Publications by authors named "Koichi Hirose"

64 Publications

T-bet and STAT6 Coordinately Suppress the Development of IL-9-Mediated Atopic Dermatitis-Like Skin Inflammation in Mice.

J Invest Dermatol 2021 May 14;141(5):1274-1285.e5. Epub 2020 Oct 14.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address:

T-bet and signal transducer and activator of transcription (STAT) 6 are critical factors for helper T-cell differentiation in humans and mice. Additionally, polymorphisms in TBX21 (T-bet) and STAT6 are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T-bet STAT6) mice. Unexpectedly, T-bet STAT6 mice but not T-bet mice or STAT6 mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4 T cells infiltrated into the skin of T-bet STAT6 mice. Adoptive transfer of CD4 T cells of T-bet STAT6 mice into severe combined immunodeficient mice induced the accumulation of eosinophils and mast cells in the skin, whereas depletion of CD4 T cells ameliorated the dermatitis in T-bet STAT6 mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet STAT6 CD4 T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet STAT6 mice. T-bet STAT6 CD4 T cells expressed functional thymic stromal lymphopoietin receptors and produced large amounts of IL-9 on thymic stromal lymphopoietin stimulation. These results indicate that T-bet and STAT6 coordinately suppress atopic dermatitis-like skin inflammation, possibly by inhibiting thymic stromal lymphopoietin-dependent IL-9 production in CD4 T cells.
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http://dx.doi.org/10.1016/j.jid.2020.08.029DOI Listing
May 2021

Sox12 enhances Fbw7-mediated ubiquitination and degradation of GATA3 in Th2 cells.

Cell Mol Immunol 2021 Jul 9;18(7):1729-1738. Epub 2020 Mar 9.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba, Japan.

Allergic asthma that is caused by inhalation of house dust mites (HDMs) is mainly mediated by Th2 cells. Recently, the roles of Sox (SRY-related high-mobility-group (HMG)-box) family members in various immune responses have been investigated. However, the roles of Sox12, a member of the SoxC group, in Th2 cell differentiation and allergic airway inflammation, remain unknown. We showed that Sox12 mRNA was significantly increased during Th2 cell differentiation. In vivo, HDM-induced eosinophil infiltration into the lung and Th2 cell differentiation were exacerbated in Sox12 mice compared with those in control Sox12 mice. In vitro, Sox12 CD4 T cells that were cultured under Th2 conditions had increased production of Th2 cytokines and GATA3 protein compared with those of control Sox12 CD4 T cells. Importantly, forced expression of Sox12 decreased the protein levels of GATA3 in CD4 T cells under Th2 conditions without affecting mRNA expression. Furthermore, Sox12 induced degradation of GATA3 through the proteasome pathway in CD4 T cells. Consistently, Sox12 enhanced ubiquitination of GATA3, which was mediated by the E3 ligase Fbw7. Finally, we found that Fbw7 knockdown partly abrogated Sox12-mediated GATA3 suppression in CD4 T cells. Taken together, these results suggest that Sox12 suppresses Th2 cell differentiation by accelerating Fbw7-mediated GATA3 degradation, and attenuates HDM-induced allergic inflammation.
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http://dx.doi.org/10.1038/s41423-020-0384-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245422PMC
July 2021

Acute Acalculous Cholecystitis Related to Primary Epstein-Barr Virus Infection.

Am J Gastroenterol 2020 10;115(10):1571

Department of Surgery, Kanazawa Municipal Hospital, Kanazawa, Japan.

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http://dx.doi.org/10.14309/ajg.0000000000000549DOI Listing
October 2020

Experience of musculoskeletal ultrasound scanning improves physicians' physical examination skills in assessment of synovitis.

Clin Rheumatol 2020 Apr 1;39(4):1091-1099. Epub 2020 Feb 1.

Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.

Objective: Musculoskeletal ultrasound (US) is more sensitive than physical examination in detecting synovitis and helps physicians to understand its pathophysiology. In this study, we aimed to determine if the experience in musculoskeletal US scanning is independently associated with improved physical examination skills to detect synovitis.

