followed by significant improvements in the three strength measures (p = 0.017 to 0.038) associated with a significant decline in serum calcium-channel antibody titers (p = 0.028). Improvement peaked at 2 to 4 weeks and was declining by 8 weeks. Mean serum titers were unchanged at 1 week, however, and direct anti-idiotypic neutralization by immunoglobulin was not demonstrable in vitro. We conclude that immunoglobulin causes a short-term improvement in muscle strength in LEMS that probably results from the induced reduction in calcium-channel autoantibodies. The reduction is not due to a direct neutralizing action of the immunoglobulin, but a delayed anti-idiotypic action cannot be excluded. Improvement following intravenous immunoglobulin in other autoantibody-mediated disorders may similarly be associated with decline in levels of pathogenic autoantibodies.

Chapel H. 1996. Hepatitis C and intravenous immunoglobulin - Concluding remarks CLINICAL THERAPEUTICS, 18 pp. 137-139. | Read more

Healey C, Chapel H. 1996. Intravenous immunoglobulin and hepatitis C virus: the British episode. Clin Ther, 18 Suppl B (SUPPL. B), pp. 93-95. | Read more

Bird AG, Chapel H. 1995. Management of anaphylactic reactions to food. Arch Dis Child, 73 (1), pp. 89. | Read more

HEALEY CJ, WATSON J, DURRIDGE M, SNOWDON N, CHRISTIE J, WONG S, READ J, KURTZ J, FLEMING KA, CHAPEL H, CHAPMAN RWG. 1995. TREATMENT OF ACUTE HEPATITIS-C WITH ALPHA-INTERFERON IN HYPOGAMMAGLOBULINEMIA - THE UK GAMMAGARD OUTBREAK GASTROENTEROLOGY, 108 (4), pp. A1082-A1082.

Chapel H, Bird G. 1995. Transfusion-related hepatitis. QJM, 88 (3), pp. 221. | Read more

HEALEY CJ, SABHARWAL NK, MCOMISH F, CHAPMAN RW, FLEMING KA, SIMMONDS P, CHAPEL H. 1994. OUTBREAK OF ACUTE HEPATITIS-C FOLLOWING INTRAVENOUS IMMUNOGLOBULIN THERAPY HEPATOLOGY, 20 (4), pp. A249-A249.

Chapel H, Dicato M, Gamm H, Brennan V, Ries F, Bunch C, Lee M. 1994. Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. Br J Haematol, 88 (1), pp. 209-212. | Show Abstract | Read more

Previous studies have shown that intravenous immunoglobulin (IVIg) therapy is useful prophylaxis against infection in patients with secondary hypogammaglobulinaemia due to a low-grade lymphoproliferative disease. This randomized double-blind study was undertaken to determine prospectively the dose regime required. 34 such patients received IVIg at either 500 or 250 mg/kg every 4 weeks for 1 year. There was no significant difference in the rates of serious infections between the two groups of patients, which were well matched for disease and laboratory parameters. The rates of infection seen were similar to those in IVIg groups of previous studies and strikingly different from those in the placebo group in the previously randomized placebo-controlled study.

Chapel HM. 1994. Consensus on diagnosis and management of primary antibody deficiencies. Consensus Panel for the Diagnosis and Management of Primary Antibody Deficiencies. BMJ, 308 (6928), pp. 581-585. | Read more

Hill A, Chapel H. 1993. X-linked immunodeficiency. The fruits of cooperation. Nature, 361 (6412), pp. 494. | Read more

Griffiths H, Lea J, Bunch C, Lee M, Chapel H. 1992. Predictors of infection in chronic lymphocytic leukaemia (CLL). Clin Exp Immunol, 89 (3), pp. 374-377. | Show Abstract | Read more

A group of patients with chronic lymphocytic leukaemia (CLL) were studied to determine whether particular clinical and laboratory parameters might help to identify those patients at risk of recurrent infection who would benefit from immunoglobulin replacement therapy. The case notes of 59 patients were reviewed with regard to stage and duration of disease, chemotherapy and frequency of infection over the preceding 2 years. Serum IgG levels and specific antibodies to tetanus, diphtheria and pneumococcal capsular polysaccharide were measured at the end of the 2-year period. A group of 56 healthy age-matched volunteers were used as controls. Eighteen patients had severe or multiple infections during the study period, 11 patients had recurrent infections and the remaining 30 patients had only minimal infections. Overall, serum IgG levels were low in 32 patients but in none of the control group (P = 8.8 x 10(-11). However, less than half of those patients with hypogammaglobulinaemia suffered from severe or multiple infections. Specific antibodies to pneumococcal capsular polysaccharide were low in 23 patients compared with six of the control group (P = 4.9 x 10(-4)). The majority of patients with severe or multiple infections (13/18) had low levels of both total IgG and specific antibodies to pneumococcal capsular polysaccharide. However, in the groups of patients with less frequent infections, a higher proportion had low serum IgG than low pneumococcal antibody levels. Low levels of pneumococcal antibodies were particularly associated with severe or multiple infections (P = less than 0.00001).

