The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

Abstract

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.

The association of Behçet's syndrome with HLA-B51 as understood in 2021

“…These diseases are also similar in other susceptibility genes, including the IL-17/23 pathway, distribution of affected organs, and some therapeutic approaches [ 32 ]. However, ERAP2, which has complementary and partially redundant effects of ERAP1 on the MHC-class I peptidome, also showed a significant association with ankylosing spondylitis and psoriasis but not with Behçet's syndrome [ 33 , 34 ]. The concept of MHC-I-opathy may be helpful for understanding the pathogenesis of MHC-class I-associated diseases more than in their clinical aspects.…”

HLA-A29 Birdshot Retinochoroiditis in Its 5th Decade: Selected Glimpses into the Intellectual Meanderings and Progresses in the Knowledge of a Long-Time Misunderstood Disease

“…Although it is not the place in this clinical perspective to give a detailed account on the immunopathogenesis of the disease, it should be briefly cited. The topic has been thoroughly investigated by Kuiper’s group and others [ 38 , 39 , 40 ]. The presence of the HLA-A29 antigen is not the only predisposing factor to develop BRC.…”

Know thy immune self and non‐self: Proteomics informs on the expanse of self and non‐self, and how and where they arise

“…[ 143 , 144 , 145 ] and reviewed in refs. [ 146 , 147 , 148 ]). The gene coding for ERAP1, more than ERAP2, is polymorphic (reviewed in refs.…”

“…The gene coding for ERAP1, more than ERAP2, is polymorphic (reviewed in refs. [ 146 , 147 , 148 ]). Amino acid altering differences map either directly to ERAP1's enzymatic site, substate‐binding site, or sites that can impact these activities (refs.…”