European studies in AS have shown that the A allele of rs1065407 and C allele of rs10050860 were reported as risk factors.
21,26 The difference in risk allele of
ERAP1 gene polymorphisms with AS as compared with BD is remarkable, but may be due to differences in the pathogenesis of these two disorders. In AS, peptide handling via HLA-B27 may lead to disease by a mechanism that is different from the HLA-B51–mediated peptide handling that may result in the development of BD. As mentioned above, the two SNPs influenced
ERAP1 expression. When comparing genotype effects using nonstimulated PBMCs, no effects were observed. Lipopolysaccharide stimulation raised the
ERAP1 expression regardless of the genotype investigated, whereby the rs1065407 AA genotype and rs10050860 CC genotype showed a higher
ERAP1 expression compared with the other genotypes. We studied the effect of
ERAP1 genotype on its mRNA expression in healthy controls to rule out confounding effects in patients due to the degree of inflammation and/or immunosuppressive treatment. Earlier studies demonstrated that LPS and IFN synergistically induced ERAP1 secretion from the endoplasmic reticulum in the murine macrophage cell line RAW264.7 via a Toll-like receptor–mediated signaling pathway and that the secreted ERAP1 directly enhanced the phagocytic activity of both RAW264.7 cells and murine peritoneal macrophages.
37,38 These authors noted an increased expression of
ERAP1 induced by LPS as well. Previous studies also found that peptide handling by ERAP1 might play a role in the pathogenesis of immune disorders such as AS.
34 Cancer studies revealed that the absence or downregulated expression of
ERAP1 is closely related to metastasis and invasion of lymph nodes in ovarian carcinoma.
39 Others have shown that
ERAP1 downregulation and partial HLA class I loss are associated with decreased survival in cervical carcinoma, with
ERAP1 loss being an independent predictor for survival.
40 Abrogation of endoplasmic reticulum aminopeptidase associated with antigen progressing (
ERAPP) in mice induces a conformational change in the MHC class I complexes resulting in the stimulation of both innate and adaptive immune responses and the rejection of a murine lymphoma that is otherwise refractory to immune elimination.
41 Knockout of the
ERAAP gene elicited a CD8
+ T-cell response specific for a tumor-associated antigen that is normally destroyed by ERAAP.
42 These studies support the function of
ERAP1 in antigen presentation and suggest that proper trimming and binding to HLA class I may play a role in the pathogenesis of BD. Moreover, we found that
ERAP1 expression in healthy controls was significantly higher than BD patients, which also supports the above-mentioned hypothesis.
ERAP1 SNPs may lead to alterations in
ERAP1 expression and/or function, leading to decreased trimming of relevant epitopes or altered substrate specificity. Expression within the normal range and proper functioning of
ERAP1 are probably necessary to maintain immune tolerance.