title: Absence of IFN-gamma or IL-12 has different effects on experimental myasthenia gravis in C57BL/6 mice.
abstract: Immunization with acetylcholine receptor (AChR) causes experimental myasthenia gravis (EMG). Th1 cells facilitate EMG development. IFN-gamma 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-gamma and IL-12 knockout mutants (IFN-gamma-/-, IL-12-/-) with Torpedo AChR (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, IFN-gamma-/- 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-gamma-/- mice had complement; WT mice had both IgG2b and IgG2c, IFN-gamma-/- 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-gamma-/- 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 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-gamma-/- mice does not suffice to reduce all complement-fixing IgG subclasses, perhaps because as in WT mice a protective Th2 response is missing.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: P I
authors.initials: PI
authors.lastname: Karachunski
authors.forename: N S
authors.initials: NS
authors.lastname: Ostlie
authors.forename: C
authors.initials: C
authors.lastname: Monfardini
authors.forename: B M
authors.initials: BM
authors.lastname: Conti-Fine
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001666:Binding Sites, Antibody; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics*; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics*; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000276:immunology / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014101:Torpedo / Q000276:immunology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; C051931:myasthenia gravis anti-skeletal muscle antibody; D018664:Interleukin-12; D007371:Interferon-gamma; D003165:Complement System Proteins