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. [unreadable] [unreadable] 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-indeed 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 D- and C1q-deficient mice. The final specific aim will determine the impact of C3 deficiency on the development of MOG-induced EAE in C57BL/6, 129 and C57BL/6 x 129 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. [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter