TLR-Dependent Dendritic Cell Activation in SLE

系统性红斑狼疮(SLE)是一种发病率较高甚至死亡率较高的系统性自身免疫性疾病。目前的治疗方法包括非特异性免疫抑制，具有许多严重的副作用。此外，对治疗的反应往往是不完全的。因此，需要更具体、毒性更低的疗法。树突状细胞(DC)由自身抗体结合的含有SLE自身抗原(DNA/蛋白质或RNA/蛋白质)的免疫复合体(IC)激活，在SLE的发病中起关键作用。我们已经通过含有DNA/蛋白质的IC确定了参与这种DC激活的新途径。一条主要途径涉及Fcγ受体III在DC表面的IC参与，随后DNA在复合体内传递到细胞内Toll样受体9(TLR9)。应用程序的目标是详细了解这种相互作用的机制和后果，并确定类似的双受体双参与机制是否适用于DC 由含RNA/蛋白质的IC激活。特定目的1比较DNA/蛋白质和含RNA/蛋白质的IC对野生型、TLR9缺陷、TLR3缺陷和不同Fcγ受体缺陷小鼠不同DC亚群的功能影响。将测试新型抑制剂阻止这种激活的能力。 特定目的2比较Fc-γ受体介导的和Fc-γ受体非依赖的抗原摄取，特别是在将抗原运送到含有TLR9的亚细胞室方面。这对T细胞激活的影响将被确定。在特定的目标3中，TLR9介导的DC激活(与TLR9介导的B细胞激活相比)在SLE发病机制中的相对重要性将通过DC过继转移实验以及TLR9在DC中特异性“敲除”的小鼠的发育来确定。预计这些研究将加强对SLE发病机制的了解，并有助于开发新的有效、安全和更特异的治疗方法。

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.