Method: Seventy patients with rheumatoid arthritis and twenty-three physicians were enrolled. Patients were first assessed by multiple physicians with a range of clinical/sonographic experience for the swelling of the wrist, metacarpophalangeal and proximal interphalangeal (PIP) joints and next underwent US assessment performed by another physician experienced in musculoskeletal US. We then calculated the positive/negative predictive values (PPV/NPV) of joint swelling to identify US-detected synovial hypertrophy. Finally, the factors independently associated with the accuracy of clinical assessment were identified by using multivariate analyses.

Results: One thousand five hundred forty joints were assessed 6116 times in total for swelling. Overall, PPV and NPV of joint swelling were 51.7% and 88.3%, respectively. Multivariate analyses identified wrist joint, tenderness, male and greater patients' age as the factors significantly associated with higher PPV. In addition, there was a trend that longer experience in rheumatology clinical practice was associated with higher PPV (p = 0.058). On the other hand, longer experience in musculoskeletal US, PIP joint and positive rheumatoid factor were identified as the significant factors for higher NPV, while wrist joint, tenderness, presence of osteophyte and obesity as those for lower NPV.

Conclusion: Our data suggest that the experience in musculoskeletal US improves physical examination skills particularly to avoid overestimation.Key Points• Physicians with longer US experience are less likely to overestimate synovitis by physical examination.• Musculoskeletal US is a useful tool for rheumatologists to improve their physical examination skill.• Presence of osteophytes, joint tenderness and obesity influence the accuracy of physical examination of joints.
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http://dx.doi.org/10.1007/s10067-020-04960-5DOI Listing
April 2020

A case of small bowel adenocarcinoma that caused intestinal obstruction after administration of patency capsule.

Clin J Gastroenterol 2020 Aug 1;13(4):522-526. Epub 2020 Jan 1.

Department of Gastroenterology, Kanazawa Municipal Hospital, Kanazawa, Japan.

An 80-year-old man was admitted to our hospital with iron deficiency anemia and exertional chest pain. Coronary artery angiography showed 90% stenosis in the middle left anterior descending branch; abdominal computed tomography (CT) showed enlarged mesenteric lymph nodes. Although his past medical history and results of imaging studies did not suggest intestinal stenosis, assessment of intestinal patency with the PillCam® patency capsule (tag-less PC) was performed. Thirty-three hours after administration, excretion of tag-less PC was not confirmed; an abdominal contrast-enhanced CT showed arrest of tag-less PC in the small bowel and thickening of the bowel wall, suggesting a small bowel tumor. Four days after administration of tag-less PC, he developed abdominal pain and vomiting. Intestinal obstruction was diagnosed by abdominal radiograph. A diagnosis of small bowel tumor with intestinal obstruction was made, and surgical resection was performed. The tumor was histologically an adenocarcinoma. It is necessary to carefully evaluate gastrointestinal patency before small intestine endoscopy especially in elderly people with reduced cardiopulmonary function and many underlying diseases.
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http://dx.doi.org/10.1007/s12328-019-01084-5DOI Listing
August 2020

Schizophyllum commune induces IL-17-mediated neutrophilic airway inflammation in OVA-induced asthma model mice.

Sci Rep 2019 12 18;9(1):19321. Epub 2019 Dec 18.

Division of Clinical Research, Medical Mycology Research Center, Chiba University, Chiba, Chiba, Japan.

Schizophyllum commune is a ubiquitous basidiomycetous fungus typically found across the world, which has been detected in indoor and outdoor air. Some studies indicated that sensitization to S. commune is correlated with asthma severity in patients. Patients with chronic severe or acute fatal asthma have neutrophil-dominant airway inflammation. We hypothesized that S. commune can exacerbate asthma. To test this hypothesis, we evaluated the direct immunomodulatory activities of S. commune in allergic airway inflammation induced by non-fungal sensitization. Ovalbumin (OVA)-induced asthma model mice were generated using wild-type (WT) and Il-17aIl-17f mice that were intratracheally exposed to S. commune, then immune responses in the lungs were assessed after 24 h. Intratracheal administration of S. commune in OVA-induced asthma model mice enhanced neutrophilic airway inflammation, increased the mRNA expression of CXCL1 and CXCL2 in the lungs, and provoked IL-17A, and IL-17F production in BAL fluid. In addition, neutrophilic airway inflammation was significantly inhibited in Il-17aIl-17f mice compared with those found in WT mice. We demonstrated that S. commune induces neutrophilic airway inflammation in OVA-induced asthma model mice, and IL-17A and IL-17F had central roles in this activity. As S. commune inhabits the general environment, including indoor and outdoor air, our results suggested that S. commune is a causative agent of asthma exacerbation. This study has provided clues regarding the mechanisms behind fungi and asthma exacerbation.
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http://dx.doi.org/10.1038/s41598-019-55836-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920419PMC
December 2019

Mice lacking fucosyltransferase 2 show reduced innate allergic inflammation in the airways.

