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.

ERAP1 Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis

“…Except for several recent studies (24,25,38), all others have investigated the functional consequences of individual SpA-associated SNPs in the ERAP1 gene (11,(21)(22)(23)39). Using a large case-control cohort from the Immunochip study, we identified strong linkage disequilibrium in the ERAP1 region, as previously described (19).…”

“…Several studies using recombinant ERAP-1 mutants and synthetic peptides showed decreased enzymatic activity of ERAP-1 in the presence of the AS-protective alleles rs30187 and rs17482078 (11,(21)(22)(23)(24)(25). It has been suggested that the reduced activity observed with the rs30187 protective allele (K528R) was linked to modifications in the structure of ERAP-1 (21,26).…”

ERAP1/ERAP2 and RUNX3 polymorphisms are not associated with ankylosing spondylitis susceptibility in Chinese Han

“…The combined risk of ERAP1/ERAP2 and HLA‐B27 in AS is up to 70% in European populations 52, 53, and these two factors are now presumed to be the main risk alleles for AS. As mentioned above, combining earlier data from Lin et al .…”

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Seregin and co-workers observed, using an in vitro cellbased antigen presentation system, that the high AS-risk ERAP1 allotype (Met349/Lys528/Asp575/Arg725/Gln730) compared with the low AS-risk allotype (Val349/Arg528/ Asn575/Gln725/Glu730) influenced antigen presentation by destroying more rapidly the majority of HLA-B27 peptides, whether from viral, bacterial or self-origin [108]. Hence, the authors speculated that the co-existence of B27 molecules and ERAP1 allotypes with enhanced enzymatic activity alters the normal presentation of microbial and self-peptides to the adaptive immune system setting the conditions to autoimmunity [108].…”

“…Hence, the authors speculated that the co-existence of B27 molecules and ERAP1 allotypes with enhanced enzymatic activity alters the normal presentation of microbial and self-peptides to the adaptive immune system setting the conditions to autoimmunity [108].…”