title: Chronic bacterial infection activates autoreactive B cells and induces isotype switching and autoantigen-driven mutations.
abstract: The links between infections and the development of B-cell-mediated autoimmune diseases are still unclear. In particular, it has been suggested that infection-induced stimulation of innate immune sensors can engage low affinity autoreactive B lymphocytes to mature and produce mutated IgG pathogenic autoantibodies. To test this hypothesis, we established a new knock-in mouse model in which autoreactive B cells could be committed to an affinity maturation process. We show that a chronic bacterial infection allows the activation of such B cells and the production of nonmutated IgM autoantibodies. Moreover, in the constitutive presence of their soluble antigen, some autoreactive clones are able to acquire a germinal center phenotype, to induce Aicda gene expression and to introduce somatic mutations in the IgG heavy chain variable region on amino acids forming direct contacts with the autoantigen. Paradoxically, only lower affinity variants are detected, which strongly suggests that higher affinity autoantibodies secreting B cells are counterselected. For the first time, we demonstrate in vivo that a noncross-reactive infectious agent can activate and induce autoreactive B cells to isotype switching and autoantigen-driven mutations, but on a nonautoimmune background, tolerance mechanisms prevent the formation of consequently dangerous autoimmunity.
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.|"Pôle de Médecine et de Chirurgie Bucco-Dentaires", University Hospital and Biological Sciences, Faculty of Dentistry, University of Strasbourg, Strasbourg, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, Connecticut, New Haven, CT, USA.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: EA 7290, "Early Bacterial Virulence", Bacteriology Institute, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Kern
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Knapp
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Eftekhari
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Da Silva
authors.affiliation: EA 7290, "Early Bacterial Virulence", Bacteriology Institute, Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Jaulhac
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.|Faculty of Pharmacy, University of Strasbourg, Illkirch-Graffenstaden, France.|Department of Clinical Immunology, University Hospital, Strasbourg, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Soulas-Sprauel
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.|Department of Clinical Immunology, University Hospital, Strasbourg, France.|Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Pasquali
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.|Department of Clinical Immunology, University Hospital, Strasbourg, France.|Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Martin
authors.affiliation: CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/ Laboratory of Excellence Medalis, Molecular and Cellular Biology Institute (IBMC), Strasbourg, France.|Department of Clinical Immunology, University Hospital, Strasbourg, France.|Faculty of Medicine, University of Strasbourg, Strasbourg, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Korganow
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D025065:Borrelia burgdorferi; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D008193:Lyme Disease / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D020349:Surface Plasmon Resonance
chemical_list: D001324:Autoantigens; D007132:Immunoglobulin Isotypes
keywords: Affinity maturation; Autoreactive B cell; B-cell tolerance; Germinal center; Infection