Allergy 2020 05 28;75(5):1253-1256. Epub 2019 Nov 28.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/all.14101DOI Listing
May 2020

Successful closure of a colon perforation via the over-the-scope-clip system after accidental ingestion of a fish bone.

Endoscopy 2020 04 25;52(4):E126-E127. Epub 2019 Oct 25.

Department of Surgery, Kanazawa Municipal Hospital, Kanazawa, Ishikawa, Japan.

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http://dx.doi.org/10.1055/a-1024-3373DOI Listing
April 2020

[IL-22 IN BRONCHIAL ASTHMA].

Arerugi 2019;68(8):923-927

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University.

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http://dx.doi.org/10.15036/arerugi.68.923DOI Listing
October 2019

IL-21 enhances mast cell accumulation in the intestine and exacerbates the development of experimental food allergy.

Clin Exp Allergy 2019 11 18;49(11):1523-1526. Epub 2019 Aug 18.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1111/cea.13473DOI Listing
November 2019

γδ T cells enhance TSLP production and ILC2 accumulation in house dust mite-induced allergic airway inflammation.

Allergol Int 2020 01 28;69(1):132-135. Epub 2019 Jun 28.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1016/j.alit.2019.05.010DOI Listing
January 2020

Fucosyltransferase 2 induces lung epithelial fucosylation and exacerbates house dust mite-induced airway inflammation.

J Allergy Clin Immunol 2019 09 21;144(3):698-709.e9. Epub 2019 May 21.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address:

Background: One of the pathognomonic features of asthma is epithelial hyperproduction of mucus, which is composed of a series of glycoproteins; however, it remains unclear how glycosylation is induced in lung epithelial cells from asthmatic patients and how glycan residues play a role in the pathogenesis of asthma.

Objective: The objective of this study was to explore comprehensive epithelial glycosylation status induced by allergic inflammation and reveal its possible role in the pathogenesis of asthma.

Methods: We evaluated the glycosylation status of lung epithelium using a lectin microarray. We next searched for molecular mechanisms underlying epithelial glycosylation. We also examined whether epithelial glycosylation is involved in induction of allergic inflammation.

Results: On allergen inhalation, lung epithelial cells were heavily α(1,2)fucosylated by fucosyltransferase 2 (Fut2), which was induced by the IL-13-signal transducer and activator of transcription 6 pathway. Importantly, Fut2-deficient (Fut2) mice, which lacked lung epithelial fucosylation, showed significantly attenuated eosinophilic inflammation and airway hyperresponsiveness in house dust mite (HDM)-induced asthma models. Proteome analyses and immunostaining of the HDM-challenged lung identified that complement C3 was accumulated in fucosylated areas. Indeed, Fut2 mice showed significantly reduced levels of C3a and impaired accumulation of C3a receptor-expressing monocyte-derived dendritic cells in the lung on HDM challenge.

Conclusion: Fut2 induces epithelial fucosylation and exacerbates airway inflammation in asthmatic patients in part through C3a production and monocyte-derived dendritic cell accumulation in the lung.
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http://dx.doi.org/10.1016/j.jaci.2019.05.010DOI Listing
September 2019

Bidirectional roles of IL-22 in the pathogenesis of allergic airway inflammation.

Allergol Int 2019 Jan 10;68(1):4-8. Epub 2018 Nov 10.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address:

Asthma is the most prevalent allergic disease of the airway, which is characterized by eosinophilic inflammation, mucus hyperproduction, and airway hyper-responsiveness. Although these pathognomonic features are mainly mediated by antigen-specific Th2 cells and their cytokines, such as IL-4, IL-5, and IL-13, recent studies have revealed that other inflammatory cells, including Th17 cells and innate lymphoid cells (ILCs), also play a critical role in the pathogenesis of asthma. IL-22, one of the cytokines produced by Th17 cells and type 3 ILCs, has distinct functional properties, as IL-22 exclusively acts on non-hematopoietic cells including epithelial cells of mucosal surface and exhibits a broad range of action in regeneration and host protection. In accordance with the fact that lung epithelial cells play a critical role in the pathogenesis of asthma, we and other groups have shown that IL-22 is involved in the regulation of allergic airway inflammation. In this review, we discuss recent advances in the biology of IL-22 and its involvement in the pathogenesis of allergic airway inflammation.
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http://dx.doi.org/10.1016/j.alit.2018.10.002DOI Listing
January 2019

Sox12 promotes T reg differentiation in the periphery during colitis.

