title: C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-gamma are susceptible to experimental autoimmune myasthenia gravis, suggesting a pathogenic role of non-Th1 cells.
abstract: Immunization with Torpedo acetylcholine receptor (TAChR) induces experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 (B6) mice. EAMG development needs IL-12, which drives differentiation of Th1 cells. The role of IFN-gamma, an important Th1 effector, is not clear and that of IL-17, a proinflammatory cytokine produced by Th17 cells, is unknown. In this study, we examined the effect of simultaneous absence of IL-12 and IFN-gamma on EAMG susceptibility, using null mutant B6 mice for the genes of both the IL-12/IL-23 p40 subunit and IFN-gamma (dKO mice). Wild-type (WT) B6 mice served as control for EAMG induction. All mice were immunized with TAChR in Freund's adjuvant. dKO mice developed weaker anti-TAChR CD4(+)T cells and Ab responses than WT mice. Yet, they developed EAMG symptoms, anti-mouse acetylcholine receptor (AChR) Ab, and CD4(+) T cell responses against mouse AChR sequences similar to those of WT mice. dKO and WT mice had similarly reduced AChR content in their muscles, and IgG and complement at the neuromuscular junction. Naive dKO mice had significantly fewer NK, NKT, and CD4(+)CD25(+)Foxp3(+) T regulatory (Treg) cells than naive WT mice. Treg cells from TAChR-immunized dKO mice had significantly less suppressive activity in vitro than Treg cells from TAChR-immunized WT mice. In contrast, TAChR-specific CD4(+) T cells from TAChR-immunized dKO and WT mice secreted comparable amounts of IL-17 after stimulation in vitro with TAChR. The susceptibility of dKO mice to EAMG may be due to reduced Treg function, in the presence of a normal function of pathogenic Th17 cells.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. wangx241@umn.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Monica
authors.initials: M
authors.lastname: Milani
authors.forename: Norma
authors.initials: N
authors.lastname: Ostlie
authors.forename: David
authors.initials: D
authors.lastname: Okita
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Agarwal
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
authors.forename: Rachel
authors.initials: R
authors.lastname: Caspi
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Conti-Fine
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics*; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics*; D020381:Interleukin-17 / Q000378:metabolism / Q000502:physiology; D053759:Interleukin-23 / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D020381:Interleukin-17; D053759:Interleukin-23; D011950:Receptors, Cholinergic; D018664:Interleukin-12; D007371:Interferon-gamma