Booy R, Taylor SA, Dobson SR, Isaacs D, Sleight G, Aitken S, Griffiths H, Chapel H, Mayon-White RT, Macfarlane JA. 1992. Immunogenicity and safety of PRP-T conjugate vaccine given according to the British accelerated immunisation schedule. Arch Dis Child, 67 (4), pp. 475-478. | Show Abstract | Read more

The immunogenicity and safety of a new Haemophilus influenzae type b conjugate vaccine, PRP-T, was studied in 107 infants from the Oxford district. The vaccine was given concurrently with diphtheria, pertussis, tetanus, and polio vaccines at 2, 3, and 4 months of age. Symptoms after immunisation were recorded by a parent. Sera were obtained before the first immunisation and at 5 months of age and the antibodies were measured by both radioimmunoassay and enzyme linked immunosorbent assay (ELISA). No serious adverse reactions were observed and there was no increase in the incidence of expected minor side effects. By radioimmunoassay, the geometric mean titre of serum anticapsular antibody increased from 0.09 micrograms/ml before immunisation to 5.01 micrograms/ml after three immunisations. Ninety eight per cent of children had antibody concentrations consistent with protection (greater than or equal to 0.15 micrograms/ml). IgG antibody concentrations measured by ELISA correlated well with total antibody concentrations measured by radioimmunoassay (r = 0.864). These results provide encouragement that routine immunisation against H influenzae type b at 2, 3, and 4 months of age, could prevent most cases of disease in children in the UK.

Reichert T, DeBruyère M, Deneys V, Tötterman T, Lydyard P, Yuksel F, Chapel H, Jewell D, Van Hove L, Linden J. 1991. Lymphocyte subset reference ranges in adult Caucasians. Clin Immunol Immunopathol, 60 (2), pp. 190-208. | Show Abstract | Read more

We report here the distributions of lymphocyte populations bearing the following antigens: CD3 (T cells), CD19 (B cells), CD4 (T helper/inducer cells), CD8 (T suppressor/cytotoxic and some NK cells), and CD3-, CD16+, and/or CD56+ (NK cells). At four sites, analyses were performed on healthy, normal subjects between the ages of 18 and 70, using identical flow cytometry systems and techniques. Reference ranges (unadjusted for sex differences and age variation) are CD3 (61 to 85%), CD19 (7 to 23%), NK (6 to 29%), CD4 (28 to 58%), and CD8 (19 to 48%). The lymphocyte subpopulation distributions for all antigens were found to be similar at all sites. By combining data from all sites, it has been possible to estimate age variation and sex differences for each of these subpopulations. Age and sex associated differences are substantial for some lymphocyte subsets (CD3, CD4, NK cells), and proper accounting of these effects is essential in evaluating the individual patient, if further disease-related variation is to be accurately and consistently assessed. It appears possible to recommend reference ranges for lymphocyte population parameters applicable across national and laboratory boundaries. These ranges provide a basis for comparing results from different institutions and for combining such results on subjects and patients from several institutions, provided the methodology and equipment are identical at all sites.

Chapel H, Brennan V. 1991. Self-infusion with immunoglobulin at home. J Clin Pathol, 44 (5), pp. 358-359. | Read more

Chapel H, Griffiths H, Brennan V, Bunch C, Lea J, Lee M. 1991. Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy. Immunol Invest, 20 (2), pp. 187-191. | Show Abstract | Read more

Bacterial infection is an important cause of morbidity and mortality in patients with B-cell tumors; this is related to their secondary hypogammaglobulinaemia. Two studies of intravenous replacement therapy [IVIg] have been performed in such patients: a crossover study over two years and a randomised, multicentre study over one year. Both involved infusions of IVIg [400 mg/Kg] or an equivalent volume of saline every three weeks for one year. In both studies, serious bacterial infections were considerably reduced by IVIg. Viral and fungal infections were uncommon. In the crossover study bacterial infections were more frequent in periods in which patients serum IgG levels were below the normal range [less than 6.4 g/l]. The sites of bacterial infection were similar in these studies to those in previously published reports, namely respiratory tract, skin, urinary tract and blood. There were a few mild adverse reactions which were related to the rate of infusion, but no serious toxic effects. Haematological parameters were not significantly changed by IVIg at this dose and disease progression did not appear to be changed.

