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

描述(申请人提供)：系统性红斑狼疮(SLE)是一种以自身免疫和进行性免疫复合体肾病为特征的异质性疾病。SLE的发病机制是复杂的、多因素的；大量的临床和实验数据支持自身抗体、免疫复合物、细胞凋亡和效应性T细胞在SLE发生发展中的作用。补体系统的紊乱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。补体激活导致过敏毒素C3a和C5a的产生，这些毒素通过普遍表达的G蛋白偶联受体(C3aR和C5aR)传递信号。通过C3aR和C5aR发出的信号历来被认为具有激活先天免疫反应的功能。这项建议中包含的研究旨在定义和表征C3aR和C5aR在一种生物相关的补体依赖人类疾病模型中改变适应性免疫反应的能力，即狼疮性肾炎的MRL/LPR小鼠模型。C3aR和C5aR靶向缺失的小鼠以及C3aR和C5aR均缺失的小鼠已在MRL/LPR遗传背景上回交9代。将进行肾脏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。此外，还将进行实验，研究肾实质对细胞增殖、细胞外基质产生和细胞凋亡的反应。这些研究旨在促进我们对补体激活产物在免疫介导的肾损伤中调节细胞免疫反应和肾实质反应的机制的理解。

DESCRIPTION (provided by applicant): 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 particularly lupus nephrits. Complement activation results in the production of anaphylatoxins, C3a and C5a, which signal through ubiquitously expressed G-protein coupled receptors (C3aR and C5aR). Signaling via the C3aR and C5aR has historically thought to function to active innate immune responses. The studies contained in this proposal are designed to define and characterize the ability of C3aR and C5aR to alter adaptive immune responses in a biologically relevant complement dependent 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 responses in terms of cellular 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.