Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Endoplasmic Reticulum Aminopeptidase 1 Interaction with Human Leukocyte Antigen B27 Influences the Unfolded Protein Response.
Haroon1, Nigil, Lin2, Aifeng, Akram1, Ali, Inman1, Robert D.
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is second only to HLA B27 in the strength of genetic association with ankylosing spondylitis. We have reported a functional interaction of ERAP1 with alteration in MHC-I free heavy chain and HLA-B27-peptide presentation. An aberrant UPR response has previously been reported in B27-positive cells, but the influence of ERAP1 on that response has not been resolved. Here we report the influence of ERAP1 on unfolded protein response (UPR) genes in HLA B27 transgenic mice.
HLA-B27 transgenic mice (B27tg) were developed on a MHC double knock out (DKO) strain which lacked endogenous murine class I MHC. These mice were crossed with ERAP1 -/- mice to generate the HLA-B27-ERAP-KO mice (B27tgE-). ERAP1 is known to have variation in tissue level of expression with high levels in the liver. Mesenteric lymph nodes (MLN), spleen and liver were obtained from age-matched B27tg and B27tgE- before and 5 days after intra-gastric Yersinia infection. Yersinia enterocolitica 0:8 was delivered to the mice by intragastric tube at a dose of 107 organisms. RNA was extracted from tissues and subjected to quantitative PCR with primers specific for the following markers of UPR: Bip, CHOP, XBP-1 and GADD45. b-actin expression was used a control.
There was consistent expression of all 4 genes of UPR in the tissues tested except for GADD45 expression in the spleen. In the liver which has the highest expression of ERAP1, the UPR genes were expressed at significantly higher levels in the B27tgE- compared to B27tg. The fold expression of the respective genes in the B27tg vs B27tgE- were: Bip (15.4 vs 30.2), CHOP (3.05 vs 4.9), XBP-1 (19.9 vs 53.9) and GADD45 (7.6 vs 12.2). The fold expression of UPR genes in the spleen were comparable between B27tg and B27tgE-: BiP (1.84 vs 1.70); CHOP (2.41 vs 2.20), XBP-1 (3.79 vs 3.52). MLN demonstrated higher expression of UPR genes in B27tg compared to B27tgE-: Bip (2.07 vs 1.21), CHOP: (1.96 vs 1.52), XBP-1 (2.78 vs 1.22), GADD45 (3.20 vs 1.27).
Following Yersinia infection, there was a downregulation of the UPR response genes, seen in both strains. In MLN and spleen, the degree of downregulation of UPR genes was comparable. However, in the liver the decrease in CHOP and XBP-1 following infection was significantly more pronounced in the B27tgE- (CHOP: 2.20 to 1.55 and XBP-1: 3.52 to 2.16) than in the B27tg (CHOP: 2.41 to 2.04 and XBP-1: 3.79 to 3.02).
ERAP1 variations and interaction with HLA-B27 results in functionally significant alteration of the UPR and show differential effects after gastrointestinal infection. The effects seen may be especially prominent in those tissue with higher endogenous ERAP1 expression.
To cite this abstract, please use the following information:
Haroon, Nigil, Lin, Aifeng, Akram, Ali, Inman, Robert D.; Endoplasmic Reticulum Aminopeptidase 1 Interaction with Human Leukocyte Antigen B27 Influences the Unfolded Protein Response. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1344