Spickett G, Prentice AG, Wallington T, Webster AD, Chapel H. 1991. Alopecia totalis and vitiligo in common variable immunodeficiency. Postgrad Med J, 67 (785), pp. 291-294. | Show Abstract | Read more

Three cases of severe and irreversible alopecia occurring in patients with common variable immunodeficiency are described. In all three cases, hair loss developed after the diagnosis of immune deficiency; one of the patients also had extensive vitiligo. A fourth patient had vitiligo in the absence of alopecia. No change in the alopecia or vitiligo was noted in any patient as a result of immunoglobulin replacement therapy.

Spickett GP, Misbah SA, Chapel HM. 1991. Primary antibody deficiency in adults. Lancet, 337 (8736), pp. 281-284. | Show Abstract | Read more

Primary antibody deficiency is defined as a reduction or absence of one or more immunoglobulin isotypes or subclasses, when no other contributory disorder is present. Some patients may have normal serum immunoglobulin concentrations but do not respond appropriately to pathogens; such patients also have a primary antibody deficiency. There are three major forms of antibody deficiency: X-linked agammaglobulinaemia (XLA, Bruton's agammaglobulinaemia), common variable immunodeficiency (CVID), which includes IgG subclass and specific antibody deficiencies, and selective IgA deficiency. 1 Other antibody deficiency syndromes are rare; in most cases clinical features, diagnosis, and treatment are similar to those of the three major deficiencies. Although all primary immunodeficiencies are rare, IgA deficiency has an estimated frequency of between 1 in 320 and 1 in 800. 2 Overall, a prevalence of 11·6 per million of population is reported, of whom 6 per million have XLA, 5 per million have CVID, and the remainder have autosomal recessive antibody deficiencies. 3 Swedish data suggest a higher prevalence of 20-40 per million of population. 4 Most primary care physicians will never see a patient, and hospital specialists, other than immunologists, will see only 2 or 3 in a lifetime of practice. Consequences of delayed diagnosis are serious: in a study of 32 patients with primary antibody deficiency, more than two-thirds experienced diagnostic delay leading to serious morbidity. 5 . © 1991.

Speirs C, Fielder AH, Chapel H, Davey NJ, Batchelor JR. 1989. Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus. Lancet, 1 (8644), pp. 922-924. | Show Abstract | Read more

21 patients with systemic lupus erythematosus induced by long-term treatment with hydralazine were investigated to see whether susceptibility to this syndrome was associated with deficiency of the classical pathway complement protein, C4. 16 of 21 (76%) patients had one or more C4 null (ie, non-productive) alleles compared with 35 of 82 normal subjects (43%). This difference was significant. The HLA-DR4 antigen, known to be in linkage disequilibrium with the C4B null allele, was also significantly more frequent in the patients (14 of 21 patients compared with 31 of 81 normal subjects). Susceptibility to hydralazine-induced lupus, as in idiopathic systemic lupus erythematosus, may depend partly upon genetically determined C4 levels.

Griffiths H, Brennan V, Lea J, Bunch C, Lee M, Chapel H. 1989. Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood, 73 (2), pp. 366-368. | Show Abstract

A randomized crossover study of prophylactic immunoglobulin (IgG) therapy was performed in patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin's lymphoma (NHL). Twelve patients with hypogammaglobulinemia or a history of recurrent infections received infusions of IgG or placebo intravenously (IV) every 3 weeks for 1 year. They were then switched to the alternative preparation for another year. The number of serious bacterial infections was significantly less (P = .001; Mainland's cross-over method) in the months in which patients received IgG. Serious bacterial infections showed a trend to be associated with an IgG level less than 6.4 g/L (P = .046; Fisher's exact test).

Faux JA, Byron MA, Chapel HM. 1989. Clinical relevance of specific IgG antibodies of cardiolipin. Lancet, 2 (8677), pp. 1457-1458. | Read more

Chapel H, Brennan V, Delson E. 1988. Immunoglobulin replacement therapy by self-infusion at home. Clin Exp Immunol, 73 (1), pp. 160-162. | Show Abstract

Twelve patients, ten with common variable hypogammaglobulinaemia and two with hypogammaglobulinaemia secondary to chronic lymphocytic leukaemia (CLL), have been taught to self-infuse their intravenous immunoglobulin replacement therapy. Follow-up of these patients has shown that regular self-infusion at home is feasible and safe. There have been no anaphylactic or other serious reactions. Excellent patient compliance results from greater convenience and control over their own lives, in addition to time and money saved by the hospital.

Bonifacio E, Lernmark A, Dawkins RL. 1988. Serum exchange and use of dilutions have improved precision of measurement of islet cell antibodies. J Immunol Methods, 106 (1), pp. 83-88. | Show Abstract | Read more

In an attempt to improve the diagnostic value of measuring antibodies to islet cell cytoplasmic antigen, coded sera were distributed to 38 laboratories and results were returned for analysis. Comparison between laboratories revealed that results for some individual sera differed by up to nine doubling dilutions and even within laboratories duplicate samples could differ by six doubling dilutions. By including dilutions of sera it was possible to draw a standard curve for each laboratory and this revealed major variations in shape, slope and intercept. However, using each laboratory's standard curve and converting results to units, a substantial improvement was obtained. The approach described improves standardisation and will permit laboratories to identify poor precision and/or any systematic change in assay performance.

Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia, Gale RP, Chapel HM, Bunch C, Rai KR, Foon K, Courter SG, Tait D. 1988. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med, 319 (14), pp. 902-907. | Show Abstract | Read more

In a double-blind study, we randomly assigned 84 patients with chronic lymphocytic leukemia who were judged to be at increased risk of bacterial infection to receive intravenous immunoglobulin G (400 mg per kilogram of body weight) or a placebo every three weeks for one year. Eligible patients had hypogammaglobulinemia, a history of infection, or both. The patients receiving immunoglobulin had significantly fewer bacterial infections during the study period than those receiving placebo (23 vs. 42; P = 0.01). This reduction was most striking in the patients who completed a full year of treatment (14 vs. 36; P = 0.001). The period from study entry to the first serious bacterial infection was significantly longer in the patients receiving immunoglobulin (P = 0.026). There was no significant difference between the two groups in the incidence of nonbacterial infection. Immunoglobulin therapy was tolerated well; there were no serious adverse reactions, and the incidence of minor reactions was low. We conclude that selected patients with chronic lymphocytic leukemia who are at risk of bacterial infection can be substantially protected from this complication by the regular intravenous administration of immunoglobulin.

Chapel HM, Brennan VM. 1988. Home intravenous immunoglobulin therapy. Lancet, 2 (8625), pp. 1423. | Read more

Bunch C. 1988. Immunoglobulin replacement in chronic lymphocytic leukaemia. Nouv Rev Fr Hematol, 30 (5-6), pp. 419-422. | Show Abstract

Infection is a frequent cause of morbidity and mortality in patients with chronic lymphocytic leukaemia (CLL) and low-grade B cell lymphomas. Several factors may contribute to an increased risk of infection in individual patients but, overall, impaired antibody production--commonly manifest as hypogammaglobulinaemia--appears to be a major factor. Early studies of immunoglobulin replacement using the intramuscular route showed equivocal results. More recently, highly purified preparations of IgG have become available for intravenous use making regular replacement therapy a realistic possibility for patients at risk. We have recently undertaken a multi-centre, randomized, double-blind, placebo-controlled study of regular intravenous immunoglobulin (IVIg) replacement in patients with CLL at risk of infection as defined by presence of hypogammaglobulinaemia, a significant infection history, or both. Eighty-four patients with CLL were randomized to receive IVIg (Gammagard Baxter Healthcare Corporation Hyland Division), 400 mg/kg body weight or an equivalent volume of normal saline every 3 weeks for a year. Patients receiving IVIg showed a 45% reduction in bacterial infection during the study period (p = 0.01). In patients completing a full year of study, a 61% reduction in bacterial infection was observed (p = 0.001). A significant reduction in bacterial infection was also seen in a blinded crossover study in which 12 patients from one centre who had completed a full year in the former study were subsequently given the alternative infusion for a further year. The incidence of serious bacterial infection was significantly less during the months in which patients received IVIg compared with placebo (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Mitchell JA, Batchelor JR, Chapel H, Spiers CN, Sim E. 1987. Erythrocyte complement receptor type 1 (CR1) expression and circulating immune complex (CIC) levels in hydralazine-induced SLE. Clin Exp Immunol, 68 (2), pp. 446-456. | Show Abstract

Family studies were carried out to look at CR1 expression in 24 hydralazine-induced SLE patients (Hz Reactors), who had been off the drug for at least 1 year and were clinically well at the time of the study. Mean expression of CR1 was reduced by 27% in the group of hypertensives who had developed Hz-induced SLE compared with a group of 35 normal individuals. CR1 expression was also slightly reduced in the relatives of the Hz Reactors compared to the normal group. Using a solid-phase Clq binding assay, CIC levels were found to be elevated in the plasma of the Hz reactors and an inverse relationship was found between CR1 levels and CIC levels in this patient group. Both CR1 levels and CIC levels in Hz Reactors and normal individuals were constant over the 36 weeks studied. This study suggests that there is an association between an inability to deal efficiently with CIC and susceptibility to developing Hz-induced SLE.

