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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042888-09
Application #
7795678
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Gwinn, Katrina
Project Start
2001-12-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$299,917
Indirect Cost
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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