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ABSTRACT: Plasmacytoid dendritic cells (PDCs) produce type I interferons (IFNs) in response to viral nucleic acids to exert antiviral immunity. However, PDCs are related to the progress and severity of autoimmune diseases, such as systemic lupus erythematosus, because they respond to host DNA. Therefore, the regulation of PDC activation is critical for maintaining adequate immune responses. Here we show that an inhibitory major histocompatibility complex class I receptor, paired immunoglobulin-like receptor B (PIR-B), suppressed Fms-like tyrosine kinase 3 ligand-induced PDC differentiation in BM cells, as well as Toll-like receptor 9-mediated IFN-α production by PDCs, through the dephosphorylation of STAT1/STAT2. In particular, PIR-B inhibited IFN-α-mediated STAT phosphorylation, suggesting that PIR-B negatively regulates the positive feedback mechanism of IFN-α secretion triggered by Toll-like receptor 9. These results demonstrate a novel regulatory role for PIR-B in PDCs.
Blood 09/2012; 120(16):3256-9. · 9.90 Impact Factor
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ABSTRACT: To identify the dosimetric parameters associated with gastrointestinal (GI) toxicity in patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based chemoradiotherapy.
The data from 40 patients were analyzed retrospectively. Chemoradiotherapy consisted of conventional fractionated three-dimensional radiotherapy and weekly gemcitabine. Treatment-related acute GI toxicity and upper GI bleeding (UGB) were graded according to the Common Toxicity Criteria Adverse Events, version 4.0. The dosimetric parameters (mean dose, maximal absolute dose which covers 2 cm(3) of the organ, and absolute volume receiving 10-50 Gy [V(10-50)]) of the stomach, duodenum, small intestine, and a composite structure of the stomach and duodenum (StoDuo) were obtained. The planning target volume was also obtained. Univariate analyses were performed to identify the predictive factors for the risk of grade 2 or greater acute GI toxicity and grade 3 or greater UGB, respectively.
The median follow-up period was 15.7 months (range, 4-37). The actual incidence of acute GI toxicity was 33%. The estimated incidence of UGB at 1 year was 20%. Regarding acute GI toxicity, a V(50) of ≥ 16 cm(3) of the stomach was the best predictor, and the actual incidence in patients with V(50) <16 cm(3) of the stomach vs. those with V(50) of ≥ 16 cm(3) was 9% vs. 61%, respectively (p = 0.001). Regarding UGB, V(50) of ≥ 33 cm(3) of the StoDuo was the best predictor, and the estimated incidence at 1 year in patients with V(50) <33 cm(3) of the StoDuo vs. those with V(50) ≥ 33 cm(3) was 0% vs. 44%, respectively (p = 0.002). The dosimetric parameters correlated highly with one another.
The irradiated absolute volume of the stomach and duodenum are important for the risk of acute GI toxicity and UGB. These results could be helpful in escalating the radiation doses using novel techniques, such as intensity-modulated radiotherapy, for the treatment of pancreatic cancer.
International journal of radiation oncology, biology, physics 02/2012; 84(2):369-75. · 4.59 Impact Factor
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ABSTRACT: To experimentally investigate the effects of variations in respiratory motion during breath-holding (BH) at end-exhalation (EE) on intensity-modulated radiotherapy (BH-IMRT) dose distribution using a motor-driven base, films, and an ionization chamber.
Measurements were performed on a linear accelerator, which has a 120-leaf independently moving multileaf collimator with 5-mm leaf width at the isocenter for the 20-cm central field. Polystyrene phantoms with dimensions of 40 × 40 × 10 cm were set on a motor-driven base. All gantry angles of seven IMRT plans (a total of 35 fields) were changed to zero, and doses were then delivered to a film placed at a depth of 4 cm and an ionization chamber at a depth of 5 cm in the phantom with a dose rate of 600 MU/min under the following conditions: pulsation from the abdominal aorta and baseline drift with speeds of 0.2 mm/s (BD(0.2mm/s)) and 0.4 mm/s (BD(0.4mm/s)). As a reference for comparison, doses were also delivered to the chamber and film under stationary conditions.
