Abstract
Virtually all patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. To investigate the relationship between both risk factors we employed label-free quantitative mass spectrometry to characterize the effects of ERAP2 on the A*29:02-bound peptidome. An ERAP2-negative cell line was transduced with lentiviral constructs containing GFP-ERAP2 or GFP alone, and the A*29:02 peptidomes from both transduced cells were compared. A similar analysis was performed with two additional A*29:02-positive, ERAP1-concordant, cell lines expressing or not ERAP2. In both comparisons the presence of ERAP2 affected the following features of the A*29:02 peptidome: 1) Length, with increased amounts of peptides >9-mers, and 2) N-terminal residues, with less ERAP2-susceptible and more hydrophobic ones. The paradoxical effects on peptide length suggest that unproductive binding to ERAP2 might protect some peptides from ERAP1 over-trimming. The influence on N-terminal residues can be explained by a direct effect of ERAP2 on trimming, without ruling out and improved processing in concert with ERAP1. The alterations in the A*29:02 peptidome suggest that the association of ERAP2 with BSCR is through its effects on peptide processing. These differ from those on the ankylosing spondylitis-associated HLA-B*27. Thus, ERAP2 alters the peptidome of distinct HLA molecules as a function of their specific binding preferences, influencing different pathological outcomes in an allele-dependent way.
Highlights
All patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele
Transduction of ERAP2 in A*29:02-positive lymphoblastoid cell line (LCL)—PF cells were transduced with a lentiviral construct including the GFP and ERAP2 (392K variant) genes (PF-ERAP2), and another containing only GFP (PF-GFP), as control
Lentiviral transduction of an ERAP2-negative, HLA-A*29: 02-positive, LCL expressing highly active ERAP1 variants was used in this study to characterize the effects of ERAP2 on the A*29:02 peptidome
Summary
All patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. A similar analysis was performed with two additional A*29:02-positive, ERAP1-concordant, cell lines expressing or not ERAP2 In both comparisons the presence of ERAP2 affected the following features of the A*29:02 peptidome: 1) Length, with increased amounts of peptides >9-mers, and 2) N-terminal residues, with less ERAP2-susceptible and more hydrophobic ones. The alterations in the A*29:02 peptidome suggest that the association of ERAP2 with BSCR is through its effects on peptide processing. Birdshot chorioretinopathy (BSCR) is a rare form of chronic posterior uveitis of unknown etiology, leading to progressive inflammation of the posterior eye segment and retinal atrophy This disease presents chorioretinal hypopigmented lesions scattered throughout the fundus. BSCR is very strongly associated with HLA-A*29:02 [10] This allele is frequent (about 7%) in European populations, but only a very small percentage of A*29:02-positive individuals develop the disease.
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