Resistance to experimental autoimmune myasthenia gravis in IL-6-deficient mice is associated with reduced germinal center formation and C3 production

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, IgG_2b, and IgG_2c, 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.