Human Lupus autoantibody-DNA Complexes Activate DCs Through Cooperation of CD32 and TLR9

J Clin Invest. 2005 Feb;115(2):407-17. doi: 10.1172/JCI23025.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcgammaRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32+, but not CD32-, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.

Publication types

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

MeSH terms

  • Antibodies, Antinuclear / immunology*
  • Antigen-Antibody Complex / immunology
  • Dendritic Cells / immunology*
  • Humans
  • Immunity, Innate
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Membrane Glycoproteins / metabolism*
  • Protein Binding / immunology
  • Receptors, Cell Surface / metabolism*
  • Receptors, IgG / metabolism*
  • Signal Transduction / immunology*
  • Toll-Like Receptor 9
  • Toll-Like Receptors

Substances

  • Antibodies, Antinuclear
  • Antigen-Antibody Complex
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, IgG
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Toll-Like Receptors