The MHC (Major Histocompatibility Complex) class I and II molecules, known as HLA (Human Leucocyte Antigen) in humans, are essential for promoting specific immunity; in particular, HLA class I molecules elicit CD8⁺ T cell responses directed against epitopes, usually nine residues in length, derived from endogenously synthesized microbial or cellular proteins [1]. These peptides, upon the N-terminal refinement by the Endoplasmic Reticulum Aminopeptidases (ERAP) 1 and 2, are accommodated into the groove of the HLA class I molecules through the so-called “anchor” residues that are embedded into specific pockets [2]. In particular, residues at position 2 (P2) and at the carboxy-terminal (PΩ) are pivotal for the correct placement of the peptides through connections with the B and F pocket, respectively [3,4]. The binding motif is generally conserved for each HLA allele. However, some circumstances, such as an inflammatory environment or the use of specific drugs concomitantly with particular ERAP1 and ERAP2 haplotypes, could allow the binding cleft to assume conformations that can become permissive for unconventional peptides. In this context, it is of interest the case of drug-hypersensitivity induced by abacavir in HLA-B*57:01 positive subjects or by carbamazepine in HLA-B*15:02 carriers [5]. In particular, the non-covalent interaction of the drug with the F pocket of HLA-B*57:01 dramatically alters the self-epitope repertoire displayed by the HLA molecule creating foreign complexes, which induce robust T cell responses in the HLA-B*57:01 carriers taking abacavir [6–8]. Moreover, several viruses (i.e., HIV, CMV, EBV) could contribute to the alteration of the peptide repertoire establishing their strategies to escape immune surveillance [9].

Ankylosing Spondylitis (AS), Psoriasis (Ps), Birdshot Chorioretinopathy (BSCR) and Behҫet’s disease (BD) are referred as “MHC-I-opathies” as they share an association with HLA-class I genes, in particular HLA-B*27, HLA-C*06:02, HLA-A*29:02 and HLA-B*51, respectively [10]. Such diseases also share ERAP1 and, in some cases, ERAP2 as susceptibility factors and display as overlapping common targets, tissues undergoing either mechanical (enthesis and bone) or environmental stress such as skin, oral mucosa, gut and eye. In spite of different manifestations, a common basis of these diseases at the crossroads between the innate and adaptive immune system, which culminates in the typical chronic inflammation, has been suggested [10].

Over time, several case-control association analyses and Genome-Wide Association Studies (GWAS) have robustly shown associations of Single Nucleotide Polymorphisms (SNPs) in ERAP1 and/or ERAP2 genes or even of entire haplotypes with the above-mentioned diseases [11–18]. Functional effects of this ERAP1 and 2 variance has also been investigated but little is known about the molecular mechanisms in the critical cells. Moreover, few genetic studies have been focused on ERAP gene promoters and on the mechanisms regulating gene expression [19]. In the case of ERAP1, ten haplotypes (Hap1 to Hap10), derived from a combination of multiple non-synonymous SNPs, account for over 99% of the natural ERAP1 variants; however, the association of these haplotypes with each disease is quite different [20]. The striking association with HLA class I molecules and the involvement of ERAPs would point out a central role for CD8⁺ T cells or even Natural Killer (NK) cells in tissue-specific damage. Accordingly, an altered antigen presentation could be one of the possible mechanisms behind the autoimmune injury caused by some haplotypes of ERAP1 and ERAP2, which are pivotal in the processing of HLA class I epitopes. In fact, an altered pool of peptides accounting for the ‘mis-immunopeptidome’ that ranges from suboptimal to pathogenetic/harmful peptides could be 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 [21].

References

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This entry is adapted from the peer-reviewed paper 10.3390/ijms21249608