In chamber measurements, means ± standard deviations of the dose deviations between stationary and moving conditions were -0.52% ± 1.03% (range: -3.41-1.05%), -0.07% ± 1.21% (range: -1.88-4.31%), and 0.03% ± 1.70% (range: -2.70-6.41%) for pulsation, BD(0.2mm/s), and BD(0.4mm/s), respectively. The γ passing rate ranged from 99.5% to 100.0%, even with the criterion of 2%/1 mm for pulsation pattern. In the case of BD(0.4mm/s), the γ passing rate for four of 35 fields (11.4%) did not reach 90% with a criterion of 3%/3 mm. The differences in γ passing rate between BD(0.2mm/s) and BD(0.4mm/s) were statistically significant for each criterion. Taking γ passing rates of > 90% as acceptable with a criterion of 3%/3 mm, large differences were observed in the γ passing rate between the baseline drift of ≤5 mm and that of >5 mm (minimum γ passing rate: 92.0% vs 82.7%; p < 0.01).
This study suggested that the baseline drift of >5 mm should be avoided in the BH-IMRT.
Medical Physics 01/2012; 39(1):48-54. · 2.83 Impact Factor
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ABSTRACT: Cells in the immune system are regulated positively or negatively by sets of receptor pairs that conduct balanced, activating, or inhibitory intracellular signaling. One such receptor pair termed paired Ig-like receptor (PIR) is composed of the inhibitory PIR-B and its activating isoform, PIR-A. Upon binding to their shared ligand, MHC class I molecules, these receptors control the threshold for immune cell activation. Gene-targeting studies on PIR-B in mice revealed the importance of the inhibition mediated by the PIR-B-MHC interaction in the immune system. Recent studies also revealed the significance of the interaction of PIR-B with neurite outgrowth inhibitors, including Nogo in the CNS. The coordinated regulation by PIR-B and PIR-A is considered to be primarily dependent on their expression balance in cells. However, the mechanism underlying transcriptional control of the genes for PIR-B and PIR-A (Pirb and Pira, respectively) remains to be clarified. In this study, we identified the major cis-acting promoter segment for Pirb and Pira in B cells as the -212 to -117 region upstream from the translation initiation codon. PU.1 and Runx3 were found to bind to this Pirb promoter. Truncation of the PU.1-binding motif significantly reduced the promoter activity, whereas the influence of elimination of the Runx3 site was marginal in B lymphoma BCL1-B20 cells. Unexpectedly, PU.1, but not Runx3, knockdown reduced the levels of both the Pirb and Pira transcripts. We conclude that the major promoter of Pirb, and probably Pira as well, is activated dominantly by PU.1 and marginally by Runx3 in B cells.
The Journal of Immunology 06/2011; 186(12):7050-9. · 5.79 Impact Factor
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Haruka Matsushita,
Shota Endo,
Eiji Kobayashi,
Yuzuru Sakamoto,
Keisuke Kobayashi,
Kohji Kitaguchi,
Kimiko Kuroki,
Arvid Söderhäll,
Katsumi Maenaka, Akira Nakamura,
Stephen M Strittmatter,
Toshiyuki Takai
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ABSTRACT: Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory role of PIR-B in neurite regeneration through binding to three axonal outgrowth inhibitors of myelin, including Nogo. Thus, it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here, we present data supporting the competition of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding only occurred with the N-terminal domains of PIR-B, whereas Nogo binding occurred with either the N- or C-terminal ectodomains. Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wild-type, but not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates Nogo-induced inhibition. Thus, we propose a novel mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the immune system.
