The role of Endoplasmic Reticulum Aminopeptidase 1(ERAP1) in Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is an inflammatory arthritis that affects the spine resulting in significant deterioration in quality of life of patients as well as accounts for significant socio-economic burden. The etiology of AS is unresolved but appears to involve both environmental and genetic factors. HLA-B27 is the strongest associated gene in AS. Recent Genome Wide Association Studies (GWAS) have implicated several other genes associated with AS thus affirming the complex, oligogenic nature of the disease. Interestingly the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) gene has the second strongest association with AS but this association is true only in HLA-B27 positive individuals. As a result there exists a strong possibility that the functional interaction of HLA-B27 and ERAP1 is pathogenic in AS. In this review we preview the biology of HLA-B27 and ERAP1 followed by a discussion of the three main hypotheses of HLA-B27 and ERAP1 interaction in the pathogenesis of AS, namely: the arthritogenic peptide, cell surface homodimer and the unfolded protein response theories of AS pathogenesis. Additionally this review seeks to provide an update on recent advances in the exciting quest to establish the role of HLA-B27 and ERAP1 in the pathogenesis of AS.