Mouse experimental myasthenia gravis (EMG) is induced by immunization with nicotinic acetylcholine receptor (AChR). Preliminary studies suggest that anti-AChR Th1 cells are pathogenic, Th2 cells are protective. Other findings suggest that the pathogenic potential of anti-AChR CD4+ cells in EMG is related to their epitope specificity. In addition, in human myasthenia gravis (MG), Th1 cells are pathogenic and Th2 cells might be protective. If this model will be verified in EMG, it might open the door to effective immunomodulatory approaches for MG. The overall question to be addressed using mouse EMG as a model is: whether it is the CD4+ subtype, or the epitope specificity, or both that makes an anti-AChR CD4+ cell pathogenic.
The specific aims will be: (1) to determine the role(s) of anti-AChR Th1 and Th2 in mouse EMG, by investigating the effects on susceptibility to EMG of manipulations of the Th1/Th2 balance obtained by altering the cytokine environment in an effort to test the hypothesis that Th1 cells are pathogenic and Th2 cells are protective; (2) to investigate the relationship between the epitope repertoire recognized by CD4+ cells on the AChR and sensitization of Th1 or Th2 cells in order to test the hypothesis that the epitope repertoire of anti-AChR CD4+ cells correlates with their propensity to EMG because it correlates with sensitization of Th1 or Th2 cells; and to also test the hypothesis that preferential Th2 sensitization against some AChR epitopes occurs either by virtue of their limited presentation and reduced TCR occupancy, or by an imperfect interaction of the peptide/MHC complex with the TCR, similar to that described for altered peptide ligands; (3) to investigate the ability of Th1 and Th2 cells specific for different AChR epitopes to facilitate or prevent EMG in order to test the hypothesis that the epitope recognized by anti-AChR CD4+ cells influences their pathogenic or protective potential and to investigate whether this is because certain epitopes are better processed and presented and able to sensitize more CD4+ cells, or because they are recognized by CD4+ cells that help synthesis of pathogenic antibody; and (4) to investigate the effects on EMG of treatments which affect the Th1/Th2 balance and to find drug treatments that might be useful in the management of MG, and exposure to antigen from pathogens known to preferentially stimulate a Th1 or Th2 response. The latter experiments will test the hypothesis that infectious diseases might affect antibody-mediated autoimmunity by acting on the Th1/Th2 balance.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Visual Sciences C Study Section (VISC)
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Nichols, Paul L
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University of Minnesota Twin Cities
Schools of Medicine
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