Absence of IFN-gamma or IL-12 has different effects on experimental myasthenia gravis in C57BL/6 mice

Immunization with acetylcholine receptor (AChR) causes experimental myasthe nia gravis (EMG), Th1 cells facilitate EMG development. IFN-gamma and IL-12 induce Th1 responses: we investigated whether these cytokines are necessar y for EMG development. We immunized wild-type (WT) C57BL/6 mice and IFN-gam ma and IL-12 knockout mutants (IFN-gamma(-/-), IL-12(-/-)) with Torpedo ACh R (TAChR), WT and IFN-gamma(-/-) mice developed EMG with similar frequency, IL-12(-/-)mice were resistant to EMG. All strains synthesized anti-AChR Ab that were not IgM or IgE, WT mice had anti-AChR IgG1, IgG2b, and IgG2c, IF N-gamma(-/-) mice had significantly less IgG2c, and IL-12(-/-) mice less Ig G2b and IgG2c. All mice had IgG bound to muscle synapses, but only WT and I FN-gamma(-/-) mice had complement; WT mice had both IgG2b and IgG2c, IFN-ga mma(-/-) only IgG2b, and IL-12(-/-) neither IgG2b nor IgG2c. CD4(+) cells f rom all AChR-immunized mice proliferated in response to AChR and recognized similar epitopes, After stimulation with TAChR, CD4(+) cells from IFN-gamm a(-/-) mice secreted less IL-2 and similar amounts of IL-4 and IL-10 as WT mice. CD4(+) cells from IL-12(-/-) mice secreted less IFN-gamma, but more I L-4 and IL-10 than WT mice, suggesting that they developed a stronger Th2 r esponse to TAChR, The EMG resistance of IL-12(-/-) mice is likely due to bo th reduction of anti-TAChR Ab that bind complement and sensitization of mod ulatory Th2 cells. The reduced Th1 function of IFN-gamma(-/-) mice does not suffice to reduce all complement-fixing IgG subclasses, perhaps because as in WT mice a protective Th2 response is missing.