Production of IgG autoantibody requires expression of activation-induced deaminase in early-developing B cells in a mouse model of SLE

Eur J Immunol. 2014 Oct;44(10):3093-108. doi: 10.1002/eji.201344282. Epub 2014 Aug 19.

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.

Keywords: AID; Pathogenic autoantibodies; Receptor editing; Systemic lupus erythemathosus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AICDA (Activation-Induced Cytidine Deaminase)
  • Animals
  • Antibodies, Antinuclear / immunology*
  • Antibody Formation / immunology
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology
  • Autoantigens / immunology
  • B-Lymphocytes / immunology*
  • Cytidine Deaminase / immunology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Immune Tolerance / immunology
  • Immunoglobulin Class Switching / immunology
  • Immunoglobulin G / immunology
  • Immunoglobulin M / immunology
  • Lupus Erythematosus, Systemic / immunology*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction

Substances

  • Antibodies, Antinuclear
  • Autoantibodies
  • Autoantigens
  • Immunoglobulin G
  • Immunoglobulin M
  • AICDA (Activation-Induced Cytidine Deaminase)
  • Cytidine Deaminase