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.