title: Spontaneous class switching and B cell hyperactivity increase autoimmunity against intracellular self antigen in Lyn-deficient mice.
abstract: IgG autoantibodies cause pathology due to their ability to bind self antigens. However, the extent to which the initial B cell activation and isotype switching is antigen-driven is unclear and it has been widely proposed that intrinsic B cell hyperactivity may be a contributing factor. To explore this issue we generated mice with B cell hyperactivity secondary to deficiency in the src kinase Lyn that also expressed a gene-targeted anti-hen egg lysozyme Ig construct (VDJkappa) capable of class switching to all isotypes. The B cell hyperactivity caused spontaneous hypersecretion of antibodies and class switching to IgM, IgA, IgG1 and IgG3 isotypes in the absence of self antigen, and this persisted as an autoimmune phenomenon in the presence of intracellularly expressed hen egg lysozyme. Exaggerated class switching was also unaffected by antigen in vitro. These findings show that systemic high-avidity intracellular self antigens do not induce self tolerance in the face of B cell hyperactivity. Under these circumstances, spontaneous activation of hyperactive B cells leads to isotype switching and the development of high titres of IgG autoantibodies against intracellular proteins.
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
authors.forename: Karlee
authors.initials: K
authors.lastname: Silver
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Bouriez-Jones
authors.forename: Tanya
authors.initials: T
authors.lastname: Crockford
authors.forename: Helen
authors.initials: H
authors.lastname: Ferry
authors.forename: H Lucy
authors.initials: HL
authors.lastname: Tang
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009113:Muramidase / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D001324:Autoantigens; D007132:Immunoglobulin Isotypes; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C421864:hen egg lysozyme; D009113:Muramidase