Journal of Biological Chemistry 06/2011; 286(29):25739-47. · 4.77 Impact Factor
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Haruka Matsushita,
Shota Endo,
Eiji Kobayashi,
Yuzuru Sakamoto,
Keisuke Kobayashi,
Kohji Kitaguchi,
Kimiko Kuroki,
Arvid Soderhall,
Katsumi Maenaka, Akira Nakamura,
Stephen M. Strittmatter,
Toshiyuki Takai
[show abstract]
[hide abstract]
ABSTRACT: Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides
constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory
role of PIR-B in neurite regeneration through binding to three axonal outgrowth inhibitors of myelin including Nogo. Thus,
it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently
or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here we present data supporting the competition
of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part
of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding
only occurred with the N-terminal domains of PIR-B, whereas the Nogo binding occurred with either the N- or C-terminal ectodomains.
Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous
Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wild-type, but
not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates the Nogo-induced inhibition. Thus, we propose a novel
mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the
immune system.
Journal of Biological Chemistry 06/2011; · 4.77 Impact Factor
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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.
Journal of Biomedicine and Biotechnology 01/2011; 2011:275302. · 2.44 Impact Factor
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Soo Ryang Kim,
Jun Saito,
Susumu Imoto,
Takamitsu Komaki,
Yoshiaki Nagata,
Ke Ih Kim,
Noriko Sasase,
Noriyo Kimura,
Kanako Sasatani,
Erika Konishi, [......], Akira Nakamura,
Shinobu Tsuchida,
Tetsuya Makino,
Tetsumi Kawada,
Takatoshi Nakajima,
Teruhisa Morikawa,
Akira Muramatsu,
Hiroshi Kasugai,
Hak Hotta,
Masatoshi Kudo
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ABSTRACT: Double-filtration plasmapheresis (DFPP) together with interferon (IFN) administration produces a substantial reduction in the viral load during the early stages of treatment.
Based on their responses to previous pegylated IFN and ribavirin (PEG-IFN/RBV) therapy, 20 patients were divided into null virological response (NVR; n = 12) and relapse (n = 8) groups. DFPP was used in combination with IFN-β/RBV with subsequent administration of PEG-IFN-α2a/RBV therapy (DFPP + IFN-β/RBV then PEG-IFN/RBV). Early viral dynamics was assessed, focusing especially on complete early virological response (cEVR) associated with sustained virological response. Additionally, the interleukin 28B gene, the IFN/RBV resistance-determining region, the IFN sensitivity-determining region and the core regions were analyzed.
Rapid virological response was achieved in 0% (0/12) of NVR and in 75% (6/8) of relapse patients, with a significant difference between the two groups (p = 0.001). Similarly, cEVR was achieved in 8% (1/12) of NVR and in 88% (7/8) of relapse patients, with a significant difference between the two groups (p = 0.037). By multivariate logistic regression analysis, interleukin-28B major was a significant determiner of cEVR (odds ratio = 24.19, p = 0.037).
DFPP + IFN-β/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients.
Digestion 01/2011; 84 Suppl 1:10-6. · 2.05 Impact Factor
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ABSTRACT: Activated mature T cells induce various inhibitory receptors implicated in maintaining peripheral tolerance in response to the trans-acting ligands. Interestingly, paired Ig-like receptor (PIR)-B, an inhibitory MHC class I receptor on B cells and myeloid cells, could be involved in regulating early T cell development because epitope for PIR is detected on pre-thymic T/NK progenitors but not on thymocytes or mature T cells. We hypothesized that PIR-B is not only a regulator for T cell development but is also detrimental if expressed on mature T cells. Here we demonstrated, using PIR-B-deficient fetuses, that PIR-B is indeed expressed on the T cell progenitors but failed to identify its distinctive roles in the development. Forced expression of PIR-B in thymocytes and mature T cells also resulted in no abnormalities in development. However, upon antigenic or allogeneic stimulation, peripheral T cells with the ectopic PIR-B showed reduced T(h) type 1 responses due to the suppression of proximal TCR signaling by constitutive binding of PIR-B to MHC class I on the same cell surface. Our findings suggest that T cell expression of PIR-B with the cis-interacting MHC class I is strictly prohibited in periphery so as to secure prompt immune responses.