Chapel HM, Warrell DA, Looareesuwan S, White NJ, Phillips RE, Supawanta V, Tharavanij S. 1987. Intrathecal immunoglobulin synthesis in cerebral malaria Clinical and Experimental Immunology, 67 (3), pp. 524-530. | Show Abstract

Local synthesis of immunoglobulin within the central nervous system has been evaluated in 37 patients with acute cerebral malaria; seven patients were also studied in the convalescent phase. There was evidence in the cerebrospinal fluid (CSF) of 21 patients that intrathecal IgG synthesis occurs in the acute phase. There was raised IgG: albumin ratios in 43% of acute patients. Oligoclonal IgG bands or cathodal IgG was seen in the CSF of 43% of patients tested by polyacrylamide electrophoresis. Only eight out of 37 acute patients (22%) had no evidence of intrathecal IgG synthesis by either method. The serial studies showed that most patients had IgG-CSF abnormalities when tested in convalescence. These studies suggest that an immune stimulus (perhaps malarial antigens or mitogens) may be present in the brain in acute cerebral malaria.

Hadley AG, Byron MA, Chapel HM, Bunch C, Holburn AM. 1987. Anti-granulocyte opsonic activity in sera from patients with systemic lupus erythematosus. Br J Haematol, 65 (1), pp. 61-65. | Show Abstract | Read more

Neutropenia is common in patients with systemic lupus erythematosus (SLE) but mechanisms of cell depletion remain obscure. To investigate the possible autoimmune aetiology of neutropenia in SLE, sera from 31 patients with this disorder were tested for anti-granulocyte activity. Granulocyte-binding immunoglobulins were detected by indirect immunofluorescence, and the ability of patient sera to opsonize granulocytes was determined by measuring the chemiluminescent response of human monocytes to granulocytes sensitized by test sera. Sera from 22 of the 31 patients bound IgG to granulocyte cell membranes and/or to nuclei, but only membrane-binding antibodies opsonized the cells for recognition by monocytes. There was no correlation between neutrophil count and the level of granulocyte-binding IgG as measured by indirect immunofluorescence. In contrast, opsonic activity and neutrophil count were inversely correlated (r = 0.5; P less than 0.05). However, opsonic activity was present in sera from most non-neutropenic patients. In patients with SLE, impaired reticuloendothelial system function may allow sensitized granulocytes to remain in the circulation.

North JP, Chapel HM. 1987. Comparison of polyacrylamide and agarose support media for detection of oligoclonal IgG bands in CSF. J Immunol Methods, 98 (1), pp. 119-122. | Show Abstract | Read more

Parallel samples of cerebrospinal fluid (CSF) from 120 patients clinically suspected of having multiple sclerosis were electrophoresed using agarose or 7% polyacrylamide. 57 samples showed oligoclonal IgG patterns in polyacrylamide but only 34 showed bands after concentration and electrophoresis in agarose. The concentrations of IgG and albumin were also measured in each sample and IgG/albumin ratios calculated. The sensitivities of the three methods for the detection of intrathecally synthesised IgG were compared. Electrophoresis in 7% polyacrylamide gave the highest proportion of significant results. In an attempt to increase the sensitivity of the agarose method, silver staining was performed on unconcentrated samples run in agarose. This did not alter the pattern of electrophoresis in samples containing oligoclonal IgG, but the sensitivity of the technique was lower than that of polyacrylamide.

Byron MA, Allington MJ, Chapel HM, Mowat AG, Cederholm-Williams SA. 1987. Indications of vascular endothelial cell dysfunction in systemic lupus erythematosus. Ann Rheum Dis, 46 (10), pp. 741-745. | Show Abstract | Read more

Fibrinolytic and other factors have been measured in 73 patients with systemic lupus erythematosus or related conditions to determine whether clinical thrombosis, a common feature of these disorders, is associated with defective fibrinolysis. Twenty five of 72 (35%) patients, compared with two of 22 (9%) controls, showed a low level of plasminogen activator activity in response to venous occlusion, suggesting decreased fibrinolytic potential. In addition, mean plasma levels of von Willebrand factor antigen and fibronectin were markedly raised in the patients (mean (SD) 384.5 (277)% and 727 (436) mg/l respectively) compared with healthy controls (100 (50)% and 306 (65) mg/l). These data suggest a degree of endothelial cell dysfunction. No clear correlation was found between a history of thrombosis and any plasma factor measured, except for prolongation of clotting tests suggestive of the 'lupus anticoagulant'.

Chapel HM, Peto TE, Luzzi GA, Thompson RA, Fielder AH, Batchelor JR. 1987. Combined familial C7 and C4B deficiency in an adult with meningococcal disease. Clin Exp Immunol, 67 (1), pp. 55-58. | Show Abstract

A case of meningococcal septicaemia is reported in an adult with a deficiency of the seventh component of complement combined with a deficiency of the B locus product of C4. A family study demonstrated that the two deficiencies were not linked. This is the first time that the individual alleles of C4 were determined in a patient with a deficiency of one component of the terminal pathway. It is possible that the heterogeneous clinical picture of a terminal pathway deficiency may, in part, be explained by the co-existence of other subtle complement defects.

