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¹ Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan
² Department of Pediatrics, Self Defense Force Sendai Hospital, Sendai 983-0041, Japan
³ Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
⁴ Laboratory of Host Defense, World Premiere International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan

CORRESPONDENCE Toshiyuki Takai: tostakai{at}idac.tohoku.ac.jp

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 B 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.

© 2009 Kubo et al.
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