The Role of C3 and C3 receptors in EAE

描述(由申请人提供)：补体在多发性硬化症(MS)及其动物模型的发展中的作用，实验性自身免疫性脑脊髓炎(EAE)几十年来一直被怀疑。尽管如此，补体在这种脱髓鞘疾病的进展和病理生理学中的作用仍然存在争议。在EAE中，很明显，通过各种机制抑制补体的激活，特别是在阻断C3激活的早期激活步骤，可以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着重要作用。然而，关于补体在脱髓鞘疾病发病机制中的确切作用，仍然存在重要的问题。例如，补体激活时产生的哪些途径和激活片段对EAE的发病最关键？靶向抑制少量补体配体和/或受体是否是治疗诸如多发性硬化症等慢性脱髓鞘疾病的有效策略？虽然补体系统激活后释放的各种蛋白质片段介导了许多效应功能，但我们认为C3片段和与这些片段结合的受体是补体在EAE中所起作用的核心。此外，我们认为补体介导的病理主要是由替代途径的激活引起的。验证这一假说的第一个特定目的是通过使用C3aR缺陷小鼠和C3a转基因小鼠来评估C3a及其受体(C3aR)在MOG诱导的EAE中的作用。在后者中，C3a是在胶质纤维酸性蛋白(GFAP)启动子的控制下在中枢神经系统表达的。第二个特定目标将评估补体受体3型(CR3或Mac-L；CD11b/CD18)和4型(CR4；CD11c/CD18)在通过CR3和CR4缺陷小鼠诱导的EAE中的作用。第三个具体目标将评估补体激活的经典途径和替代途径在使用B和C4因子缺乏的MOG诱导的EAE小鼠的发展和进展中所起的作用。这些拟议的研究将提供有关补体在脱髓鞘疾病中的作用的重要新信息，并指出治疗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.