Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus.
Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus.
复制标题
Bruton的酪氨酸激酶是B细胞信号通路的一个成分，在狼疮的发病机理中具有多个作用。
DOI：
10.3389/fimmu.2017.01986
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发表时间：
2017
影响因子：
7.3
通讯作者：
Satterthwaite AB
中科院分区：
文献类型：
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作者：
Satterthwaite AB
系统性红斑狼疮(SLE)是一种自身免疫性疾病，其特征是对含有核酸的抗原失去获得性免疫耐受。由此产生的自身抗体形成免疫复合体，促进炎症和组织损伤。确定驱动致病自身抗体产生的信号是开发更有针对性的狼疮治疗方法的重要一步，目前狼疮的治疗主要是非特异性免疫抑制。在这里，我们回顾了布鲁顿酪氨酸激酶(BTK)，B细胞和髓系细胞信号通路的组成部分，在小鼠狼疮模型疾病中的作用。功能获得和功能丧失的遗传学研究都表明，BTK在自身抗体的产生中扮演着多种角色。这些包括促进自身反应性B细胞的激活、浆细胞分化和类别转换。在几种狼疮模型中，BTK的小分子抑制剂在降低自身抗体水平、B细胞激活和肾脏损伤方面都是有效的。这些研究表明，BTK可能通过促进自身抗体的产生和介导髓系细胞对这些免疫复合体的炎症反应来促进终末器官损伤。虽然在Gwas研究中，BTK与SLE没有关联，但SLE B细胞在BTK上游和下游的成分中都显示出信号缺陷，这与BTK信号通路的增强激活一致。综上所述，这些观察表明，限制BTK活性对于维持B细胞耐受和预防自身免疫性疾病的发展至关重要。BTK抑制剂一般耐受性良好，并被批准用于治疗B细胞恶性肿瘤，因此可能是一种有用的SLE治疗方法。
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of adaptive immune tolerance to nucleic acid-containing antigens. The resulting autoantibodies form immune complexes that promote inflammation and tissue damage. Defining the signals that drive pathogenic autoantibody production is an important step in the development of more targeted therapeutic approaches for lupus, which is currently treated primarily with non-specific immunosuppression. Here, we review the contribution of Bruton’s tyrosine kinase (Btk), a component of B and myeloid cell signaling pathways, to disease in murine lupus models. Both gain- and loss-of-function genetic studies have revealed that Btk plays multiple roles in the production of autoantibodies. These include promoting the activation, plasma cell differentiation, and class switching of autoreactive B cells. Small molecule inhibitors of Btk are effective at reducing autoantibody levels, B cell activation, and kidney damage in several lupus models. These studies suggest that Btk may promote end-organ damage both by facilitating the production of autoantibodies and by mediating the inflammatory response of myeloid cells to these immune complexes. While Btk has not been associated with SLE in GWAS studies, SLE B cells display signaling defects in components both upstream and downstream of Btk consistent with enhanced activation of Btk signaling pathways. Taken together, these observations indicate that limiting Btk activity is critical for maintaining B cell tolerance and preventing the development of autoimmune disease. Btk inhibitors, generally well-tolerated and approved to treat B cell malignancy, may thus be a useful therapeutic approach for SLE.