Opposing Roles of TLR7 and TLR9 Signaling in Systemic Lupus Erythematosus

描述(申请人提供)：最近发现系统性红斑狼疮中抗RNA和DNA自身抗原的自身抗体的产生依赖于通过TLR7和TLR9的信号。基因敲除研究意外地证明，尽管TLR9有助于产生抗DNA抗体，但它具有整体保护作用，而TLR7信号有助于疾病和抗RNA抗体的产生。这些发现令人惊讶，因为这两种受体被认为具有相似的表达模式和下游信号通路。这里提出的研究将剖析这两个先天免疫信号分子对复杂狼疮疾病表型的贡献。我们将通过同时敲除狼疮小鼠模型中的两个受体来检查这两个信号之间的遗传交互作用。我们将通过混合骨髓嵌合体和细胞类型特异性消融来确定这两种受体在B细胞和髓系细胞中的细胞特异性作用。最后，我们将探讨TLR9和TLR7在狼疮发病机制中发挥不同作用的可能机制。这些研究将增加我们对狼疮发病机制的了解，从而可能为合理的药物设计找到新的治疗靶点。世俗描述：系统性红斑狼疮是一种自身免疫性疾病，每10万名美国人中就有40人受到影响。最近的工作已经确定了免疫系统的两个基因，它们通常参与检测感染，这两个基因在狼疮的发生和发展中至关重要。这里描述的实验将扩大和加强我们对这些基因在自身免疫性疾病中的作用的理解，从而可能导致改进狼疮和其他相关疾病的治疗策略。

DESCRIPTION (provided by applicant): Production of autoantibodies to RNA and DNA self-antigens in systemic lupus erythematosus has recently been shown to be dependent on signals through TLR7 and TLR9. Knockout studies unexpectedly demonstrated that TLR9 has an overall protective effect despite its contribution to anti-DNA antibody production, while TLR7 signals contribute to disease and anti-RNA antibody production. These findings were surprising, as the two receptors are thought to have similar expression patterns and downstream signaling pathways. The studies proposed here will dissect the contributions of these two innate immune signaling molecules to the complex lupus disease phenotype. We will examine the genetic interaction between the two signals by simultaneous knockout of both receptors in a mouse model of lupus. We will determine the cell-specific roles of the two receptors in B cells and myeloid cells through mixed bone marrow chimeras and cell-type specific ablation of the receptors. Finally, we will examine possible mechanisms by which TLR9 and TLR7 can exert their differential effects on lupus pathogenesis. These studies will increase our understanding of the mechanisms of lupus pathogenesis and may therefore lead to identification of new treatment targets for rational drug design. Lay description: Systemic lupus erythematosus is an autoimmune disease affecting as many as 40 in 100,000 Americans. Recent work has identified two genes of the immune system normally involved in detecting infection which are critically important in the initiation and progression of lupus. The experiments described here will expand and enhance our understanding of the effects of these genes on autoimmune disease and may thereby lead to improved treatment strategies for lupus and other related diseases.