Background/Purpose ：B cells can function as potent effector cells by production of autoantibody, immune complex formation and inflammatory cytokines. Clinical efficacy of B-cell depletion therapy underscores a pathogenic role of B cells in autoimmune diseases such as rheumatoid arthritis (RA). A recent study suggests that infiltrating B cells in the joints of RA express RANKL, which plays a key role in osteoclastogenesis and inflammatory bone loss. In the RA joints, abundant accumulation of B cells expressing chemokine receptor CXCR3 was also noted, however the role of these cells in bone destruction of RA remains to be established. In this study, we have sought to elucidate the relationship of RANKL- and CXCR3-expressing B cells and their role in osteoclast differentiation.

Methods: Levels of RANKL/CXCR3 mRNA and protein in B cells from peripheral blood of normal subjects and RA patients were evaluated using quantitative RT-PCR and flow cytometry, respectively. Highly-pure B cell subsets were isolated using cell sorter. To validate the functional significance of osteoclast differentiation, B cells were co-cultured with osteoclast precursor cells and the formation of tartrate-resistant acid phosphatase (TRAP)-positive cells were assessed thereafter. 

Results: Without stimuli, freshly-isolated B cells only marginally expressed RANKL mRNA and protein. Combined stimulation of B cells with B-cell receptor (BCR) and CD40, mimicked as chronic inflammation stimuli, however, significantly induced RANKL expression. Among B cell subsets, switched-memory (CD27+IgD-) B cells, a normal counterpart of pathogenic B cells in the joints, expressed RANKL at the highest levels. Upon the same stimulation, the levels of joint-homing receptor CXCR3 increased from 30 to 80%, representing the state of activation, but not plasma cell differentiation. Switched-memory B cells of RA patients expressed higher levels of CD80/CD86 than that of healthy control. In addition, highly-activated switched-memory B cells expressing CD80/CD86 double-positive B cells from RA patients expressed RANKL and CXCR3 at higher levels than those from normal subjects. Consistent with these findings, these subsets induced osteoclast formation as assessed by TRAP staining compared with other B cell subsets.

Conclusion: Our current findings shed the light on a pathogenic role of switched-memory B cells in bone damage associated with RA via production of RANKL, and regulation of CXCR3-expressing B cells may provide a novel strategy for the treatment for this devastating disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pathogenic-role-of-cxc-chemokine-receptor-3-positive-b-cells-in-bone-destruction-of-rheumatoid-arthritis/