Pathogenesis of anti-ganglioside antibody-mediated neuropathies

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DESCRIPTION (provided by applicant): Anti-ganglioside antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies termed Guillain-Barre syndrome (GBS). Abs with GM1 and GD1a specificity are associated with the motor axonal variant of GBS and poor recovery in both axonal and demyelinating forms of the disease. A puzzling clinical finding is that patients with anti-ganglioside Abs of same specificities have variations in clinical phenotype and outcome. Our overall goal is to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on intact and injured nerve fibers. Our preliminary studies show that: a) anti-ganglioside Abs induce dysfunction at specialized regions of the nerves, nodes of Ranvier and motor nerve terminals; b) an anti-ganglioside Ab inhibits regeneration of injured nerve fibers in an animal model; and C) a monoclonal Ab with high affinity has pathobiologic effects on intact and injured nerve fibers in two animal models. From these results we hypothesize that anti-ganglioside Abs: 1) induce reversible nerve dysfunction by altering ion channels and/or proteins of exocytic machinery at nodes of Ranvier and motor nerve terminals; 2) inhibit nerve regeneration, which is one mechanism of poor recovery in GBS patients with anti-ganglioside Abs; and 3) Ab affinity determines extent and type of nerve injury and clinical phenotype. This renewal will test these hypotheses by the following specific aims: Aim 1 will examine the effects of anti-ganglioside Abs on intact nodes of Ranvier in an intraneural injection model; how these Abs affect neuromuscular transmission will be investigated by macro-patch-clamp studies in Aim 2; in Aim 3, effects of these Abs on nerve regeneration will be studied in sciatic nerve crush and nerve transplant models; and Aim 4 will evaluate the role of Ab affinity in neuropathic injury by correlating Ab affinity (as determined in solid phase assays) and pathogenicity in animal and tissue culture models of nerve injury. These studies will provide detailed pathogenesis of Ab-mediated axon injury, which will help in developing therapies for autoimmune conditions like immune neuropathies and multiple sclerosis where axonal damage is central to poor recovery. Public information statement: This translational research project seeks to examine mechanisms of axonal injury in GBS. These studies will help develop treatment strategies to prevent axonal degeneration and enhance axonal regeneration in autoimmune neuropathies.