TLR4调控系统性红斑狼疮中自身反应性B-1a细胞活化的作用及机理研究

Activation of autoreactive B cells plays crucial roles in the disease pathogenesis of systemic lupus erythematosus (SLE). Recently, our group reported a new subset of autoreactive CXCR4+TLR4+ plasma cells in triggering lupus progression, however, the major source and underlying mechanisms of the autoreactive plasma cells are still largely unknown. Our current studies found that TLR4 was highly expressed on lupus B-1a cells, deletion of B-1a cells could significantly reduce the serum autoantibody levels and ameliorate lupus progression. Moreover, reduced renal-infiltrated B-1a cells, decreased serum autoantibody levels and ameliorated lupus progression was observed in Tlr4-/- mice with lupus induction. Further functional analysis revealed dampened anti-dsDNA IgG secretion in Tlr4-/- lupus B-1a cells. In this proposal, we aim to determine the underlying mechanisms of TLR4 activation in B-1a and the role of B-1a cell-intrinsic TLR4 pathway during the pathogenesis of lupus in both MRL/lpr mice and chromatin-induced lupus mice. The expected findings will provide novel mechanisms in understanding innate B cell activation in SLE progression and therapeutic interventions.

自身反应性B细胞的活化和大量扩增是系统性红斑狼疮发病的主要致病机理。申请人近期报道了狼疮发病进程中存在一群自身反应性CXCR4+TLR4+浆细胞的大量扩增，其来源和诱导机理尚不明确。申请人前期研究发现TLR4高表达于狼疮B-1a细胞表面，在体清除B-1a细胞能够显著降低自身抗体水平并改善狼疮发病；而Tlr4-/-狼疮鼠中B-1a细胞分泌抗dsDNA IgG抗体的能力减弱、血浆自身抗体水平降低伴随狼疮发病改善。因此，我们推测TLR4及其下游信号通路的激活介导了狼疮中B-1a细胞的活化、向靶器官的迁移及其自身抗体分泌，从而加速狼疮发病和靶器官炎症进程。为验证这一假说，我们拟在狼疮鼠中分析B-1a细胞的TLR4通路活化机理、B-1a细胞的TLR4下游关键转录因子在狼疮发病中的作用并阐明其分子机制。本研究的完成有助于深入理解固有B细胞在SLE发病中的诱导活化机理并为SLE治疗提供新线索。

本项目基于自发狼疮的MRL/Lpr鼠和诱导狼疮发病的免疫小鼠（chromatin-induced lupus， CIL）为模型，共同发现B-1a细胞在狼疮鼠中具有分泌抗磷脂抗体的能力，体内清除B-1a细胞或阻断TLR通路激活均可抑制B-1a细胞分泌抗磷脂抗体，而过继性回输抗磷脂特异性B-1a细胞则可显著加速狼疮发病。体外研究使用分离纯化的染色质组分处理狼疮B-1a细胞后，则能够诱导B-1a细胞的分化及抗磷脂抗体的分泌。后续研究通过使用阻断剂调节 TLR/Syk 轴，提示其参与 B -1a细胞分化成熟和抗磷脂抗体分泌。本项目的研究发现有助于深入理解B-1细胞的功能及其参与自身免疫反应的机制，从而为系统性红斑狼疮的临床治疗提供了新的靶点。

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