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

Department of Experimental Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
Journal of Experimental Medicine (Impact Factor: 12.52). 09/2009; 206(9):1971-82. DOI: 10.1084/jem.20082392
Source: PubMed


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.

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    • "B1 cells express various TLRs (TLR1, 2, 3, 4, 7, 8, and 9) [31]; and are more prone to terminal ASC differentiation than B2 cells upon TLRs stimulation [32]. B1 cell activation and B1 cell mediated autoantibody production are augmented upon stimulation via TLR4 or TLR9 [33], [34]. Also, TLRs signaling in B1 cells plays an important role in the clearance of various pathogens such as influenza virus, pneumococcus, and Borrelia spp [35]–[37]. "
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    ABSTRACT: This study was undertaken to gain better insights into the role of TLRs and MyD88 in the development and differentiation of memory B cells, especially of ASC, during the Th2 polarized memory response induced by Natterins. Our in vivo findings demonstrated that the anaphylactic IgG1 production is dependent on TLR2 and MyD88 signaling, and that TLR4 acts as adjuvant accelerating the synthesis of high affinity-IgE. Also, TLR4 (MyD88-independent) modulated the migration of innate-like B cells (B1a and B2) out of the peritoneal cavity, and the emigration from the spleen of B1b and B2 cells. TLR4 (MyD88-independent) modulated the emigration from the spleen of Bmem as well as ASC B220(pos). TLR2 triggered to the egress from the peritoneum of Bmem (MyD88-dependent) and ASC B220(pos) (MyD88-independent). We showed that TLR4 regulates the degree of expansion of Bmem in the peritoneum (MyD88-dependent) and in BM (MyD88-independent) as well as of ASC B220(neg) in the spleen (MyD88-independent). TLR2 regulated the intensity of the expansion of Bmem (MyD88-independent) and ASC B220(pos) (MyD88-dependent) in BM. Finally, TLR4 signals sustained the longevity of ASC B220(pos) (MyD88-independent) and ASC B220(neg) into the peritoneum (MyD88-dependent) and TLR2 MyD88-dependent signaling supported the persistence of B2 cells in BM, Bmem in the spleen and ASC B220(neg) in peritoneum and BM. Terminally differentiated ASC B220(neg) required the cooperation of both signals through TLR2/TLR4 via MyD88 for longevity in peritoneum, whereas Bmem required only TLR2/MyD88 to stay in spleen, and ASC B220(pos) rested in peritoneum dependent on TLR4 signaling. Our data sustain that earlier events on memory B cells differentiation induced in secondary immune response against Natterins, after secondary lymph organs influx and egress, may be the key to determining peripheral localization of innate-like B cells and memory B cells as ASC B220(pos) and ASC B220(neg).
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "B-1 cells are more prone to terminal plasma cell differentiation than B-2 cells upon TLR stimulation (Genestier et al., 2007). B-1 cell activation and B-1 cell mediated auto-antibody production are augmented upon stimulation via TLR4 or TLR9 (Murakami et al., 1994; Kubo et al., 2009). Also, TLR signaling in B-1 cells plays an important role in the clearance of various pathogens such as influenza virus, pneumococcus, and Borrelia spp. "
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    ABSTRACT: B-1 cells constitute a unique subset of B cells identified in several species including mice and humans. B-1 cells are further subdivided into B-1a and B-1b subsets as the former but not the later express CD5. The B-1a subset contributes to innate type of immune responses while the B-1b B cell subset contributes to adaptive responses. B-1 cell responses to B cell receptor (BCR) as well as Toll-like receptor (TLR) ligation are tightly regulated due to the cross-reactivity of antigen specific receptors on B-1 cells to self-antigens. B-1 cells are elevated in several autoimmune diseases. CD5 plays a major role in down regulation of BCR responses in the B-1a cell subset. Reduced amplification of BCR induced signals via CD19 and autoregulation of BCR and TLR responses by B-1 cell produced IL-10 appear to have a role in regulation of both B-1a and B-1b B cell responses. Siglec G receptors and Lyn kinase also regulate B-1 cell responses but their differential role in the two B-1 cell subsets is unknown.
    Full-text · Article · Dec 2012 · Frontiers in Immunology
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    • "However, it has not been determined how the B-1a cell compartment is regulated by PIR-B or what the physiological or pathological consequence of the expanded B-1a cells is in the contexts of infection and autoimmunity. We found that PIR-B on B-1 cells suppresses TLR9 signaling via Bruton's tyrosine kinase (Btk) dephosphorylation, which leads to attenuated activation of NF-κB p65RelA and blocks the production of natural IgM antibodies, including anti-IgG Fc autoantibodies or rheumatoid factor (RF) in particular [11]. "
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    ABSTRACT: PIR-B, an inhibitory receptor expressed on murine B cells and myeloid cells, regulates humoral and cellular immune responses via its constitutive binding to the ligand, MHC class I molecules, on the same cells (cis) or on different cells (trans). Although it has been speculated that PIR-B is important for maintaining peripheral tolerance, PIR-B single deficiency does not cause overt autoimmune diseases. Recently, however, the combination of its deficiency with the Fas lpr mutation was found to result in augmented production of autoantibodies such as IgG rheumatoid factor and anti-DNA IgG, leading to glomerulonephritis in mice. Although the precise molecular mechanism for the overall scenario is unclear, PIR-B was found to suppress TLR9-mediated production of naturally autoreactive antibodies by innate B cells or B-1 cells by inhibiting the activation of Bruton's tyrosine kinase. Thus, PIR-B is an important regulator of innate immunity mediated by TLR9 in B-1 cells, which can otherwise provoke autoimmunity when overactivated.
    Full-text · Article · Jan 2011 · BioMed Research International
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