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.

Keywords: CD8+ T cells; ERAP1 and ERAP2 ER aminopeptidases; HLA class I molecules; antigen presentation; autoimmune/autoinflammatory disorders; immunopeptidome.

Figure 1

The crosstalk between different variants of ERAP1 and ERAP2 and the HLA class I molecules: contribution to the autoinflammatory/autoimmune diseases. Ankylosing Spondylitis (AS), Psoriasis (Ps), Birdshot Chorioretinopathy (BSCR) and Behçet’s disease (BD) share the association with variants of ERAP1 and ERAP2, beside the strong link with a specific HLA class I molecule, that is HLA-B*27, HLA-C*06:02, HLA-A*29:02 and HLA-B*51, respectively. Intriguingly, the contribution of ERAP1 is related both to the high or low enzymatic activity variant, partially due to the ligandome of the HLA class I involved in the disease; in fact, the former represents a risk for AS and Ps, while the latter is predisposing for BSCR and BD. The role of ERAP2 is still under investigation with no evidence of a compelling involvement in Ps and BD, while its presence seems to predispose to AS and BSCR, although combined with high or low variants of ERAP1, respectively. The arrows pointing upwards indicate allelic variants with high enzymatic activity; the arrow pointing downwards indicates allelic variants with low enzymatic activity; the question mark denotes no evidence of disease association as for BD or absence of compelling data defining the risk alleles as in Ps.