| Myasthenia gravis (MG) is a T cell-dependent antibody-mediated autoimmune disease. The cause of symptoms is the reduction of functional acetylcholine receptors (AChR) at the postsynaptic membrane, mediated by autoantibodies against AChR; thereby, causing muscle weakness and fatigability. Previous research showed that IL-12, a major inducer of IFN-γ production, enhanced clinical experimental autoimmune myasthenia gravis (EAMG). IL-12 is known to increase the complement fixing isotype IgG2a in mice via IFN-γ.; Our current research demonstrated that Torpedo californica AChR (TAChR) immunized, IL-12-treated bm12 mice remained resistant to EAMG, even though they produced similar amounts of anti-TAChR IgG2a and total anti-TAChR IgG as did similarly treated B6 mice, which showed muscle weakness. Interestingly, these bm12 mice produced much less IFN-γ than the B6 mice. Our results suggest that IFN-γ may influence muscle weakness independently of the change in isotype distribution.; To investigate the effects of IL-12 on EAMG independent of antibody properties, we performed passive transfer experiments with mAb35 (a monoclonal rat anti-AChR IgG1). In the transfer experiment, B6 mice were immunized with Tα146–162 (T cell epitope) and treated with IL-12 followed by mAb35. IL-12 enhanced disease, even though the amount and properties of anti-AChR were the same in treated and untreated mice. T cell priming with Tα146–162 was not required for the enhancement of passive disease. To examine the role of IFN-γ in IL-12 effects, we conducted passive transfer experiments with IFN-γ−/− mice. Interestingly, no passive EAMG was induced in these mice, with or without IL-12 treatment. These results suggest a significant role for innate immune responses and IFN-γ in enhancing muscle weakness, possibly by direct effects on muscle cells. Clarifying these effects may help in understanding the lack of correlation between anti-AChR titers and disease severity in MG. (Supported by NIH AI 43061)... |
