title: Production of IgG autoantibody requires expression of activation-induced deaminase in early-developing B cells in a mouse model of SLE.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of pathogenic IgG antinuclear antibodies. Pathogenic IgG autoantibody production requires B-cell activation, leading to the production of activation-induced deaminase (AID) and class switching of IgM genes to IgG. To understand how and when B cells are activated to produce these IgG autoantibodies, we studied cells from 564Igi, a mouse model of SLE. 564Igi mice develop a disease profile closely resembling that found in human SLE patients, including the presence of IgG antinucleic acid Abs. We have generated 564Igi mice that conditionally express an activation-induced cytidine deaminase transgene (Aicda(tg) ), either in all B cells or only in mature B cells. Here, we show that class-switched pathogenic IgG autoantibodies were produced only in 564Igi mice in which AID was functional in early-developing B cells, resulting in loss of tolerance. Furthermore, we show that the absence of AID in early-developing B cells also results in increased production of self-reactive IgM, indicating that AID, through somatic hypermutation, contributes to tolerance. Our results suggest that the pathophysiology of clinical SLE might also be dependent on AID expression in early-developing B cells.
authors.affiliation: Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA; Department of Integrative Physiology and Pathobiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Umiker
authors.forename: Gabrielle
authors.initials: G
authors.lastname: McDonald
authors.forename: Amma
authors.initials: A
authors.lastname: Larbi
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Medina
authors.forename: Elias
authors.initials: E
authors.lastname: Hobeika
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
authors.forename: Thereza
authors.initials: T
authors.lastname: Imanishi-Kari
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D003564:Cytidine Deaminase / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007108:Immune Tolerance / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: AID; Pathogenic autoantibodies; Receptor editing; Systemic lupus erythemathosus