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The endoplasmic reticulum aminopeptidase 1 (ERAP1) performs a major role in antigen processing, trimming N-terminally extended peptides to the final epitope for presentation by major histocompatibility complex class I molecules. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within ERAP1 as being associated with disease, in particular ankylosing spondylitis (AS). AS is a polygenic chronic inflammatory disease with a strong genetic link to HLA-B27 known for over 40 years. The association of ERAP1 SNPs with AS susceptibility is only observed in HLA-B27-positive individuals, which intersect on the antigen processing pathway. Recent evidence examining the trimming activity of polymorphic ERAP1 highlights its role in generating peptides for loading onto and stabilizing HLA-B27, and the consequent alterations in the interaction of specific NK cell receptors, and the activation of the unfolded protein response as important in the mechanism of disease pathogenesis. Here, we discuss the recent genetic association findings linking ERAP1 SNPs with AS disease susceptibility and the effect of these variants on ERAP1 function, highlighting mechanisms by which AS may arise. The identification of these functional variants of ERAP1 may lead to better stratification of AS patients by providing a diagnostic tool and a potential therapeutic target.

Original publication

DOI

10.1007/s12026-014-8576-2

Type

Journal article

Journal

Immunologic research

Publication Date

12/2014

Volume

60

Pages

257 - 269

Addresses

Cancer Sciences Unit, Somers Cancer Research Building, Southampton General Hospital, Mailpoint 824, Tremona Road, Southampton, SO16 6YD, UK.

Keywords

Animals, Humans, Spondylitis, Ankylosing, Autoimmune Diseases, Aminopeptidases, Histocompatibility Antigens Class I, HLA-B27 Antigen, Minor Histocompatibility Antigens, Antigen Presentation, Polymorphism, Single Nucleotide, Genome-Wide Association Study