Dataset Information

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

ABSTRACT: Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ?0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self-derived peptides by the adaptive immune system.

SUBMITTER: Seregin SS

PROVIDER: S-EPMC4104477 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

Seregin Sergey S SS Rastall David P W DP Evnouchidou Irini I Aylsworth Charles F CF Quiroga Dionisia D Kamal Ram P RP Godbehere-Roosa Sarah S Blum Christopher F CF York Ian A IA Stratikos Efstratios E Amalfitano Andrea A

Autoimmunity 20130913 8

Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ∼0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 a ...[more]

PMID: 24028501

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Project description:BackgroundThe association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort.MethodsA total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects.ResultsA strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10-244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10-19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10-4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10-241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians.ConclusionsThis study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.

Dataset Information

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

Publications

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

Similar Datasets

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