title: IL-17-producing CD4(+) T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis.
abstract: The role of Th17 cells in the pathogenesis of autoantibody-mediated diseases is unclear. Here, we assessed the contribution of Th17 cells to the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), which is induced by repetitive immunizations with Torpedo californica acetylcholine receptor (tAChR). We show that a significant fraction of tAChR-specific CD4(+) T cells is producing IL-17. IL-17(ko) mice developed fewer or no EAMG symptoms, although the frequencies of tAChR-specific CD4(+) T cells secreting IL-2, IFN-γ, or IL-21, and the percentage of FoxP3(+) Treg cells were similar to WT mice. Even though the total anti-tAChR antibody levels were equal, the complement fixating IgG2b subtype was reduced in IL-17(ko) as compared to WT mice. Most importantly, pathogenic anti-murine AChR antibodies were significantly lower in IL-17(ko) mice. Furthermore, we confirmed the role of Th17 cells in EAMG pathogenesis by the reconstitution of TCR β/δ(ko) mice with WT or IL-17(ko) CD4(+) T cells. In conclusion, we show that the level of IgG2b and the loss of B-cell tolerance, which results in pathogenic anti-murine AChR-specific antibodies, are dependent on IL-17 production by CD4(+) T cells. Thus, we describe here for the first time how Th17 cells are involved in the induction of classical antibody-mediated autoimmunity.
authors: Department of Experimental Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors: Hanne
authors: H
authors: Schaffert
authors: Department of Experimental Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors: Andreas
authors: A
authors: Pelz
authors: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Abhishek
authors: A
authors: Saxena
authors: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Mario
authors: M
authors: Losen
authors: Department of Experimental Neurology, Charité-University Medicine Berlin, Berlin, Germany.|NeuroCure Clinical Research Center (NCRC), Charité-University Medicine Berlin, Berlin, Germany.|Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors: Andreas
authors: A
authors: Meisel
authors: Department of Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors: Andreas
authors: A
authors: Thiel
authors: Department of Experimental Neurology, Charité-University Medicine Berlin, Berlin, Germany.|NeuroCure Clinical Research Center (NCRC), Charité-University Medicine Berlin, Berlin, Germany.|Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors: Siegfried
authors: S
authors: Kohler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology*; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics; D011950:Receptors, Cholinergic / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D014101:Torpedo / Q000276:immunology
chemical_list: D000941:Antigens; D007074:Immunoglobulin G; D020381:Interleukin-17; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011950:Receptors, Cholinergic
keywords: Autoantibodies; B-cell tolerance; Experimental autoimmune myasthenia gravis; IL-17; IgG subtypes; Th17 cells