Animal models of myasthenia gravis

Myasthenia gravis (MG) is an antibody-mediated, autoimmune neuromuscular di sease. Animal models of experimental autoimmune myasthenia gravis (EAMG) ca n be induced in vertebrates by immunization with Torpedo californica acetyl choline receptors (AChR) in complete Freund's adjuvant. The MHC class II ge nes influence the cellular and humoral immune response to AChR and are invo lved in the development of clinical EAMG in mice. A dominant epitope within the AChR alpha 146-162 region activates MHC class II-restricted CD4 cells and is involved in the production of pathogenic anti-AChR antibodies by B c ells. Neonatal or adult tolerance to this T-cell epitope could prevent EAMG . During an immune response to AChR in vivo, multiple TCR genes are used. T he CD28-B7 and CD40L-CD40 interaction is required during the primary immune response to AChR, However, CTLA-4 blockade augmented T- and B-cell immune response to AChR and disease. Cytokines IFN-gamma and IL-12 upregulate, whi le IFN-alpha downregulates, EAMG pathogenesis, However, the Th2 cytokine IL -4 fails to play a significant role in the development of antibody-mediated EAMG. Systemic or mucosal tolerance to AChR or its dominant peptide(s) has prevented EAMG in an antigen-specific manner. Antigen-specific tolerance a nd downregulation of pathogenic cytokines could achieve effective therapy o f EAMG and probably MG. (C) 2000 Academic Press.