ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2082

ERAP1 Deficiency Partially Relieves HLA-B27-Induced ER Stress and IL-23 Expression, but Does Not Restore Dendritic Cell Function in Experimental Spondyloarthritis

Tri Tran1, Vance Holt2, Tejpal Gill1, Joshua R. Bennett2, Joel Taurog3 and Robert Colbert4, 1National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 2National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 3Dept Int Med-Rheum Dis Div, University of Texas Southwestern Medical Center, Dallas, TX, 4National Institute of Arthritis and Musculuskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Date: Tuesday, October 23, 2018

Title: Spondyloarthritis Including Psoriatic Arthritis – Basic Science Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Preliminary results suggest that endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) deficiency partially protects HLA-B27/human b2m transgenic (B27-Tg) rats from spondyloarthritis (SpA) as evidenced by a reduced frequency of arthritis and orchitis, but not gastrointestinal inflammation. Protection is associated with reduced HLA-B27 misfolding and unfolded protein response (UPR) activation in rat bone marrow macrophages (BMM). Here, we investigated whether ERAP1 deficiency impacts HLA-B27 misfolding-induced IL-23p19 expression in rat BMMs, and/or defective dendritic cell (DC) costimulatory function , both of which have been linked to pathogenesis.

Methods: BMMs from 2-3 month old B27-Tg rats, with ERAP1+/+ and ERAP1-/- genotypes were pre-treated with IFNg (18 hrs) then stimulated with LPS for up to 8 hrs. Relative expression of mRNAs for IL-23p19, BiP, and CHOP were measured by RT-qPCR. Allogeneic DC function was measured using splenic DCs purified from wild type (WT) and B27-Tg rats with ERAP1+/+ and ERAP1-/- genotypes using Nycodenz followed by magnetic separation with anti-CD103 (OX62 Ab) microbeads. Resting CD4+ T-cells from Dark Agouti (DA) WT rats were purified by negative selection employing a combination of OX33, OX42, 3.2.3, and OX8 antibodies. DCs at 0, 1, 3, 10, 30 (x103) cells were co-cultured with 1×105 CD4+ T-cells for 5 days; proliferation of T-cells was analyzed by cell counting using IncuCyte.

Results: ERAP1 deficiency reduced LPS-induced IL-23p19 mRNA expression by about 50% (p<0.05) in BMMs from B27-Tg rats, as well as UPR genes BiP and CHOP by 30% (p<0.05). DCs from B27-Tg rats (ERAP1+/+) showed a significant defect in stimulating T-cell proliferation compared to DCs from WT (ERAP1+/+) rats (p<0.05), confirming previous results. However, ERAP1 deficiency did not restore the function of B27-expressing DCs, as there was no improvement in T-cell proliferation.

Conclusion: These results implicate ERAP1 function in modulating aberrant HLA-B27 folding and its effects on IL-23 induction, possibly through UPR activation, in B27-Tg rats. These effects of ERAP1 on HLA-B27 are associated with partial reduction of the experimental SpA phenotype (arthritis and orchitis) but not gastrointestinal inflammation.

Disclosure: T. Tran, None; V. Holt, None; T. Gill, None; J. R. Bennett, None; J. Taurog, AbbVie, Inc, 2, 9,Novartis, Inc, 9; R. Colbert, None.

To cite this abstract in AMA style:

Tran T, Holt V, Gill T, Bennett JR, Taurog J, Colbert R. ERAP1 Deficiency Partially Relieves HLA-B27-Induced ER Stress and IL-23 Expression, but Does Not Restore Dendritic Cell Function in Experimental Spondyloarthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/erap1-deficiency-partially-relieves-hla-b27-induced-er-stress-and-il-23-expression-but-does-not-restore-dendritic-cell-function-in-experimental-spondyloarthritis/. Accessed .

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/erap1-deficiency-partially-relieves-hla-b27-induced-er-stress-and-il-23-expression-but-does-not-restore-dendritic-cell-function-in-experimental-spondyloarthritis/