International Immunology 09/2009; 21(10):1151-61. · 3.41 Impact Factor
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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 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.
Journal of Experimental Medicine 09/2009; 206(9):1971-82. · 13.85 Impact Factor
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Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 06/2009; 54(8 Suppl):1108-13.
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Atsuhiro Masuda,
Masaru Yoshida,
Hideyuki Shiomi,
Yoshinori Morita,
Hiromu Kutsumi,
Hideto Inokuchi,
Shigeto Mizuno, Akira Nakamura,
Toshiyuki Takai,
Richard S Blumberg,
Takeshi Azuma
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ABSTRACT: It has been forty years since the discovery of Fc Receptors and their function. Fc Receptors include the IgG receptors (FcgammaR), high-affinity IgE receptor (FcepsilonRI), IgA and IgA/IgM receptors, and neonatal Fc receptor for IgG (FcRn). In particular, the FcgammaRs have been well known to play an important role in many biologic processes including those associated with the response to infection and cancer as well as in the pathogenesis of immune-mediated diseases. Both positive and negative regulatory function has ascribed to Fc receptors and FcgammaRs in particular which serve to establish a threshold for immune cell activation. In other cases, Fc receptors such as FcRn possess a novel structure and function by playing a major role in the transport of IgG across polarized epithelial barriers at mucosal surfaces and in the regulation of IgG half-life. These diverse functions highlight the potential effectiveness of targeting Fc receptors for therapeutic purposes. This review summarizes new information available in the therapeutic applications of this biology.
Inflammation & allergy drug targets. 04/2009; 8(1):80-6.
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Masanori Inui,
Yuki Kikuchi,
Naoko Aoki,
Shota Endo,
Tsutomu Maeda,
Akiko Sugahara-Tobinai,
Shion Fujimura, Akira Nakamura,
Atsushi Kumanogoh,
Marco Colonna,
Toshiyuki Takai
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ABSTRACT: Osteoclasts, cells of myeloid lineage, play a unique role in bone resorption, maintaining skeletal homeostasis in concert with bone-producing osteoblasts. Osteoclast development and maturation (osteoclastogenesis) is driven by receptor activator of NF-kappaB ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common gamma chain or DNAX-activating protein (DAP)12 (also referred to as KARAP or TYROBP) that associates with the cognate immunoreceptors. Here, we show that a third adaptor, YINM costimulatory motif-harboring DAP10, triggers osteoclastogenesis and bone remodeling. DAP10-deficient (DAP10(-/-)) mice become osteopetrotic with age, concomitant with a reduction in osteoclasts. The DAP10-associating receptor was identified as myeloid DAP12-associating lectin-1 (MDL-1), whose physiologic function has not been found. MDL-1-mediated stimulation of osteoclast precursor cells resulted in augmented osteoclastogenesis in vitro. MDL-1 associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, where DAP10 association depends almost entirely on DAP12, suggesting a formation of MDL-1-DAP12/DAP10 trimolecular complexes harboring ITAM/YINM stimulatory/costimulatory motifs within a complex that could be a novel therapeutic target for skeletal and inflammatory diseases.
Proceedings of the National Academy of Sciences 03/2009; 106(12):4816-21. · 9.68 Impact Factor
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Yu Mori,
Sukenao Tsuji,
Masanori Inui,
Yuzuru Sakamoto,
Shota Endo,
Yumi Ito,
Shion Fujimura,
Takako Koga, Akira Nakamura,
Hiroshi Takayanagi,
Eiji Itoi,
Toshiyuki Takai
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ABSTRACT: Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-kappaB ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.
