Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity.
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.
Kubo
Tomohiro
T
Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
Uchida
Yuki
Y
Watanabe
Yuko
Y
Abe
Masahiro
M
Nakamura
Akira
A
Ono
Masao
M
Akira
Shizuo
S
Takai
Toshiyuki
T
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
D001323:Autoantibodies; D016328:NF-kappa B; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; D051217:Toll-Like Receptor 9; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse
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