After the near eradication of polio, Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis. Anti-ganglioside/glycan antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies grouped under the term GBS. Despite the availability of two immunomodulatory therapies, a significant proportion of patients are left with permanent neurologic sequelae. Patients with neurologic sequelae almost always have failure of axon regeneration and target reinnervation. Several studies indicate that specific anti-glycan Abs associate with poor recovery. Our group examined the effects of anti- glycan Abs on peripheral nerve repair and found these Abs inhibit regeneration of injured axons in preclinical models. The overall goals of this translational project are to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on axon regeneration and to develop strategies that could prevent the deleterious effects of anti-glycan Abs on nerve repair. Our preliminary results show that specific activating Fc-gamma receptors (Fc?Rs) particularly on macrophages recruited in the injured nerves are key determinants of Ab-mediated inhibition of nerve repair. Further, glycosylation of anti-ganglioside Abs is critical in their interactions with Fc?Rs and deglycosylation of anti-glyca Abs suppresses their inhibitory effects on nerve repair. Further, sialylated- fraction of human intravenous immunoglobulins (sIVIG), a minor component of IVIG, suppresses Ab-mediated inhibition of axon regeneration. We hypothesize that anti-glycan Abs bind to gangliosides on neural cell surfaces to form immune complexes on the proximal tips of injured axons and these in turn bind to specific activating Fc?Rs expressed by adjacent glial cells to induce tissue inflammation affecting axon regeneration. Furthermore, IgG Fc interactions with innate immune receptors are critically dependent on the IgG glycosylation and this glycosylation status can be manipulated (on pathogenic Abs and IVIG) to alter anti- ganglioside Ab- or IVIG-mediated effects. This renewal application will test these hypotheses by the following specific aims:
Aim 1 will examine the role of specific Fc?Rs and glial cells expressing Fc?Rs in mediating nerve injury;
Aim 2 will examine the role of N-glycan structures, carried by anti-glycan Abs, in their interactions with Fc?Rs to induce inflammation;
and Aim 3 will examine the role of Fc/IgG sialylation as determinants of IVIG efficacy via the so-called 'DC-SIGN-Th2'anti-inflammatory pathway. These translational and 'proof of principle'studies have pathobiologic and therapeutic implications for failure of axon regeneration particularly that seen after immune insults/inflammation in autoimmune conditions like immune neuropathies and multiple sclerosis where failure of axonal repair is central to severity of the disease and recovery.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS054962-06A1
Application #
8761854
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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
Zhang, Gang; Bogdanova, Nataliia; Gao, Tong et al. (2014) Fc? receptor-mediated inflammation inhibits axon regeneration. PLoS One 9:e88703
Ubogu, Eroboghene E; Yosef, Nejla; Xia, Robin H et al. (2012) Behavioral, electrophysiological, and histopathological characterization of a severe murine chronic demyelinating polyneuritis model. J Peripher Nerv Syst 17:53-61
Zhang, Gang; Lehmann, Helmar C; Manoharan, Sowmia et al. (2011) Anti-ganglioside antibody-mediated activation of RhoA induces inhibition of neurite outgrowth. J Neurosci 31:1664-75
Zhang, Gang; Lehmann, Helmar C; Bogdanova, Nataliia et al. (2011) Erythropoietin enhances nerve repair in anti-ganglioside antibody-mediated models of immune neuropathy. PLoS One 6:e27067
Lehmann, Helmar C; Zhang, Jiangyang; Mori, Susumu et al. (2010) Diffusion tensor imaging to assess axonal regeneration in peripheral nerves. Exp Neurol 223:238-44
Yasser, Sadia; Fecto, Faisal; Siddique, Teepu et al. (2010) An unusual case of familial ALS and cerebellar ataxia. Amyotroph Lateral Scler 11:568-70
Lopez, Pablo H; Zhang, Gang; Zhang, Jiangyang et al. (2010) Passive transfer of IgG anti-GM1 antibodies impairs peripheral nerve repair. J Neurosci 30:9533-41
Sheikh, Kazim A (2010) Non-invasive imaging of nerve regeneration. Exp Neurol 223:72-6
Zhang, Jiangyang; Zhang, Gang; Morrison, Brett et al. (2008) Magnetic resonance imaging of mouse skeletal muscle to measure denervation atrophy. Exp Neurol 212:448-57

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