Objective We undertook this study to investigate the effect of B cell depletion on fibrosis in systemic sclerosis (SSc) and its mechanism of action. Methods Mice with bleomycin‐induced SSc (BLM‐SSc) were treated with anti‐CD20 antibody, and skin and lung fibrosis were histopathologically evaluated. T cells and macrophages were cocultured with B cells, and the effect of B cells on their differentiation was assessed by flow cytometry. We also cocultured B cells and monocytes from SSc patients and analyzed the correlation between fibrosis and profibrotic macrophage induction by B cells. Results B cell depletion inhibited fibrosis in mice with BLM‐SSc. B cells from mice with BLM‐SSc increased proinflammatory cytokine–producing T cells in coculture. In mice with BLM‐SSc, B cell depletion before BLM treatment (pre‐depletion) inhibited fibrosis more strongly than B cell depletion after BLM treatment (post‐depletion) (P < 0.01). However, the frequencies of proinflammatory T cells were lower in the post‐depletion group than in the pre‐depletion group. This discrepancy suggests that the effect of B cell depletion on fibrosis cannot be explained by its effect on T cell differentiation. On the other hand, profibrotic macrophages were markedly decreased in the pre‐depletion group compared to the post‐depletion group (P < 0.05). Furthermore, B cells from mice with BLM‐SSc increased profibrotic macrophage differentiation in coculture (P < 0.05). In SSc patients, the extent of profibrotic macrophage induction by B cells correlated with the severity of fibrosis (P < 0.0005). Conclusion These findings suggest that B cell depletion inhibits tissue fibrosis via suppression of profibrotic macrophage differentiation in mice with BLM‐SSc, providing a new rationale for B cell depletion therapy in SSc.

These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.

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Systemic sclerosis (SSc) is an autoimmune disorder characterized by excessive extracellular matrix deposition. Although SSc-associated interstitial lung disease (ILD) is one of the most important complications as a cause of death in SSc, prediction factors of treatment reactivity in SSc-ILD are still unclear. To assess relationships between interleukin (IL)-6 and reactivity to treatment, we measured serum IL-6 levels in 23 of active SSc-ILD patients under i.v. cyclophosphamide (IVCY) therapy and 20 of stabilized SSc-ILD, using the high-sensitivity enzyme-linked immunoassay system. Serum IL-6 levels in active SSc-ILD patients were significantly higher than those in stabilized SSc-ILD patients. Among active SSc-ILD patients, baseline serum IL-6 levels were not significantly different between IVCY responders and non-responders. Meanwhile, serum IL-6 levels after three IVCY doses out of a total of six were decreased in responders but not in non-responders. Regarding changes of parameters by the three doses of a total of six of IVCY, change in serum IL-6 levels correlated inversely with that in values of pulmonary function test. Thus, the rapid decrease in serum IL-6 levels during a couple of doses may predict the efficacy of IVCY therapy against SSc-ILD.

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