6533b850fe1ef96bd12a83c9

RESEARCH PRODUCT

Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA-B27 Activates the Unfolded Protein Response.

Dm Nigil Haroon Md. PhdGiuliana GugginoFanxing ZengKirby YeeZhenbo ZhangFrancesco CicciaGiovanni TrioloRiccardo AlessandroHasan AbdullahMark S. Silverberg

subject

0301 basic medicineMaleX-Box Binding Protein 1Aminopeptidases0302 clinical medicineImmunology and AllergyRNA Small InterferingEndoplasmic Reticulum Chaperone BiPHLA-B27 AntigenHeat-Shock ProteinsAlleleBlottingReverse Transcriptase Polymerase Chain ReactionHeat-Shock ProteinSingle NucleotideMiddle AgedFlow CytometryCCAAT-Enhancer-Binding Protein3. Good healthUp-RegulationFemaleWesternHumanAnkylosingAdultAminopeptidaseMononuclearImmunologyBlotting WesternSingle-nucleotide polymorphismBiologyMajor histocompatibility complexSmall InterferingPolymorphism Single NucleotideAdult; Alleles; Aminopeptidases; Blotting Western; CCAAT-Enhancer-Binding Proteins; Cell Line; Female; Flow Cytometry; HLA-B27 Antigen; Heat-Shock Proteins; Humans; Leukocytes Mononuclear; Male; Middle Aged; Polymorphism Single Nucleotide; RNA Small Interfering; Reverse Transcriptase Polymerase Chain Reaction; Spondylitis Ankylosing; Unfolded Protein Response; Up-Regulation; X-Box Binding Protein 1; Immunology and Allergy; Rheumatology; ImmunologyCell Line03 medical and health sciencesDownregulation and upregulationRheumatologyHumansSpondylitis AnkylosingAllelePolymorphismAlleles030203 arthritis & rheumatologySpondylitiHLA-B27LeukocyteEndoplasmic reticulum aminopeptidase 2X-Box Binding Protein 1Molecular biologySettore MED/16 - Reumatologia030104 developmental biologyUnfolded protein responsebiology.proteinCCAAT-Enhancer-Binding ProteinsLeukocytes MononuclearUnfolded Protein ResponseRNA

description

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 HLA–B27 expression in patients with AS, specifically focusing on the functional interaction of ERAP2 and HLA–B27 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 HLA–B27 (pB27) or the major histocompatibility complex class I free heavy chains (FHCs) was assessed in PBMCs isolated from HLA–B27–positive patients with AS. ERAP2-suppressed, stable B27–expressing 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 RNA–treated 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.

yearjournalcountryeditionlanguage
2017-01-01Arthritisrheumatology (Hoboken, N.J.)
10.1002/art.40033https://pubmed.ncbi.nlm.nih.gov/28029742