Guillian-Barre syndrome (GBS), an autoimmune post-infectious disorder is a frequent cause of acute flaccid paralysis in the post-polio era. Recently, two major types of GBS have been described: acute inflammatory demyelinating polyneuropathy (AIDP) characterized by complement and antibody deposition at the abaxonal (outer) Schwann cell plasmalemma and inflammatory demyelination in both motor and sensory nerves; and acute motor axonal neuropathy (AMAN) characterized by complement and antibody deposition at the nodes of Ranvier of motor nerves. Campylobacter jejuni infection is an important antecedent infection in both patterns of disease. Anti-glycoconjugate antibodies have frequently been reported and glycoconjugate-like epitopes have been found in strains of Campylobacter isolated from patients. These results suggest that antibody-mediated injury contributes to the fiber injury in both demyelinating and axonal GBS, but basic issues of the pathophysiology remain unresolved. This proposal will focus on mechanisms of immune-mediated injury to axons and myelin. In parallel studies of AIDP and AMAN, four questions will be examined. 1) To what structures of rate nerve fibers does GBS immunoglobulin bind in vitro? 2) How does the binding of GBS immunoglobulin affect nerve fibers? 3) What are the roles of complement activation, of calcium entry into the fibers, and of pathogenetically relevant enzymes? 4) Are gangliosides the target epitopes? These questions will be examined in short-term culture of rat dorsal and ventral rat roots and Wld(S) mouse sciatic nerves, and in long-term cultures of rat myelinating dorsal root ganglia and spinal chord. Samples of well- characterized GBS sera from our extensive collection will be added to these cultures and the effects of adding complement, changing the calcium concentrations, and inhibiting enzymes such as phospholipase A2 and calpain will be examined. Findings in motor and sensory nerves will be compared. Finally, studies will determine whether the effect of GBS sera can be blocked by selectively inhibiting the expression of different gangliosides, and whether reconstitution of individual gangliosides can restore these effects. These studies should shed light on the targets of immune attack and on the mechanisms of axonal degeneration and demyelination in GBS, and will further our understanding of peripheral nerve myelination, or the organization of nodes of Ranvier, and of other immune-mediated neuropathies.
|Hoke, Ahmet; Ho, Tony; Crawford, Thomas O et al. (2003) Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers. J Neurosci 23:561-7|
|Lu, J L; Sheikh, K A; Wu, H S et al. (2000) Physiologic-pathologic correlation in Guillain-Barre syndrome in children. Neurology 54:33-9|
|Ho, T W; Bristol, L A; Coccia, C et al. (2000) TGFbeta trophic factors differentially modulate motor axon outgrowth and protection from excitotoxicity. Exp Neurol 161:664-75|
|Yuki, N; Ho, T W; Tagawa, Y et al. (1999) Autoantibodies to GM1b and GalNAc-GD1a: relationship to Campylobacter jejuni infection and acute motor axonal neuropathy in China. J Neurol Sci 164:134-8|
|Ho, T W; Willison, H J; Nachamkin, I et al. (1999) Anti-GD1a antibody is associated with axonal but not demyelinating forms of Guillain-Barre syndrome. Ann Neurol 45:168-73|