Transgenic Expression of IL-10 in T Cells Facilitates Development of Experimental Myasthenia Gravis

Abstract

Ab to the acetylcholine receptor (AChR) cause experimental myasthenia gravis (EMG). Th1 cytokines facilitate EMG, whereas Th2 cytokines might be protective. IL-10 inhibits Th1 responses but facilitates B cell proliferation and Ig production. We examined the role of IL-10 in EMG by using wild-type (WT) C57BL/6 mice and transgenic (TG) C57BL/6 mice that express IL-10 under control of the IL-2 promoter. We immunized the mice with doses of AChR that cause EMG in WT mice or with low doses ineffective at causing EMG in WT mice. After low-dose AChR immunization, WT mice did not develop EMG and had very little anti-AChR serum Ab, which were mainly IgG1, whereas TG mice developed EMG and had higher levels of anti-AChR serum Ab, which were mainly IgG2, in addition to IgG1. At the higher doses, TG mice developed EMG earlier and more frequently than WT mice and had more serum anti-AChR Ab. Both strains had similar relative serum concentrations of anti-AChR IgG subclasses and IgG and complement at the muscle synapses. CD8+-depleted splenocytes from all AChR-immunized mice proliferated in the presence of AChR and recognized a similar epitope repertoire. CD8+-depleted splenocytes from AChR-immunized TG mice stimulated in vitro with AChR secreted significantly more IL-10, but less of the prototypic Th1 cytokine IFN-γ, than those from WT mice. They secreted comparable amounts of IL-4 and slightly but not significantly reduced amounts of IL-2. This suggests that TG mice had reduced activation of anti-Torpedo AChR Th1 cells, but increased anti-AChR Ab synthesis, that likely resulted from IL-10-mediated stimulation of anti-AChR B cells. Thus, EMG development is not strictly dependent on Th1 cell activity.

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.…”

The Susceptibility to Experimental Myasthenia Gravis of STAT6−/− and STAT4−/− BALB/c Mice Suggests a Pathogenic Role of Th1 Cells

“…Th1 cells have a pathogenic role in MG and EMG (e.g., 1, 9 -12); in contrast, Th2 cells may have a protective role (13)(14)(15). However, IL-10 facilitate EMG development (16,17).…”

Ex Vivo Generated Regulatory T Cells Modulate Experimental Autoimmune Myasthenia Gravis

“…Although the symptoms of MG and EAMG are mediated primarily by autoantibodies, CD4 ϩ T cells specific for the target autoantigen have a crucial role in the disease. Both Th1 and Th2 cells produce disease-associated cytokines, which are involved in the immunopathogenesis of MG and EAMG (1)(2)(3).…”