The Role of C3 and C3 receptors in EAE

描述（由申请人提供）：补体在多发性硬化（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）的发展中的作用已经被怀疑了几十年。尽管如此，补体对这种脱髓鞘疾病的进展和病理生理学的贡献仍然存在争议。在EAE中，很明显，通过多种机制抑制补体的活化，特别是在阻断C3活化的早期活化步骤，完全减轻或预防临床疾病。这表明C3在脱髓鞘疾病的发病机制中起重要作用。然而，关于补体在脱髓鞘疾病发病机制中的确切作用仍然存在重要问题。例如，补体激活后产生的哪些途径和激活片段对EAE的发病机制最关键？靶向抑制一小部分补体配体和/或受体是慢性脱髓鞘疾病（如MS）的有效治疗策略吗？虽然有许多效应子功能介导的各种蛋白质片段释放后激活的补体系统，我们认为，C3的片段和受体结合这些片段，在EAE中发挥的作用补体的核心。此外，我们认为补体介导的病理学主要是由旁路途径的激活引起的。检验这一假设的第一个具体目标是通过使用C3 aR缺陷小鼠和C3 a转基因小鼠评估C3 a及其受体（C3 aR）在MOG诱导的EAE中的作用。在后者中，C3 a在神经胶质细胞酸性蛋白（GFAP）启动子的控制下在CNS中表达。第二个具体目的是通过使用CR 3和CR 4缺陷型小鼠评估补体受体3型（CR 3或Mac-l; CD 11b/CD 18）和4型（CR 4; CD 11 c/CD 18）在MOG诱导的EAE中的作用。第三个具体目标将使用因子B和C4缺陷小鼠评估补体激活的经典途径与替代途径在促进MOG诱导的EAE的发展和进展中的作用。这些拟议的研究将提供关于补体在脱髓鞘疾病中的作用的重要新信息，并指出MS的潜在治疗方法。

DESCRIPTION (provided by applicant): A role for complement in the development of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) has been suspected for many decades. Despite this, the contribution of complement to the progression and pathophysiology of this demyelinating disease remains controversial. In EAE, it is clear that inhibiting the activation of complement by a variety of mechanisms, particularly at early activation steps that block activation of C3, attenuates or prevents clinical disease altogether. This indicates an important role for C3 in the pathogenesis of demyelinating disease. Nevertheless important questions remain with respect to the exact role complement plays in the pathogenesis of demyelinating disease. For example, which of the pathways and activation fragments generated upon complement activation are most critical to the pathogenesis of EAE? Is targeted inhibition of a small set of complement ligands and/or receptors a valid therapeutic strategy in a chronic demyelinating disease such as MS? Although there are many effector functions mediated by the various protein fragments liberated upon activation of the complement system, we believe that fragments of C3 and the receptors that bind these fragments, are central to the role complement plays in EAE. Further we believe that complement-mediated pathology results primarily from activation of the alternative pathway. The first specific aim to test this hypothesis will assess the role of the C3a and its receptor (C3aR) in MOG-induced EAE through the use of C3aR-deficient mice and C3a transgenic mice. In the latter C3a is expressed in the CNS under the control of a glial fibrillary acidic protein (GFAP) promoter. The second specific aim will assess the roles of the complement receptors type 3 (CR3 or Mac-l; CD11b/CD18) and type 4 (CR4; CD11c/CD18) in MOG-induced EAE through the use of CR3- and CR4-deficient mice. The third specific aim will assess the role of the classical versus alternative pathways of complement activation in contributing to the development and progression of MOG-induced EAE using factor B- and C4-deficient mice. These proposed studies will provide important new information with respect to the role of complement in demyelinating disease and point to potential therapeutic approaches for MS.