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The role of complement in the immunological demyelination of the adult rat spinal cord Bourque, Jason Alain

Abstract

Previous work in Dr. John Steeves' laboratory has described a transient, myelinspecific, galactocerebroside (GalC) antibody-mediated, complement-dependent protocol that suppresses the onset of myelination in embryonic birds, and focally demyelinates the central nervous system (CNS) of adult birds and rodents after intraspinal infusion. After spinal injury, this procedure has been observed to facilitate axonal regeneration, often with accompanying recovery of behavior. In order to identify the relative necessity of different complement proteins in this protocol, I assessed the effects of infusions of GalC-antibody and human serum deficient for a particular complement protein (i.e. C3, C4, C5, or Factor B was immunoadsorbed prior to infusion) on spinal myelin. Spinal treated tissue was evaluated ultrastructurally using a transmission electron microscope. Upon removal of the C3 protein, common to both the classical and alternative complement pathways, or the C4 protein, a classical pathway protein, normal myelin was observed (i.e. no demyelination). Using serum deficient in Factor B, an alternative pathway protein, demyelination was still observed; in addition, large numbers of macrophages containing myelin debris were present in these regions. These results suggest that the classical serum complement pathway has a fundamental role in this immunological demyelination protocol. Upon removal of C5, a Membrane Attack Complex (MAC) protein, substantial demyelination was again observed, once more accompanied by macrophages, suggesting that some of the demyelination may be occurring through macrophage-mediated events involving complement-derived anaphylatoxins and membrane receptors. Taken together, these findings suggest that the classical pathway of complement activation and anti-GalC IgG antibody are sufficient, and thus the alternative pathway and the MAC are not necessary, for focal demyelination of the adult rat spinal cord, and that this demyelination occurs in a macrophagedependent manner.

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