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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046032-03
Application #
6990480
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$261,947
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Bullard, Daniel C; Hu, Xianzhen; Crawford, David et al. (2014) Expression of a single ICAM-1 isoform on T cells is sufficient for development of experimental autoimmune encephalomyelitis. Eur J Immunol 44:1194-9
Read, Russell W; Vogt, Susan D; Barnum, Scott R (2013) The complement anaphylatoxin receptors are not required for the development of experimental autoimmune uveitis. J Neuroimmunol 264:127-9
Darley, M M; Ramos, T N; Wetsel, R A et al. (2012) Deletion of carboxypeptidase N delays onset of experimental cerebral malaria. Parasite Immunol 34:444-7
Wheeler, Crystal; Nabors, L Burt; Barnum, Scott et al. (2012) Sex hormone-dependent attenuation of EAE in a transgenic mouse with astrocytic expression of the RNA regulator HuR. J Neuroimmunol 246:34-7
Hu, Xianzhen; Barnum, Scott R; Wohler, Jillian E et al. (2010) Differential ICAM-1 isoform expression regulates the development and progression of experimental autoimmune encephalomyelitis. Mol Immunol 47:1692-1700
Osmers, Inga; Smith, Sherry S; Parks, Brian W et al. (2009) Deletion of the G2A receptor fails to attenuate experimental autoimmune encephalomyelitis. J Neuroimmunol 207:18-23
Ramos, Theresa N; Wohler, Jillian E; Barnum, Scott R (2009) Deletion of both the C3a and C5a receptors fails to protect against experimental autoimmune encephalomyelitis. Neurosci Lett 467:234-6
Wohler, Jillian E; Barnum, Scott R (2009) Nylon wool purification alters the activation of T cells. Mol Immunol 46:1007-10
Wohler, Jillian; Bullard, Dan; Schoeb, Trent et al. (2009) LFA-1 is critical for regulatory T cell homeostasis and function. Mol Immunol 46:2424-8
Dugger, Kari J; Zinn, Kurt R; Weaver, Casey et al. (2009) Effector and suppressor roles for LFA-1 during the development of experimental autoimmune encephalomyelitis. J Neuroimmunol 206:22-7

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