title: Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice.
abstract: Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies that are frequently directed against nucleic acid-associated antigens. To better understand how B cells reactive with such antigens are regulated, we generated a model system in which heavy and light chain genes encoding 564 immunoglobulin have been targeted to the heavy and light chain loci of the nonautoimmune C57BL/6 mouse strain. This antibody recognizes RNA, single-stranded DNA, and nucleosomes. We show that B cells expressing this immunoglobulin were activated, producing class-switched autoantibody in vivo despite the apparently normal induction of anergy. This autoantibody production was largely dependent on Toll-like receptor 7 (TLR7). We further show that production of these autoantibodies was sufficient to cause kidney pathology in these mice. These results demonstrate that the particular threat of nucleic acid-containing autoantigens lies in their ability to bind both antigen receptor and TLR7.
authors.affiliation: Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Berland
authors.forename: Luis
authors.initials: L
authors.lastname: Fernandez
authors.forename: Elina
authors.initials: E
authors.lastname: Kari
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Han
authors.forename: Ina
authors.initials: I
authors.lastname: Lomakin
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Henry H
authors.initials: HH
authors.lastname: Wortis
authors.forename: John F
authors.initials: JF
authors.lastname: Kearney
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Ucci
authors.forename: Thereza
authors.initials: T
authors.lastname: Imanishi-Kari
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7