Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus

Immunity. 2013 Mar 21;38(3):528-40. doi: 10.1016/j.immuni.2012.11.017. Epub 2013 Mar 14.

Abstract

Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Fas(lpr) mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Antinuclear / blood
  • Antibodies, Antinuclear / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Nephritis / genetics
  • Lupus Nephritis / immunology
  • Lupus Nephritis / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology*
  • Myeloid Differentiation Factor 88 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism

Substances

  • Antibodies, Antinuclear
  • Cytokines
  • Immunoglobulin G
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88