Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis.

B cells play an important pathological role in rheumatoid arthritis (RA). In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA.Peripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms.Higher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared to the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression.mTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.



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Authors: Shigeru Iwata, Mingzeng Zhang, Maiko Hajime, Naoaki Ohkubo, Koshiro Sonomoto, Keiichi Torimoto, Yukihiro Kitanaga, Gulzhan Trimova, Yasuyuki Todoroki, Hiroko Miyata, Masanobu Ueno, Atsushi Nagayasu, Ryuichiro Kanda, Kazuhisa Nakano, Shingo Nakayamada, Kei Sakata, Yoshiya Tanaka