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 grouped under the term Guillain-Barr¿ syndrome (GBS). Abs with different specificities have strongest association with axonal variants of GBS. Nodes of Ranvier and axons bear the brunt of damage in axonal GBS. The pathogenesis of Ab-mediated damage to nodes of Ranvier and axonal integrity is not completely understood. A fundamental limitation in studying anti-glycan Ab-mediated neuropathy is lack of reliable passive transfer models to induce injury to the intact fibers in experimental animals. Our overall goal is to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on intact nerve fibers. Our preliminary studies show that passive transfer with anti-ganglioside Abs in a new model of leaky blood-nerve barrier (BNB) induces sequential injury to nodes of Ranvier and axons mimicking pathology seen in patients with axonal GBS. In mutant mice with altered ganglioside or complement (C5) expression nodal and axonal injury by Abs is mediated directly through specific corresponding ganglioside and is independent of complement-mediated cytolytic injury. Notably, neural injury in this model is dependent on expression of activating Fc-gamma receptors (Fc?Rs) in injured nerves. From these results we hypothesize that anti- ganglioside Abs bind to gangliosides on neural cell surfaces to form immune complexes in the injured nerves and these immune complexes engage specific activating Fc?Rs expressed by adjacent glial cells to induce tissue inflammation that affects nodal and axonal integrity. This renewal will test these hypotheses by the following specific aims: Aim 1 will characterize a new passive transfer animal model of altered BNB permeability and anti-glycan Ab-mediated neuropathy; Aim 2 will examine whether expression of specific activating Fc?Rs in injured nerves is necessary to induce neuropathy; and Aim 3 will examine the role of specific glial cells expressing Fc?Rs in mediating nerve injury. These translational studies will provide detailed pathogenesis of Ab-mediated axon injury and evaluate whether immune complex-induced inflammation is a mechanism of axonal degeneration. These studies will help in developing therapies for autoimmune conditions like immune neuropathies and multiple sclerosis where axonal damage is central to severity of the disease and recovery. PUBLIC HEALTH RELEVANCE: Guillain-Barr¿ syndrome is the commonest cause of acute flaccid paralysis worldwide. This disease is strongly associated with autoantibodies directed against cell surface glycans called gangliosides. Presently, how these antibodies cause nerve injury is not completely understood. This project proposes to examine immune mechanisms and cells involved in antibody-mediated nerve damage. These studies may facilitate development of new therapies for patients with Guillain-Barr¿ syndrome.