Windebank KP, Faux JA, Chapel HM. 1987. ELISA determination of IgG antibodies to pneumococcal capsular polysaccharides in a group of children. J Immunol Methods, 104 (1-2), pp. 143-148. | Show Abstract | Read more

An enzyme-linked immunosorbent assay (ELISA) was developed to measure specific IgG antibody levels to pneumococcal polysaccharide antigens in 300 children attending various hospital departments. By expressing the results as a specific binding index (SBI) of given high and low controls, good reproducibility was obtained. Serum levels of the antibodies were found to fall rapidly during the 1st year of life, plateau during the 2nd and then rise steadily, reaching adult levels by the 7th year.

Khokher MA, Avasthy N, Taylor AM, Fonseca VA, Dandona P. 1987. Insulin-receptor antibody and hypoglycaemia associated with Hodgkin's disease. Lancet, 1 (8534), pp. 693-694. | Read more

Braund WJ, Naylor BA, Williamson DH, Buley ID, Clark A, Chapel HM, Turner RC. 1987. Autoimmunity to insulin receptor and hypoglycaemia in patient with Hodgkin's disease. Lancet, 1 (8527), pp. 237-240. | Show Abstract | Read more

A 76-year-old man with fasting hypoglycaemia had impaired in-vitro binding of insulin to erythrocyte receptors. The immunoglobulin fraction of his plasma inhibited binding of insulin to normal donor erythrocytes in vitro. Autoantibodies may have stimulated the insulin receptor and produced hypoglycaemia. Hodgkin's disease developed and may have induced the autoimmunity. The hypoglycaemia did not respond to plasmapheresis or azathioprine alone, but it remitted after the addition of prednisolone, and the erythrocyte receptor binding of insulin became normal.

Warrell DA, Looareesuwan S, Phillips RE, White NJ, Warrell MJ, Chapel HM, Areekul S, Tharavanij S. 1986. Function of the blood-cerebrospinal fluid barrier in human cerebral malaria: rejection of the permeability hypothesis. Am J Trop Med Hyg, 35 (5), pp. 882-889. | Show Abstract | Read more

We tested the hypothesis that cerebral malaria is caused by blood-brain barrier inflammation and cerebral edema. In a group of 157 Thai patients with strictly defined cerebral malaria, cerebrospinal fluid (CSF) opening pressures were normal in 79% and were lower in fatal cases than in survivors (means +/- 1 SD, 144 +/- 58 and 167 +/- 51 mm CSF, respectively, P = 0.051). CSF: serum albumin ratios (X 10(3)) in 39 of them were significantly higher than in 61 British controls (medians 8.5 and 5.5, respectively, P = 0.04), but were no higher in 7 fatal cases. In a group of 12 patients this ratio was not significantly higher during coma than after full recovery (means +/- 1 SD, 9.0 +/- 6.2 and 6.7 +/- 4.2, respectively, P greater than 0.1). CSF alpha 2-macroglobulin concentrations were always normal. CSF : serum 77Br- ratios were elevated in 11/19 comatose cases but fell to normal 4 to 9 days later in 11/11 cases. Dexamethasone treatment had no significant effect on bromide partition. The percentage of an intravenously administered dose of 125I-human serum albumin detectable per ml of CSF 6 hr after intravenous injection was 2.4 +/- 1.3 X 10(-5) in 14 comatose patients and 4.4 +/- 4.0 X 10(-5) in 9 of them during convalescence (P greater than 0.1). These results demonstrate that the blood-CSF barrier is essentially intact in patients with cerebral malaria and give no support to the idea that cerebral edema is the cause of coma.

Hadley AG, Holburn AM, Bunch C, Chapel H. 1986. Anti-granulocyte opsonic activity and autoimmune neutropenia. Br J Haematol, 63 (3), pp. 581-589. | Show Abstract | Read more

Sera from patients with unexplained neutropenia have been assayed for anti-granulocyte opsonic activity using a chemiluminescence technique which measures the metabolic response of human monocytes to antibody-coated granulocytes. This rapid and simple technique was more sensitive than indirect immunofluorescence in the detection of anti-granulocyte antibodies. Anti-granulocyte opsonic activity was detected in sera from 17 of 31 patients, suggesting that their neutropenia may have had an autoimmune basis. The opsonic activity of five of the 17 sera was increased when granulocytes were sensitized in the presence of fresh serum. Four of these sera bound IgM and C3b to granulocytes in the immunofluorescence test. Human IgG when added to the monocyte suspension medium inhibited monocyte response to IgG antibody-opsonized granulocytes. This inhibition was less when granulocytes were opsonized with sera containing IgM and complement granulocyte-binding activity. This observation may be relevant to the selection of neutropenic patients for therapeutic use of intravenous immunoglobulin.

