Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphism relevant to inflammatory disease shapes the peptidome of the birdshot chorioretinopathy-associated HLA-A∗29:02 Antigen

Abstract

Birdshot chorioretinopathy is a rare ocular inflammation whose genetic association with HLA-A∗29:02 is the highest between a disease and a major histocompatibility complex (MHC) molecule. It belongs to a group of MHCI- Associated inflammatory disorders, also including ankylosing spondylitis, psoriasis, and Behç et's disease, for which endoplasmic reticulum aminopeptidases (ERAP) 1 and/or 2 have been identified as genetic risk factors. Since both enzymes are involved in the processing of MHC-I ligands, it seems reasonable that common peptide- mediated mechanisms may underlie the pathogenesis of these diseases. In this study, comparative immunopeptidomics was used to characterize >5000 A∗29:02 ligands and quantify the effects of ERAP1 polymorphism and expression on the A∗29:02 peptidome in human cells. The peptides predominant in an active ERAP1 context showed a higher frequency of nonamers and bulkier amino acid side chains at multiple positions, compared with the peptides predominant in a less active ERAP1 background. Thus, ERAP1 polymorphism has a large influence, shaping the A∗29:02 peptidome through length-dependent and length-independent effects. These changes resulted in increased affinity and hydrophobicity of A∗29:02 ligands in an active ERAP1 context. The results reveal the nature of the functional interaction between A∗29:02 and ERAP1 and suggest that this enzyme may affect the susceptibility to birdshot chorioretinopathy by altering the A∗29:02 peptidome. The complexity of these alterations is such that not only peptide presentation but also other potentially pathogenic features could be affectedThis work was supported by grants SAF2011/25681 (Plan Nacional de I+D+i) to JALC, Binational Science Foundation Grant 2009393 to AA, and an institutional grant of the Fundacion Ramon Areces to the CBMS