INTERFERON-GAMMA (IFN-GAMMA) IS NECESSARY FOR THE GENESIS OF ACETYLCHOLINE RECEPTOR-INDUCED CLINICAL EXPERIMENTAL AUTOIMMUNE MYASTHENIA-GRAVIS IN MICE

Experimental autoimmune myasthenia gravis (EAMG) is an animal model of human myasthenia gravis (MG). In mice, EAMG is induced by immunizatio n with Torpedo californica acetylcholine receptor (AChR) in complete F reund's adjuvant (CFA). However, the role of cytokines in the pathogen esis of EAMG is not clear. Because EAMG is an antibody-mediated diseas e, it is of the prevailing notion that Th2 but not Th1 cytokines play a role in the pathogenesis of this disease. To test the hypothesis tha t the Th1 cytokine, interferon (IFN)-gamma, plays a role in the develo pment of EAMG, we immunized IFN-gamma knockout (IFN-gko) (-/-) mice an d wild-type (WT) (+/+) mice of H-2b haplotype with AChR in CFA. We obs erved that AChR-primed lymph node cells from IFN-gko mice proliferated normally to AChR and to its dominant pathogenic alpha 146-162 sequenc e when compared with these cells from the WT mice. However, the IFN-gk o mice had no signs of muscle weakness and remained resistant to clini cal EAMG at a time when the WT-mice exhibited severe muscle weakness a nd some died. The resistance of IFN-gko mice was associated with great ly reduced levels of circulating anti-AChR antibody levels compared wi th those in the WT mice. Comparatively, immune sera from IFN-gko mice showed a dramatic reduction in mouse AChR-specific IgG1 and IgG2a anti bodies. However, keyhole limpet hemocyanin (KLH)-priming of IFN-gko mi ce readily elicited both T cell and antibody responses, suggesting tha t IFN-gamma regulates the humoral immune response distinctly to self ( AChR) versus foreign (KLH) antigens. We conclude that IFN-gamma is req uired for the generation of a pathogenic anti-AChR humoral immune resp onse and for conferring susceptibility of mice to clinical EAMG.