The Journal of Immunology 11/2008; 181(7):4742-51. · 5.79 Impact Factor
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ABSTRACT: Dendritic cells (DC) play pivotal roles in the induction and regulation of both innate and acquired immunity. DC express several cell-surface immune inhibitory receptors. However, little is known about their potential immunoregulatory functions in the context of T-cell activation. Here we report that murine gp49B, a member of the immunoglobulin superfamily, harboring immunoreceptor tyrosine-based inhibitory motifs, is expressed on DC and downregulates cellular activity to prevent the excessive activation of T cells in vitro and in vivo. Bone marrow-derived DC (BMDC) from newly generated gp49B-deficient (gp49B(-/-)) mice induced enhanced proliferation and IL-2 release of antigen-specific CD4(+) and CD8(+) T cells compared with BMDC from wild-type mice, in a cell-cell contact manner. The enhanced proliferation by gp49B(-/-) BMDC was also observed in allogeneic CD4(+) and CD8(+) T cells. Moreover, the transfer of allogeneic BALB/c splenocytes into C57BL/6 gp49B(-/-) mice induced severe acute graft-versus-host disease with an augmented upregulation of CD86 on CD11c(+) splenic gp49B(-/-) DC, while transfer of C57BL/6 gp49B(-/-) splenocytes into BALB/c mice did not, suggesting the exacerbation of the disease was due, at least in part, to augmented activation of recipient gp49B(-/-) DC. These findings demonstrate a novel regulatory role of gp49B in the function of DC.
European Journal of Immunology 10/2008; 38(9):2426-37. · 5.10 Impact Factor
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ABSTRACT: Priming of cytotoxic T lymphocytes (CTLs) by dendritic cells (DCs) is crucial for elimination of pathogens and malignant cells. To activate CTLs, DCs present antigenic peptide-complexed MHC class I molecules (MHC-I) that will be recognized by the CTLs with T cell receptors and CD8 molecules. Here we show that paired Ig-like receptor (PIR)-B, an MHC-I receptor expressed on antigen-presenting cells, can regulate CTL triggering by blocking the access of CD8 molecules to MHC-I. PIR-B-deficient DCs evoked CTLs more efficiently, leading to accelerated graft and tumor rejection. PIR-B(+) non-DC transfectant cells served as less efficient stimulators and targets for CTLs than PIR-B(-) cells at the effector phase in vitro. On surface plasmon resonance analysis, PIR-B and CD8alpha alpha were revealed to compete in binding to MHC-I. Our results may provide a novel strategy for regulating CTL-mediated immunity and diseases in a sterical manner.
Proceedings of the National Academy of Sciences 10/2008; 105(38):14515-20. · 9.68 Impact Factor
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Atsuhiro Masuda,
Masaru Yoshida,
Hideyuki Shiomi,
Satoshi Ikezawa,
Tetsuya Takagawa,
Hiroshi Tanaka,
Ryo Chinzei,
Tsukasa Ishida,
Yoshinori Morita,
Hiromu Kutsumi,
Hideto Inokuchi,
Shuo Wang,
Kanna Kobayashi,
Shigeto Mizuno, Akira Nakamura,
Toshiyuki Takai,
Richard S Blumberg,
Takeshi Azuma
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ABSTRACT: Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the colon utilizing attaching and effacing lesions to adhere specifically to the surfaces of intestinal epithelial cells and cause mucosal inflammation. CD4+ T cells, B cells, and immunoglobulin G (IgG), but not secretory IgA or IgM, play a critical role in eradicating this pathogen. Consistent with the importance of IgG in C. rodentium eradication, IgG transport by the neonatal Fc receptor for IgG within the intestinal epithelium also has a critical role in the regulation of C. rodentium infection. It remains to be determined, however, whether Fcgamma receptors (FcgammaRs), the receptors for the Fc portion of IgG, regulate this bacterial infection within mucosal tissues. Therefore, we investigated the roles of FcgammaRs during C. rodentium infection. Fc receptor common gamma chain (FcRgamma)-deficient mice were more susceptible to C. rodentium-induced colitis. This occurred through decreased efficiency of FcR-mediated endocytosis and maturation of dendritic cells and consequently T-cell activation of antigen-specific T cells. Moreover, in the absence of FcgammaRs, phagocytosis by macrophages was significantly diminished. Therefore, activating FcgammaRs play an important role in defending against C. rodentium infection, indicating that the critical role played by IgG in this infection is not mediated by IgG alone but is dependent upon this class of receptors.
