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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Gwinn, Katrina
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University of Texas Health Science Center Houston
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Rozés Salvador, Victoria; Heredia, Florencia; Berardo, Andrés et al. (2016) Anti-glycan antibodies halt axon regeneration in a model of Guillain Barrè Syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2. Exp Neurol 278:42-53
Zhang, Gang; Massaad, Cynthia A; Gao, Tong et al. (2016) Sialylated intravenous immunoglobulin suppress anti-ganglioside antibody mediated nerve injury. Exp Neurol 282:49-55
Asthana, Pallavi; Vong, Joaquim Si Long; Kumar, Gajendra et al. (2016) Dissecting the Role of Anti-ganglioside Antibodies in Guillain-Barré Syndrome: an Animal Model Approach. Mol Neurobiol 53:4981-91
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Joshi, Abhijeet R; Bobylev, Ilja; Zhang, Gang et al. (2015) Inhibition of Rho-kinase differentially affects axon regeneration of peripheral motor and sensory nerves. Exp Neurol 263:28-38
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He, Lan; Zhang, Gang; Liu, Weiqiang et al. (2015) Anti-Ganglioside Antibodies Induce Nodal and Axonal Injury via Fcγ Receptor-Mediated Inflammation. J Neurosci 35:6770-85
Massaad, Cynthia A; Zhang, Gang; Pillai, Laila et al. (2015) Fluorescently-tagged anti-ganglioside antibody selectively identifies peripheral nerve in living animals. Sci Rep 5:15766
Zhang, Gang; Hoffman, Paul N; Sheikh, Kazim A (2014) Axonal degeneration in dorsal columns of spinal cord does not induce recruitment of hematogenous macrophages. Exp Neurol 252:57-62
Derksen, Angelika; Ritter, Christian; Athar, Parveen et al. (2014) Sural sparing pattern discriminates Guillain-Barré syndrome from its mimics. Muscle Nerve 50:780-4

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