TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE

Marc Ehlers, Hidehiro Fukuyama, Tracy L. McGaha, Alan Aderem, Jeffrey V. Ravetch

Research output: Contribution to journalArticle

267 Scopus citations

Abstract

Loss of tolerance in systemic lupus erythematosus (SLE) leads to the generation of autoantibodies, which accumulate in end-organs where they induce disease. Here we show that immunoglobulin (Ig)G2a and 2b autoantibodies are the pathogenic isotypes by recruiting FcγRIV expressing macrophages. Class switching, but not development, of IgM anti-self B cells to these pathogenic subclasses requires the innate immune receptor Toll-like receptor (TLR)9 and MyD88 signaling. In their absence, switching of autoreactive B cells to the IgG2a and 2b subclasses is blocked, resulting in reduced pathology and mortality. In contrast, switching of anti-self B cells to IgG1 is not perturbed and generation of nonautoreactive IgG2a and 2b antibodies is not impaired in TLR9-deficient mice. Thus, the TLR9 pathway is a potential target for therapeutic intervention in SLE. JEM

Original languageEnglish (US)
Pages (from-to)553-561
Number of pages9
JournalJournal of Experimental Medicine
Volume203
Issue number3
DOIs
StatePublished - Mar 20 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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