Objective: The basic mechanisms underlying the pathogenesis of ankylosing spondylitis (AS) remain unresolved. We previously reported an association of the single-nucleotide polymorphism (SNP) rs2549782 in the endoplasmic reticulum aminopeptidase 2 gene (ERAP2) with AS. It is known that patients homozygous for the G allele (GG) of another ERAP2 SNP, rs2248374, lack expression of ERAP2 (ERAP2 null). The present study utilized this information to study the impact of ERAP2 deficiency on HLAâB27 expression in patients with AS, specifically focusing on the functional interaction of ERAP2 and HLAâB27 in peripheral blood mononuclear cells (PBMCs) from patients with AS and assessing the effects in vitro in specific cell lines. Methods: Expression of intact peptide HLAâB27 (pB27) or the major histocompatibility complex class I free heavy chains (FHCs) was assessed in PBMCs isolated from HLAâB27âpositive patients with AS. ERAP2-suppressed, stable B27âexpressing C1R cells (C1R-B27) were tested for the expression levels of pB27 and FHCs, as well as for markers of the unfolded protein response (UPR). Distribution of the ERAP2 SNPs rs2549782 and rs2248374 in patients with AS and in patients with Crohn's disease was assessed. Results: PBMCs from AS patients lacking ERAP2 expressed higher levels of FHCs than did PBMCs from patients positive for ERAP2. This finding was replicated in C1R-B27 cells after suppression of ERAP2. In addition, ERAP2 suppression led to increased levels of the UPR markers BiP, CCAAT/enhancer binding protein homologous protein 10, and X-box binding protein 1 [spliced] as compared to that in short hairpin RNAâtreated control cells. There was strong linkage disequilibrium in the ERAP2 locus. All patients with the rs2549782 T allele (which reportedly increases the function of the ERAP-2 protein) were homozygous for the G allele of rs2248374, leading to absence of ERAP2. Conclusion: ERAP2 deficiency causes increased FHC expression and up-regulation of the UPR pathway.
|Numero di pagine||7|
|Rivista||ARTHRITIS & RHEUMATOLOGY|
|Stato di pubblicazione||Published - 2017|
All Science Journal Classification (ASJC) codes
- Immunology and Allergy