C3aR and C5aR Modulate T-cell Responses in the MRL Mouse

系统性红斑狼疮(SLE)是一种以自身免疫为特征的异质性疾病。 进行性免疫复合体肾病的发展。系统性红斑狼疮的发病机制是复杂的、多方面的。 大量的临床和实验数据支持自身抗体、免疫复合体、 细胞凋亡和效应T细胞在SLE发生发展中的作用补体系统中的干扰是 与多种形式的系统性红斑狼疮，特别是狼疮性肾炎的发生和发展密切相关。 补体激活导致产生过敏性毒素C3a和C5a，它们通过 广泛表达G蛋白偶联受体(C3aR和C5aR)。通过C3aR和C5aR传递信号 历来认为发挥作用的是活跃的先天免疫反应。这篇文章中包含的研究 旨在定义和表征C3aR和C5aR改变获得性免疫的能力 人类疾病的生物相关补体依赖模型中的反应，即MRL/LPR 狼疮性肾炎小鼠模型。靶向C3aR和C5aR缺失的小鼠以及 C3aR和C5aR都在MRL/LPR遗传背景上回交了9代。 肾损伤和免疫反应的比较研究，包括抗血清提呈细胞功能， T细胞和B细胞功能将被执行。此外，研究肾实质的实验 在细胞增殖、细胞外基质产生和细胞凋亡方面的反应将被执行。 这些研究旨在促进我们对补体的机制的理解 活化产物在免疫中调节细胞免疫反应和肾实质反应 介导性肾损伤。

Systemic Lupus Erythematosus (SLE) is a heterogeneous disorder characterized by autoimmunity and the development of progressive immune complex renal disease. The pathogenesis of SLE is complex and multi- factorial; substantial clinical and experimental data supports roles for auto-antibodies, immune complexes, apoptosis, and effector T-cells in the development of SLE. Disturbances in the complement system are strongly associated with the development and progression of many forms of SLE particularily lupus nephrits. Complement activation results in the production of anaphylatoxins, C3a and C5a, which signal through ubiquitiously expressed G-protein coupled receptors (C3aR and C5aR). Signaling via the C3aR and C5aR have historically thought to function to active innate immune responses. The studies contained in this proposal are desinged to define and characterize the ability of C3aR and C5aR to alter adaptive immune responses in a biologically relevant complement depedent model of human disease, namely the MRL/lpr mouse model of lupus nephritis. Mice with targeted deletions of C3aR and C5aR as well as mice deficient in both the C3aR and the C5aR have been back-crossed 9 generations on to the MRL/lpr genetic background. Comparative studies of renal injury and immunologic responses including antigent presenting cell function, T-cell, and B-cell function will be performed. Additionally, experiments investigating renal parenchymal reponses in terms of cellualr proliferation, extra-cellular matrix production, and apoptosis will be performed. These studies are designed to advance our understanding of the mechanisms by which complement activation products modulate cellular immune responses and renal parenchymal responses in immune mediated renal injury.