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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS042888-10
Application #
8373698
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Gwinn, Katrina
Project Start
2001-12-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$332,500
Indirect Cost
$113,750
Name
University of Texas Health Science Center Houston
Department
Neurology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Zhang, Gang; Lin, Jianxin; Ghauri, Sameera et al. (2017) Modulation of IgG-FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration. Acta Neuropathol 134:321-324
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
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
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
Nguyen, Thy P; Biliciler, Suur; Wiszniewski, Wojciech et al. (2015) Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease. J Clin Neuromuscul Dis 17:69-71
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
Vegosen, Leora; Breysse, Patrick N; Agnew, Jacqueline et al. (2015) Occupational Exposure to Swine, Poultry, and Cattle and Antibody Biomarkers of Campylobacter jejuni Exposure and Autoimmune Peripheral Neuropathy. PLoS One 10:e0143587
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
He, Lan; Zhang, Gang; Liu, Weiqiang et al. (2015) Anti-Ganglioside Antibodies Induce Nodal and Axonal Injury via Fc? Receptor-Mediated Inflammation. J Neurosci 35:6770-85
Zhang, Gang; Bogdanova, Nataliia; Gao, Tong et al. (2014) Fc? receptor-mediated inflammation inhibits axon regeneration. PLoS One 9:e88703

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