Infection and immunity 05/2008; 76(4):1728-37. · 4.21 Impact Factor
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ABSTRACT: Fc receptors (FcRs) play an important role in the maintenance of an adequate activation threshold of various cells in antibody-mediated immune responses. Analyses of murine models show that the inhibitory FcR, FcyRIIB plays a pivotal role in the suppression of antibody-mediated allergy and autoimmunity. On the other hand, the activating-type FcRs are essential for the development of these diseases, suggesting that regulation of inhibitory or activating FcR is an ideal target for a therapeutic agent. Recent experimental or clinical studies also indicate that FcRs function as key receptors in the treatment with monoclonal antibodies (mAbs) therapy. This review summarizes FcR functions and highlights possible FcR-targeting therapies including mAb therapies for allergy, autoimmune diseases and cancer.
Advances in experimental medicine and biology 02/2008; 640:220-33. · 1.09 Impact Factor
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ABSTRACT: Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet beta cells are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show early infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet beta cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D. Fc gammaRs are multipotent molecules that play important roles in Ab-mediated regulatory as well as effector functions in autoimmune diseases. To investigate the possible role of Fc gammaRs in NOD mice, we generated several Fc gammaR-less NOD lines, namely FcR common gamma-chain (Fc Rgamma)-deficient (NOD.gamma(-/-)), Fc gammaRIII-deficient (NOD.III(-/-)), Fc gammaRIIB-deficient (NOD.IIB(-/-)), and both Fc Rgamma and Fc gammaRIIB-deficient NOD (NOD.null) mice. In this study, we show significant protection from diabetes in NOD.gamma(-/-), NOD.III(-/-), and NOD.null, but not in NOD.IIB(-/-) mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.gamma(-/-) mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.gamma(-/-) animals more susceptible to diabetes, suggesting a possible scenario in which activating Fc gammaRs on dendritic cells enhance autoantigen presentation leading to the activation of autoreactive T cells, and Fc gammaRIII on NK cells trigger Ab-dependent effector functions and inflammation. These findings highlight the critical roles of activating Fc gammaRs in the development of T1D, and indicate that Fc gammaRs are novel targets for therapies for T1D.
The Journal of Immunology 08/2007; 179(2):764-74. · 5.79 Impact Factor
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ABSTRACT: Allergy is caused by immune effector cells, including mast cells and basophils. Cellular signaling that activates these effector cells is regulated by different inhibitory receptors on their surface. We show that human leukocyte immunoglobulin (Ig)-like receptor (LILR) B2 and its mouse orthologue, paired Ig-like receptor (PIR)-B, constitutively associate to major histocompatibility complex (MHC) class I on the same cell surface (in cis). The IgE-mediated effector responses were augmented in beta(2)-microglobulin (beta(2)m) and PIR-B-deficient mast cells. In addition, the increased cytokine production of beta(2)m-deficient mast cells was not affected by the co-culture with MHC class I-positive mast cells, showing that less cis interaction between PIR-B and MHC class I on mast cells led to the increased cytokine release. Thus, the constitutive cis binding between LILRB2 or PIR-B and MHC class I has an essential role in regulating allergic responses.
Journal of Experimental Medicine 05/2007; 204(4):907-20. · 13.85 Impact Factor
