Chromatin-IgG Complexes Activate B Cells by Dual Engagement of IgM and Toll-like Receptors

Nature. 2002 Apr 11;416(6881):603-7. doi: 10.1038/416603a.

Abstract

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigen-Antibody Complex
  • Antigens, Differentiation / metabolism
  • B-Lymphocytes / immunology*
  • Chromatin / immunology*
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Deoxyribonuclease I / metabolism
  • Drosophila Proteins*
  • Immunoglobulin G / immunology*
  • Immunoglobulin M / immunology*
  • Lymphocyte Activation*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / metabolism*
  • Receptors, Complement 3b / deficiency
  • Receptors, Complement 3b / immunology
  • Receptors, Complement 3d / deficiency
  • Receptors, Complement 3d / immunology
  • Receptors, Immunologic / metabolism
  • Rheumatoid Factor / immunology*
  • Signal Transduction
  • Toll-Like Receptor 9
  • Toll-Like Receptors

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigen-Antibody Complex
  • Antigens, Differentiation
  • Chromatin
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Immunoglobulin G
  • Immunoglobulin M
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Cell Surface
  • Receptors, Complement 3b
  • Receptors, Complement 3d
  • Receptors, Immunologic
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Rheumatoid Factor
  • Deoxyribonuclease I