Interferon γ (IFN-γ) Is Necessary for the Genesis of Acetylcholine Receptor–induced Clinical Experimental Autoimmune Myasthenia gravis in Mice

Abstract

Experimental autoimmune myasthenia gravis (EAMG) is an animal model of human myasthenia gravis (MG). In mice, EAMG is induced by immunization with Torpedo californica acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA). However, the role of cytokines in the pathogenesis of EAMG is not clear. Because EAMG is an antibody-mediated disease, 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 that the Th1 cytokine, interferon (IFN)-γ, plays a role in the development of EAMG, we immunized IFN-γ knockout (IFN-gko) (−/−) mice and wild-type (WT) (+/+) mice of H-2b haplotype with AChR in CFA. We observed that AChR-primed lymph node cells from IFN-gko mice proliferated normally to AChR and to its dominant pathogenic α146–162 sequence when compared with these cells from the WT mice. However, the IFN-gko mice had no signs of muscle weakness and remained resistant to clinical EAMG at a time when the WT mice exhibited severe muscle weakness and some died. The resistance of IFN-gko mice was associated with greatly reduced levels of circulating anti-AChR antibody levels compared with those in the WT mice. Comparatively, immune sera from IFN-gko mice showed a dramatic reduction in mouse AChR-specific IgG1 and IgG2a antibodies. However, keyhole limpet hemocyanin (KLH)–priming of IFN-gko mice readily elicited both T cell and antibody responses, suggesting that IFN-γ regulates the humoral immune response distinctly to self (AChR) versus foreign (KLH) antigens. We conclude that IFN-γ is required for the generation of a pathogenic anti-AChR humoral immune response and for conferring susceptibility of mice to clinical EAMG.

Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4

“…The suppressive effect of anti-CD40L Ab in suppression of ongoing chronic EAMG in our study was associated with down-regulation of the pathogenic inflammatory cytokine IFN-␥ and of IL-12 ( Fig. 2), both of which have been previously demonstrated to be directly or indirectly involved in induction of EAMG (31)(32)(33)(34)(35). The selective suppressive effect on Th1-type differentiation by anti-CD40L treatment is consistent with models of other autoimmune diseases such as multiple sclerosis, diabetes, and thyroiditis (17,18,36,37), and with graft-vshost disease and graft rejection (38,39).…”

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…Although earlier work had indicated that ectopic expression of IFN-c at the neuromuscular junction provoked MG-like disease [33], our current understanding of the role of IFN-c in EAMG is far from conclusive. For example, mice deficient of IFN-c [25] or IFN-c receptor [26] are resistant to EAMG, yet some groups have shown that IFN-c deficiency may not significantly alter the course of disease [27,34]. Thus, while Th1 responses may possibly play a role in the disease depending on the experimental system used, the question arises on whether other inflammatory cytokine(s) with potent propathogenic effects, such as IL-17, are required for the expression of EAMG.…”

“…We and others [25][26][27] have previously found that the development of EAMG is not dramatically altered by IFN-c deficiency. To investigate whether the effects of IL-17 on EAMG were related to or depended on IFN-c, we treated IFN-c -/-mice with IL-17 during EAMG induction, using the same regimen used for the B6 mice.…”

Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis

“…However, IFN-g is still a controversial factor in the pathogenesis of EAMG. B6 Mice with IFN-g or IFN-gR deficiency are less susceptible to EAMG [25,30]. On the contrary, IFN-gdeficient B6 mice developed EAMG with a frequency similar to Spleen and lymph node MNC were obtained from rats receiving TGF-b1-DC, naïve DC or PBS on day 39 p.i.…”