Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: B cells play a crucial role through producing autoantibodies and activating osteoclasts in synovium in rheumatoid arthritis (RA). Recently “Immunometabolism” attract much attention, and mTORC1 is well known as a key player for anabolic change and contributes to B cell activation. However, it remained elusive by which mTORC1 in B cells involved in the pathogenesis of RA.
Methods: PBMCs were obtained from 32 healthy controls (HCs) and 86 patients with RA who were refractory to MTX-treatment and bio-naïve, and analyzed by flow cytometry. In addition, we examined the role of mTORC1 for induction of chemokine receptors on B cells in vitro.
Results: Baseline characteristics of patients with RA in this study were males : females =21:65, age 55.8 years, disease duration 55.8 months, stage I/II/III/ Ⅳ:35/33/9/9, MTX dose 13.8mg/week, tender joints 9.1, swollen joints 7.2, DAS28-CRP 4.7, DAS28-ESR 5.4, CDAI 25.9, SDAI 28.2, RF169.6, anti-CCP Abs 336.0, HAQ 1.2. The percentage of CXCR3+CD27+CD19+ cells among CD19+ cells decreased in the periphery of patients with RA compared to those of HCs. The level of mTORC1 phosphorylation (p-mTORC1) enhanced in CXCR3+CD27+CD19+ cells, but not in CXCR3–CD27+CD19+ cells from patients with RA. The level of p-mTORC1 in CXCR3+CD27+CD19+ cells were correlated with tender joints, swollen joints, disease activity such as DAS28-CRP, CDAI, SDAI, but not RF and anti-CCP antibodies. We examined the change of percentage of CXCR3+CD27+CD19+ cells and the level of p-mTORC1 before and at 1 year after treatment with biologics (37 patients, TNF inhibitors (n=19: adalimumab:11, certolizumab:7, etanercept:1), abatacept (n=16), tocilizumab (n=2)). The percentage of CXCR3+CD27+CD19+ cells were recovered and the level of p-mTORC1 decreased selectively in TNF inhibitors treatment group, but not in abatacept treatment group at 1 year. Finally, we examined the role of mTORC1 for induction of chemokine receptor expression on B cells in vitro. Combined stimulation of BCR, CD40L and IFN-γ induced CXCR3 expression on B cells, which were abrogated by mTORC1 inhibitors, Rapamycin. It has been reported that concentration of CXCL10 (IP-10), ligand of CXCR3, increased in RA synovium. We found that TNF-α stimulation induced CXCL10 production from RA patients-derived fibroblast like synoviocytes (FLS), which was abrogated by TNF inhibitors.
Conclusion: Taken together, activation of mTORC1 is involved in the accumulation of CXCR3-positive memory B cells in RA synovium and TNF inhibitors possibly target at this in patients with RA.
To cite this abstract in AMA style:Iwata S, Zhang M, Hajime M, Ohkubo N, Kitanaga Y, Trimova G, Nakano K, Nakayamada S, Yamagata K, Sakata K, Tanaka Y. mTORC1-phosphorylated CXCR3+memory B Cells and Their Potential as a New Mode of Action of TNF Inhibitors in RA [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/mtorc1-phosphorylated-cxcr3memory-b-cells-and-their-potential-as-a-new-mode-of-action-of-tnf-inhibitors-in-ra/. Accessed November 13, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mtorc1-phosphorylated-cxcr3memory-b-cells-and-their-potential-as-a-new-mode-of-action-of-tnf-inhibitors-in-ra/