MCGOVERN M, RIZZA CR, CHAPEL H, NEIL V. 1986. A SERIAL PROSPECTIVE-STUDY OF THE IMMUNE STATUS OF A SELECTED GROUP OF HEMOPHILIACS RICERCA IN CLINICA E IN LABORATORIO, 16 (1), pp. 87-88.

Ball MJ, Spriggs V, Sutton PM, Chapel H. 1986. Effect of beta-propiolactone--an inhibitor of HTLV III/LAV activity--on immunological analyses. J Immunol Methods, 95 (1), pp. 113-116. | Show Abstract | Read more

beta-Propiolactone (BPL) inactivates LAV/HTLV III, the retrovirus associated with acquired immune deficiency syndrome (AIDS). Addition to specimens from patients with suspected AIDS or antibodies to LAV/HTLV III could reduce any occupational risk to laboratory staff. This study demonstrates that BPL treatment does not significantly affect the immunological analyses commonly required on these patients, namely measurements of serum immunoglobulins, complement components C3 and C4 and other serum proteins, detection of autoantibodies and estimations of T lymphocyte subpopulations.

Esiri MM, Chapel HM, Morton JA, Wilcock GK. 1985. Non-immunoglobin in cerebrospinal fluid of patients with Alzheimer's disease and cerebral amyloid angiopathy. Lancet, 2 (8453), pp. 507-508. | Read more

Luzzi GA, Kurtz JB, Chapel H. 1985. Human parvovirus arthropathy and rheumatoid factor. Lancet, 1 (8439), pp. 1218. | Read more

BUCHANAN M, BUTT R, CHAPEL H, COATES G, HUSSEIN A, LEE GD, LOYD J, OBRODOVICH H, TAGARI P. 1985. CELLULAR MEDIATORS IN HIGH PERMEABILITY LUNG EDEMA INTERNATIONAL JOURNAL OF MICROCIRCULATION-CLINICAL AND EXPERIMENTAL, 4 (2), pp. 195-195.

HUSSEIN A, LOYD J, TAGARI P, CHAPEL H, LEE GD, BUCHANAN M, BUTT R, COATES G, OBRODOVICH H. 1984. GRANULOCYTES AND SLOW REACTING SUBSTANCES (SRS) IN HIGH PERMEABILITY LUNG EDEMA OF ADULT RESPIRATORY-DISTRESS SYNDROME (ARDS) CLINICAL SCIENCE, 67 pp. P52-P52.

Chapel HM, Esiri MM, Wilcock GK. 1984. Immunoglobulin and other proteins in the cerebrospinal fluid of patients with Alzheimer's disease. J Clin Pathol, 37 (6), pp. 697-699. | Show Abstract | Read more

Immunoglobulin has been measured and studied electrophoretically in cerebrospinal fluid (CSF) from 14 patients with Alzheimer's disease and 25 undemented controls. Presence or absence of the diagnosis of Alzheimer's disease was confirmed histologically, as these were postmortem specimens. There was no increased incidence of oligoclonal IgG bands in either group, and no significant differences in the levels of IgG and albumin. Non-immunoglobulin bands were found in the gamma region in some samples from Alzheimer's disease patients and controls; such bands are not found in the CSF from younger patients. There was a significantly increased incidence of double transferrin and double tau protein bands in the Alzheimer's group, suggesting that further studies of genetic markers might be worthwhile.

CLARK A, SMITH D, CHAPEL H. 1983. ISLET CELL AUTOANTIBODIES - WHICH METHOD LANCET, 1 (8322), pp. 479-480. | Read more

Thompson RA, Yap PL, Brettle RB, Dunmow RE, Chapel H. 1983. Meningococcal meningitis associated with persistent hypocomplementaemia due to circulating C3 nephritic factor. Clin Exp Immunol, 52 (1), pp. 153-156. | Show Abstract

Two teenage patients who presented with meningococcal meningitis were found to have persistently low C3 levels even after recovery. This was accompanied by circulating C3 nephritic factor, which persisted for more than 12 months in each case. Neither patient had evidence of partial lipodystrophy or of glomerulonephritis initially, although one patient subsequently developed mesangioproliferative glomerulonephritis following a second admission with pneumococcal pneumonia. It is possible that the generation of the nephritic factor was initiated during the presenting illness.

Emerson PM, Slack MP, Chapel HM, Mayon-White R. 1979. Trial of pneumococcal vaccine for asplenic patients. Lancet, 2 (8153), pp. 1191. | Read more

Gouilleux-Gruart V, Chapel H, Chevret S, Lucas M, Malphettes M, Fieschi C, Patel S, Boutboul D, Marson M-N, Gérard L et al. 2013. Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor. Clin Exp Immunol, 171 (2), pp. 186-194. | Show Abstract | Read more

Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An 'efficiency' index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig.

