Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Currently, both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear. In this study, we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A (IL-17) stimulation in SLE patients and lupus mice. Using a humanized lupus mouse model, we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs. Moreover, long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU⁺ subsets among IL-17 receptor-expressing plasma cells. Lupus mice deficient in IL-17 or IL-17 receptor C (IL-17RC) exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage, while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice. In reconstituted chimeric mice, IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells. Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization. Together, our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis, which may provide new therapeutic strategies for the treatment of SLE.

最近的研究表明，浆细胞在自身免疫性疾病如系统性红斑狼疮 (SLE) 的发展中发挥着核心作用。目前，SLE 发病过程中自身反应性浆细胞的表型特征和功能调节仍不清楚。在这项研究中，我们首先发现在 SLE 患者和狼疮小鼠中，IL-17A (IL-17) 刺激后，表达 IL-17 受体的浆细胞的主要子集有效地产生抗 dsDNA IgG。使用人源化狼疮小鼠模型，我们发现与总 SLE PBMC 的转移相比，从狼疮患者转移 Th17 细胞耗尽的 PBMC 会导致受体小鼠的浆细胞反应显着降低并减轻肾损伤。此外，在狼疮小鼠中长期掺入 BrdU 检测到高度富集的长寿命 BrdU⁺表达 IL-17 受体的浆细胞中的亚群。缺乏 IL-17 或 IL-17 受体 C (IL-17RC) 的狼疮小鼠表现出浆细胞反应减弱和自身抗体产生减少，肾损伤减轻，而 Th17 细胞的过继转移引发了浆细胞反应和 IL 中的肾损伤-17-缺陷型狼疮小鼠。在重组嵌合小鼠中，IL-17RC 缺乏导致浆细胞生成严重受损，但对生发中心 B 细胞没有明显影响。进一步的机制研究表明，IL-17 通过 p38 介导的 Bcl-xL显着促进浆细胞存活转录稳定。总之，我们的研究结果确定了 IL-17 在增强浆细胞存活以在狼疮发病机制中产生自身抗体方面的新功能，这可能为 SLE 的治疗提供新的治疗策略。