Resistance to Experimental Autoimmune Myasthenia Gravis in IL-6-Deficient Mice Is Associated with Reduced Germinal Center Formation and C3 Production

Abstract

To provide direct genetic evidence for a role of IL-6 in experimental autoimmune myasthenia gravis (EAMG), IL-6 gene KO (IL-6−/−) mice in the C57BL/6 background were immunized with Torpedo californica acetylcholine receptor (AChR) and evaluated for EAMG. Only 25% of AChR-immunized IL-6−/− mice developed clinical EAMG compared to 83% of C57BL/6 (wild-type) mice. A significant reduction in the secondary anti-AChR Ab of IgG, IgG2b, and IgG2c, but not the primary or secondary IgM response was observed in AChR-immunized IL-6−/− mice, suggesting a possible defect in T cell help and class switching to anti-AChR IgG2 isotype. The AChR-specific lymphocyte proliferative response, IFN-γ, and IL-10 production were suppressed in AChR-immunized IL-6−/− mice. EAMG resistance in IL-6−/− mice was associated with a significant reduction in germinal center formation and decreased serum complement C3 levels. The data provide the first direct genetic evidence for a key role of IL-6 in the autoimmune response to AChR and in EAMG pathogenesis.

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

“…Since this could be secondary to IL-6 deficiency, we measured autoantigen-induced Th17 responses in IL-6 -/-mice immunized with AChR/CFA. Consistent with previous reports [24], IL-6 -/-mice were resistant to the induction of EAMG. Importantly, IL-6 -/-mice had impaired capacity to mount AChR-induced production of IL-17 in CD4 + cells, while IFN-c production was not altered significantly (Fig.…”

“…In a previous study, IL-6 -/-mice were found resistant to the induction of EAMG [24]. Our current data taken in the content of recent findings [9] suggest that the resistance to EAMG could derive from faulty development of Th17 cells.…”

“…We found that CCL2-deficient mice developed milder behavioral and histological disease following the induction of EAMG. This result was surprising because monocyte infiltrates, the hallmark of CCL2 action, are not prominent in EAMG muscle [24]. This defect was not caused by impaired function of autoreactive B cells, which remained intrinsically intact in the absence of CCL2.…”

“…It has been reported that IL-6 -/-mice had impaired anti-AChR IgG2b response upon immunization with AChR [24]. The question arises as whether the impaired IgG2b response is due to the lack of IL-6, or altered IL-17 response in IL-6 -/-mice, or both.…”

An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

“…However, only the two-component system was strongly dependent on the endogenous IL-6 activity in vivo (Figure 8). This was expected as the complement C3 upregulation in response to an immunogen was completely absent in the IL-6 À/À mice 41,42 and was probably regulated at the level of complement C3 promoter activation. 43,44 It is known that the TAT protein can transactivate inflammatory host genes, 45 including the IL-6 gene.…”