Chapel H, Lucas M, Patel S, Lee M, Cunningham-Rundles C, Resnick E, Gerard L, Oksenhendler E. 2012. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts. J Allergy Clin Immunol, 130 (5), pp. 1197-1198.e9. | Read more

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Chapel H, Lucas M, Patel S, Lee M, Cunningham-Rundles C, Resnick E, Gerard L, Oksenhendler E. 2012. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts Journal of Allergy and Clinical Immunology, 130 (5), | Read more

da Silva SP, Resnick E, Lucas M, Lortan J, Patel S, Cunningham-Rundles C, Gatter K, Liu Q, Jaffe ES, Chapel H. 2011. Lymphoid proliferations of indeterminate malignant potential arising in adults with common variable immunodeficiency disorders: unusual case studies and immunohistological review in the light of possible causative events. J Clin Immunol, 31 (5), pp. 784-791. | Show Abstract | Read more

Patients with common variable immunodeficiency disorders (CVIDs) who developed B cell lymphoproliferation of indeterminate malignant potential are described in order to raise a discussion of the relationship between infection and lymphoproliferation in infection prone patients. Those with CVID are at risk of developing either polyclonal or monoclonal lymphoproliferation in part due to the dysregulation of their adaptive immune systems. The aetiologies of the lymphoproliferations are unknown but intriguing; the relevance of infection being particularly problematic. The patients described here demonstrate variability in preceding infection, age at presentation, response to antibiotics and other types of therapy as well as outcome. The question of treatment is also controversial; issues include whether antibiotics or chemotherapy are the first line of therapy in all patients and whether transformation to aggressive B cell malignancy is inevitable or depends on other factors and if so, the length of time for such progression.

Rigaud S, Lopez-Granados E, Sibéril S, Gloire G, Lambert N, Lenoir C, Synaeve C, Stacey M, Fugger L, Stephan J-L et al. 2011. Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG. Blood, 118 (2), pp. 252-261. | Show Abstract | Read more

The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.

Dhalla F, da Silva SP, Lucas M, Travis S, Chapel H. 2011. Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme. Clin Exp Immunol, 165 (1), pp. 1-7. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy.

Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, Kim CE, Hou C, Wang F, Chiavacci R et al. 2011. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol, 127 (6), pp. 1360-7.e6. | Show Abstract | Read more

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities. OBJECTIVE: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. METHODS: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. RESULTS: Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10(-7)) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10(-16)), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. CONCLUSION: Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model.

Cited:

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Scopus

Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M, Ferry B, Kim CE, Hou C, Wang F, Chiavacci R et al. 2011. Genome-wide association identifies diverse causes of common variable immunodeficiency Journal of Allergy and Clinical Immunology, 127 (6), | Show Abstract | Read more

Background: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities. Objective: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. Methods: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. Results: Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10 -7 ) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10 -16 ), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. Conclusion: Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model. © 2011 American Academy of Allergy, Asthma & Immunology.

Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. 2010. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol, 125 (6), pp. 1354-1360.e4. | Show Abstract | Read more

BACKGROUND: Common variable immunodeficiency disorders (CVIDs) are the most common forms of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment, although there are few consistent data on optimal dosages and target trough IgG levels required for infection prevention. OBJECTIVE: To provide data to support the hypothesis that each patient requires an individual dose of therapeutic immunoglobulin to prevent breakthrough infections and that efficacious trough IgG levels vary between patients. METHODS: Data, collected prospectively from a cohort of 90 patients with confirmed CVIDs from 1 center over a follow-up period of 22 years, was validated and analyzed. Immunoglobulin doses had been adjusted in accordance with infections rather than to achieve a particular trough IgG level. Doses to achieve infection-free periods were determined and resultant trough levels analyzed. A smaller group of patients with X-linked agammaglobulinemia was analyzed for comparison. RESULTS: Patients with a CVID had a range of trough IgG levels that prevented breakthrough bacterial infections (5-17 g/L); viral and fungal infections were rare. Doses of replacement immunoglobulin to prevent breakthrough infections ranged from 0.2 to 1.2 g/kg/mo. Those with proven bronchiectasis or particular clinical phenotypes required higher replacement doses. Patients with X-linked agammaglobulinemia showed a similar range of IgG levels to stay infection-free (8-13 g/L). CONCLUSION: These data offer guidance regarding optimal doses and target trough IgG levels in individual patients with CVIDs with or without bronchiectasis and for particular clinical phenotypes. The goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level.

Packwood K, Drewe E, Staples E, Webster D, Witte T, Litzman J, Egner W, Sargur R, Sewell W, Lopez-Granados E et al. 2010. NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders. Clin Exp Immunol, 161 (3), pp. 536-541. | Show Abstract | Read more

Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.

Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L. 2008. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood, 112 (2), pp. 277-286. | Show Abstract | Read more

The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.

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