ERAP1 in the pathogenesis of ankylosing spondylitis

Emma Reeves, Tim Elliott, Edward James, Christopher J. Edwards

The endoplasmic reticulum aminopeptidase 1 (ERAP1) performs a major role in antigen processing, trimming N-terminally extended peptides to the final epitope for presentation by major histocompatibility complex class I molecules. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within ERAP1 as being associated with disease, in particular ankylosing spondylitis (AS). AS is a polygenic chronic inflammatory disease with a strong genetic link to HLA-B27 known for over 40 years. The association of ERAP1 SNPs with AS susceptibility is only observed in HLA-B27-positive individuals, which intersect on the antigen processing pathway. Recent evidence examining the trimming activity of polymorphic ERAP1 highlights its role in generating peptides for loading onto and stabilizing HLA-B27, and the consequent alterations in the interaction of specific NK cell receptors, and the activation of the unfolded protein response as important in the mechanism of disease pathogenesis. Here, we discuss the recent genetic association findings linking ERAP1 SNPs with AS disease susceptibility and the effect of these variants on ERAP1 function, highlighting mechanisms by which AS may arise. The identification of these functional variants of ERAP1 may lead to better stratification of AS patients by providing a diagnostic tool and a potential therapeutic target.