TLR-Dependent Dendritic Cell Activation in SLE

系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病，发病率高，甚至死亡率高。目前的治疗包括具有许多严重副作用的非特异性免疫抑制。此外，对治疗的反应往往是不完全的。因此，需要更具体和毒性更小的治疗。SLE自身抗原（DNA/蛋白或RNA/蛋白）与自身抗体结合形成的免疫复合物（IC）对树突状细胞（DC）的异常激活被认为在SLE发病机制中起关键作用。我们已经确定了新的途径参与这种DC激活的DNA/蛋白质含有IC。一种主要途径涉及DC表面上Fc γ受体III的IC接合，随后将复合物内的DNA递送至细胞内Toll样受体9（TLR 9）。该应用程序的目标是获得这种相互作用的机制和后果的详细了解，并确定是否类似的两个受体的双重参与机制适用于DC 通过含有RNA/蛋白质的IC激活。具体目标1比较了含DNA/蛋白质和RNA/蛋白质的IC对来自野生型、TLR 9缺陷型、TLR 3缺陷型和各种Fc γ受体缺陷型小鼠的各种DC亚群的功能作用。将测试新型抑制剂阻断这种激活的能力。 具体目标2比较了Fc γ受体介导的和Fc γ受体非依赖性的抗原摄取，特别是关于将抗原递送至含TLR 9的亚细胞区室。这对T细胞活化的影响将被确定。在具体的目的3中，TLR 9介导的DC活化（与TLR 9介导的B细胞活化相比）在SLE发病机制中的相对重要性将使用DC过继转移实验以及通过其中TLR 9在DC中被特异性“敲除”的小鼠的发育来确定。预计这些研究将提高对SLE发病机制的认识，并有助于开发新的有效，更安全和更特异性的治疗方法。

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with appreciable morbidity and even mortality. Current treatment comprises non-specific immunosuppression with many serious side-effects. Furthermore, response to therapy is often incomplete. More specific, and less toxic therapies are thus required. Aberrant dendritic cell (DC) activation by immune complexes (IC) containing the prototypic autoantigens in SLE (DNA/protein or RNA/protein) bound to autoantibody is believed to play a key role in SLE pathogenesis. We have identified novel pathways involved in this DC activation by DNA/protein-containing IC. One major pathway involves IC engagement of Fc gamma receptor III on the DC surface, with subsequent delivery of DNA within the complex to intracellular Toll-like receptor 9 (TLR9). The application's objectives are to obtain a detailed understanding of the mechanisms and consequences of this interaction, and to determine whether a similar two receptor dual engagement mechanism applies to DC activation by RNA/protein-containing IC. Specific aim 1 compares the functional effects of DNA/protein and RNA/protein-containing IC on various DC subsets from wildtype, TLR9 deficient, TLR3 deficient, and various Fc gamma receptor deficient mice. Novel inhibitors will be tested for their ability to block this activation. Specific aim 2 compares Fc gamma receptor-mediated and Fc gamma receptor-independent uptake of antigen, particularly as regards delivery of antigen to TLR9-containing subcellular compartments. The consequences of this on T cell activation will be ascertained. In specific aim 3, the relative importance of TLR9-mediated DC activation (as compared to TLR9-mediated B cell activation) in SLE pathogenesis will be determined using DC adoptive transfer experiments, as well as by the development of mice in which TLR9 is specifically "knocked-out" in DC. It is anticipated that these studies will enhance the understanding of SLE pathogenesis and contribute to the development of new effective, safer and more specific therapies.