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Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims peptides for MHC class I presentation, influencing the degree and specificity of CD8(+) T cell responses. Single-nucleotide polymorphisms within the exons encoding ERAP1 are associated with autoimmune diseases and cervical carcinoma, but it is not known whether they act independently or as disease-associated haplotypes. We sequenced ERAP1 from 20 individuals and show that single-nucleotide polymorphisms occur as distinct haplotypes in the human population and that these haplotypes encode functionally distinct ERAP1 alleles. Using a wide range of substrates, we are able to demonstrate that for any given substrate distinct ERAP1 alleles can be "normal," "hypofunctional," or "hyperfunctional" and that each allele has a trend bias toward one of these three activities. Thus, the repertoire of peptides presented at the cell surface for recognition by CTL is likely to depend on the precise combination of both MHC class I and ERAP1 alleles expressed within an individual, and has important implications for predisposition to disease.

Original publication

DOI

10.4049/jimmunol.1300598

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

07/2013

Volume

191

Pages

35 - 43

Addresses

Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Keywords

Cell Line, Humans, Autoimmune Diseases, Aminopeptidases, Peptides, Minor Histocompatibility Antigens, Substrate Specificity, Haplotypes, Polymorphism, Single Nucleotide, Alleles, Uterine Cervical Neoplasms, Female