Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Elizabeth A. Leadbetter, Ian R. Rifkin, Adreas M. Hohlbaum, Britte C. Beaudette, Mark J. Shlomchik, Ann Marshak-Rothstein

Research output: Contribution to journalArticlepeer-review

1538 Scopus citations

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-γ (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.

Original languageEnglish (US)
Pages (from-to)603-607
Number of pages5
JournalNature
Volume416
Issue number6881
DOIs
StatePublished - Apr 11 2002
Externally publishedYes

ASJC Scopus subject areas

  • General

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