title: Preferential production of IgG1, IL-4 and IL-10 in MuSK-immunized mice.
abstract: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness associated with acetylcholine receptor (AChR), muscle-specific receptor kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4)-antibodies. MuSK-antibodies are predominantly of the non-complement fixing IgG4 isotype. The MuSK associated experimental autoimmune myasthenia gravis (EAMG) model was established in mice to investigate immunoglobulin (Ig) and cytokine responses related with MuSK immunity. C57BL/6 (B6) mice immunized with 30μg of recombinant human MuSK in incomplete or complete Freund's adjuvant (CFA) showed significant EAMG susceptibility (>80% incidence). Although mice immunized with 10μg of MuSK had lower EAMG incidence (14.3%), serum MuSK-antibody levels were comparable to mice immunized with 30μg MuSK. While MuSK immunization stimulated production of all antibody isotypes, non-complement fixing IgG1 was the dominant anti-MuSK Ig isotype in both sera and neuromuscular junctions. Moreover, MuSK immunized IgG1 knockout mice showed very low serum MuSK-antibody levels. Sera and MuSK-stimulated lymph node cell supernatants of MuSK immunized mice showed significantly higher levels of IL-4 and IL-10 (but not IFN-γ and IL-12), than those of CFA immunized mice. Our results suggest that through activation of Th2-type cells, anti-MuSK immunity promotes production of IL-4, which in turn activates anti-MuSK IgG1, the mouse analog of human IgG4. These findings might provide clues for the pathogenesis of other IgG4-related diseases as well as development of disease specific treatment methods (e.g. specific IgG4 inhibitors) for MuSK-related MG.
authors.affiliation: Department of Neuroscience, Institute for Experimental Medical Research, University of Istanbul, Istanbul 34393, Turkey.
authors.forename: Canan
authors.initials: C
authors.lastname: Ulusoy
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Eunmi
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Institute for Experimental Medical Research, University of Istanbul, Istanbul 34393, Turkey. Electronic address: drerdem@yahoo.com.
authors.forename: Erdem
authors.initials: E
authors.lastname: Tüzün
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Ruksana
authors.initials: R
authors.lastname: Huda
authors.affiliation: Department of Physiology, Istanbul Faculty of Medicine, University of Istanbul, Istanbul 34393, Turkey.
authors.forename: Vuslat
authors.initials: V
authors.lastname: Yılmaz
authors.affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Patras 26504, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Poulas
authors.affiliation: Hellenic Pasteur Institute, Athens 115 21, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Trakas
authors.affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Patras 26504, Greece; Hellenic Pasteur Institute, Athens 115 21, Greece.
authors.forename: Lamprini
authors.initials: L
authors.lastname: Skriapa
authors.affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Patras 26504, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Niarchos
authors.affiliation: Department of Pediatrics and Cincinnati Children's Hospital Division of Emergency Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Strait
authors.affiliation: Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45229, USA; Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.affiliation: Department of Neuroscience, Institute for Experimental Medical Research, University of Istanbul, Istanbul 34393, Turkey.
authors.forename: Selin
authors.initials: S
authors.lastname: Turan
authors.affiliation: Hellenic Pasteur Institute, Athens 115 21, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Zisimopoulou
authors.affiliation: Department of Pharmacy, School of Health Sciences, University of Patras, Patras 26504, Greece; Hellenic Pasteur Institute, Athens 115 21, Greece.
authors.forename: Socrates
authors.initials: S
authors.lastname: Tzartos
authors.affiliation: Department of Physiology, Istanbul Faculty of Medicine, University of Istanbul, Istanbul 34393, Turkey.
authors.forename: Güher
authors.initials: G
authors.lastname: Saruhan-Direskeneli
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Premkumar
authors.initials: P
authors.lastname: Christadoss
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009157:Myasthenia Gravis / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; D007074:Immunoglobulin G; D016753:Interleukin-10; D015847:Interleukin-4; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases
keywords: Anti-MuSK IgG1; Experimental autoimmune myasthenia gravis; IL-10; IL-4; Muscle specific kinase; Myasthenia gravis