University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Keio University School of Integrated Design Engineering, Tokyo, Japan.
Arthritis Rheumatol. 2021 Nov;73(11):2086-2095. doi: 10.1002/art.41798. Epub 2021 Sep 28.
We undertook this study to investigate the effect of B cell depletion on fibrosis in systemic sclerosis (SSc) and its mechanism of action.
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.
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).
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.
本研究旨在探讨 B 细胞耗竭对系统性硬皮病（SSc）纤维化的影响及其作用机制。
采用博来霉素诱导的 SSc（BLM-SSc）小鼠模型，用抗 CD20 抗体进行治疗，并对皮肤和肺纤维化进行组织病理学评估。将 T 细胞和巨噬细胞与 B 细胞共培养，通过流式细胞术评估 B 细胞对其分化的影响。我们还共培养了 SSc 患者的 B 细胞和单核细胞，并分析了 B 细胞诱导纤维化与成纤维细胞样巨噬细胞诱导之间的相关性。
B 细胞耗竭抑制 BLM-SSc 小鼠的纤维化。BLM-SSc 小鼠的 B 细胞在共培养中增加了促炎细胞因子产生的 T 细胞。在 BLM-SSc 小鼠中，BLM 治疗前（预耗竭）的 B 细胞耗竭比 BLM 治疗后（后耗竭）的 B 细胞耗竭更强烈地抑制纤维化（P < 0.01）。然而，在后耗竭组中促炎 T 细胞的频率低于预耗竭组。这种差异表明，B 细胞耗竭对纤维化的影响不能用其对 T 细胞分化的影响来解释。另一方面，与后耗竭组相比，预耗竭组中的成纤维细胞样巨噬细胞明显减少（P < 0.05）。此外，BLM-SSc 小鼠的 B 细胞在共培养中增加了成纤维细胞样巨噬细胞的分化（P < 0.05）。在 SSc 患者中，B 细胞诱导成纤维细胞样巨噬细胞分化的程度与纤维化的严重程度相关（P < 0.0005）。
这些发现表明，B 细胞耗竭通过抑制 BLM-SSc 小鼠中成纤维细胞样巨噬细胞的分化来抑制组织纤维化，为 SSc 的 B 细胞耗竭治疗提供了新的理论依据。
