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 
MHC-I-associated inflammatory disorders, also including ankylosing spondylitis, 
psoriasis, and Behçet'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 affected.