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or IL-12 Has Different Effects on Experimental Myasthenia Gravis in C57BL/6 Mice1
*
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, St. Paul, MN 55108; and
Department of Pharmacology, University of Minnesota, School of Medicine, Minneapolis, MN 55455
Immunization with acetylcholine receptor (AChR) causes experimental
myasthenia gravis (EMG). Th1 cells facilitate EMG development. IFN-
and IL-12 induce Th1 responses: we investigated whether these cytokines
are necessary for EMG development. We immunized wild-type (WT) C57BL/6
mice and IFN- and IL-12 knockout mutants (IFN--/-,
IL-12-/-) with Torpedo AChR (TAChR). WT
and IFN--/- 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, IFN--/- mice had
significantly less IgG2c, and IL-12-/- mice less IgG2b
and IgG2c. All mice had IgG bound to muscle synapses, but only WT and
IFN--/- mice had complement; WT mice had both IgG2b
and IgG2c, IFN--/- only IgG2b, and
IL-12-/- neither IgG2b nor IgG2c. CD4+ cells
from all AChR-immunized mice proliferated in response to AChR and
recognized similar epitopes. After stimulation with TAChR,
CD4+ cells from IFN--/- 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-, but more
IL-4 and IL-10 than WT mice, suggesting that they developed a stronger
Th2 response to TAChR. The EMG resistance of IL-12-/-
mice is likely due to both reduction of anti-TAChR Ab that bind
complement and sensitization of modulatory Th2 cells. The reduced Th1
function of IFN--/- mice does not suffice to reduce
all complement-fixing IgG subclasses, perhaps because as in WT mice a
protective Th2 response is missing.
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