Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity

Tomohiro Kubo, Yuki Uchida, Yuko Watanabe, Masahiro Abe, Akira Nakamura, Masao Ono, Shizuo Akira, Toshiyuki Takai

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

Pathogens are sensed by Toll-like receptors (TLRs) expressed in leukocytes in the innate immune system. However, excess stimulation of TLR pathways is supposed to be connected with provocation of autoimmunity. We show that paired immunoglobulin (Ig)-like receptor B (PIR-B), an immunoreceptor tyrosine-based inhibitory motif-harboring receptor for major histocompatibility class I molecules, on relatively primitive B cells, B-1 cells, suppresses TLR9 signaling via Bruton's tyrosine kinase (Btk) dephosphorylation, which leads to attenuated activation of nuclear factor κB p65RelA but not p38 or Erk, and blocks the production of natural IgM antibodies, including anti-IgG Fc autoantibodies, particularly rheumatoid factor. The autoantibody production in PIR-B-deficient ( Pirb-/-) mice was further augmented in combination with the Fas lpr mutation, which might be linked to the development of autoimmune glomerulonephritis. These results show the critical link between TLR9-mediated sensing and a simultaneously evoked, PIR-B-mediated inhibitory circuit with a Btk intersection in B-1 cells, and suggest a novel way toward preventing pathogenic natural autoantibody production.

Original languageEnglish
Pages (from-to)1971-1982
Number of pages12
JournalJournal of Experimental Medicine
Volume206
Issue number9
DOIs
Publication statusPublished - 2009 Aug 31

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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