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 kappaB 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.