Acetylcholine receptors (AChR) are expressed on muscle membranes and are responsible for the reception of signals from nerves that stimulate muscle contraction. Myasthenia gravis (MG) is a neuromuscular disease that is the result of impaired muscle contraction caused by autoantibodies directed at the AChR. However, circulating serum titers of anti-AChR antibodies do not correlate well with disease severity in patients with MG and this lack of correlation has led to the search for other factors which may help determine eventual disease severity. Therefore, it is our hypothesis that muscle is not a passive participant in the development of disease symptoms in MG and, in fact, plays a very important active role by producing immunomodulating factors that can influence the eventual immunopathological impact of the immune system on muscle. The experimental rat model for MG is to be used to test this hypothesis. Accordingly, Lewis rats are to be immunized with purified AChR which results in the production of anti-AChR antibodies and Experimental Autoimmune Myasthenia Gravis (EAMG). Studies will focus on the production of, and responses to, cytokines by muscle cells in rats with EAMG. In this regard, muscle cell lines will be exposed in vitro to selected cytokines in the presence or absence of anti-AChR antibodies derived from Lewis rats. The readout will be the induction of myocyte products with immunomodulating activities (i.e., cytokines, chemokines, membrane interaction molecules). Similarly, myocyte cell lines derived from a rat strain known to be resistant to the induction of EAMG (Wistar Furth) will be evaluated for differences in myocyte responses that would explain differences in disease susceptibility. Conclusions based on in vitro observations will then be verified in AChR-immunized Lewis rats during the induction phase of the immune response, as well as in rats that have received pre-formed anti-AChR antibodies known to possess differing abilities to induce disease symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038904-01
Application #
2884219
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Nichols, Paul L
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Reyes-Reyna, Sara; Stegall, Timothy; Krolick, Keith A (2002) Muscle responds to an antibody reactive with the acetylcholine receptor by up-regulating monocyte chemoattractant protein 1: a chemokine with the potential to influence the severity and course of experimental myasthenia gravis. J Immunol 169:1579-86
Garcia, Y R; May, J J; Green, A M et al. (2001) Acetylcholine receptor-reactive antibody induces nitric oxide production by a rat skeletal muscle cell line: influence of cytokine environment. J Neuroimmunol 120:103-11
Stegall, T; Krolick, K A (2001) Myocytes respond in vivo to an antibody reactive with the acetylcholine receptor by upregulating interleukin-15: an interferon-gamma activator with the potential to influence the severity and course of experimental myasthenia gravis. J Neuroimmunol 119:377-86
Stegall, T; Krolick, K A (2000) Myocytes respond to both interleukin-4 and interferon-gamma: cytokine responsiveness with the potential to influence the severity and course of experimental myasthenia gravis. Clin Immunol 94:133-9
Stegall, T; Krolick, K A (2000) A monoclonal lewis rat myocyte line that responds to interferon-gamma: responsiveness with the potential to influence subsequent interactions with the immune system. Clin Immunol 94:125-32
Reyes-Reyna, S M; Krolick, K A (2000) Chemokine production by rat myocytes exposed to interferon-gamma. Clin Immunol 94:105-13