mTORC1-phosphorylated CXCR3+memory B Cells and Their Potential as a New Mode of Action of TNF Inhibitors in RA

Shigeru Iwata¹, Mingzeng Zhang ¹, Maiko Hajime ¹, Naoaki Ohkubo ¹, Yukihiro Kitanaga ¹, Gulzhan Trimova ¹, Kazuhisa Nakano ², Shingo Nakayamada ¹, Kaoru Yamagata ¹, Kei Sakata ¹ and Yoshiya Tanaka ³, ¹The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan, Kitakyushu, Japan, ²The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan, Kitakyushu, ³University of Occupational and Environmental Health Japan, Kitakyushu, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: B cells, immunometabolism and TNF inhibitors, mTORC1, RA

Session Information

Date: Sunday, November 10, 2019

Title: RA – Etiology & Pathogenesis Poster I

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.

Disclosure: S. Iwata, None; M. Zhang, None; M. Hajime, None; N. Ohkubo, None; Y. Kitanaga, Astellas Pharm, 3; G. Trimova, None; K. Nakano, Bristol Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Pfizer, 8; S. Nakayamada, Bristol Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Pfizer, 8; K. Yamagata, None; K. Sakata, Mitsubishi Tanabe Pharma, 3; Y. Tanaka, Abbvie, 8, AbbVie, 5, 8, Asahi-kasei, 2, Asahi-Kasei, 2, Asahi-kasei, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Ono, Pfizer, Sanofi, Takeda, UCB, 2, Astellas, 8, Astellas Pharma, 9, Astellas Pharma, Inc., 2, 3, 5, 8, 9, Astellas, BMS, Chugai, Daiichi-Sankyo, Eli Lilly, Janssen, Mitsubishi-Tanabe, Pfizer, Sanofic, UCB, YL Biologics, 8, BMS, 2, 5, 8, Bristol-Myers, 2, 8, Bristol-Myers Squibb, 2, 8, Chugai, 2, 8, Daiichi-Sankyo, 2, 8, Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, 8, Eisai, 2, 8, Eli Lilly, 5, 8, Eli Lilly and Company, 8, Genzyme, 5, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi-kasei, 8, Janssen, 8, Mitsubishi-Tanabe, 2, 8, Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, Taisho-Toyama., 2, Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Abbvie, Eisai, 2, Novartis, 8, Ono, 2, Pfizer, 5, 8, Pfizer Inc, 8, Roche, 5, Sanofi, 2, Takeda, 2, 8, Teijin, 8, UCB, 2, YL Biologics, 8.

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 .

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