J Exp Med 2018 10 6;215(10):2509-2519. Epub 2018 Sep 6.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Japan

Peripherally induced regulatory T (pT reg) cells play indispensable roles in regulating gut inflammation; however, the mechanism underling the differentiation of pT reg cells under inflammatory conditions remains largely unknown. Here, we show that the expression of Sox12, a member of SoxC family, is significantly induced in T reg cells in colitic mice. We also show that TCR-NFAT signaling induces Sox12 expression in CD4 T cells. Although Sox12 is not required for the development of thymus-derived T reg (tT reg) cells, Sox12 is involved in the development of pT reg cells under inflammatory conditions in an adoptive transfer colitis model. Moreover, we found that enforced expression of Sox12 is sufficient to promote Foxp3 expression in CD4 T cells even in the absence of TGF-β or IL-2 and that Sox12 binds to Foxp3 promoter and drives its transcription. These results suggest that TCR-NFAT signaling induces the development of pT reg cells in colitic mice partly through Sox12 induction.
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http://dx.doi.org/10.1084/jem.20172082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170178PMC
October 2018

Roles of Dectin-1 in Allergic Airway Inflammation.

Crit Rev Immunol 2017 ;37(1):15-21

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.

Asthma is a chronic allergic inflammatory disease of the airways. The symptoms can be controlled by inhaled corticosteroids together with long-acting β2 agonists in the majority of patients; however, in some patients, their symptoms remain uncontrolled even under intensive treatment. Although underlying mechanisms of the heterogeneous responses to the treatment are largely unknown, a series of recent epidemiological studies have suggested a link between the severity of asthma and the sensitization to fungi. Dectin-1, a C-type lectin receptor expressed on myeloid cells and plays protective roles against fungi by recognizing a cell-wall component of fungi, has recently been suggested to be involved in the development of severe asthma. In this review, we summarize the roles of Dectin-1 in the pathogenesis of severe asthma and discuss the possibility of its therapeutic application.
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http://dx.doi.org/10.1615/CritRevImmunol.2017024718DOI Listing
April 2019

Roles of IL-22 in allergic airway inflammation in mice and humans.

Int Immunol 2018 08;30(9):413-418

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.

Asthma is a chronic inflammatory disease of the airways that is characterized by eosinophilic inflammation, mucus hypersecretion and airway remodeling that leads to airway obstruction. Although these pathognomonic features of asthma are primarily mediated by allergen-specific T helper type 2 cells (Th2 cells) and their cytokines, recent studies have revealed critical roles of lung epithelial cells in the pathogenesis of asthma. Lung epithelial cells not only form physical barriers by covering the surfaces of the airways but also sense inhaled allergens and initiate communication between the environment and the immune system. The causative involvement of lung epithelium in the pathogenesis of asthma suggests that some molecules that modulate epithelial function have a regulatory role in asthma. IL-22, an IL-10-family cytokine produced by IL-17A-producing T helper cells (Th17 cells), γδ T cells and group 3 innate lymphoid cells (ILC3s), primarily targets epithelial cells and promotes their proliferation. In addition, IL-22 has been shown to induce epithelial production of various molecules that regulate local immune responses. These findings indicate that IL-22 plays crucial roles in the pathogenesis of asthma by regulating epithelial function. Here, we review the current understanding of the molecular and cellular mechanisms underlying IL-22-mediated regulation of airway inflammation in asthma.
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http://dx.doi.org/10.1093/intimm/dxy010DOI Listing
August 2018

IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite-induced asthma models.

J Exp Med 2017 Oct 15;214(10):3037-3050. Epub 2017 Aug 15.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan

Previous studies have shown that IL-22, one of the Th17 cell-related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen-specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3γ production from lung epithelial cells through STAT3 activation and that neutralization of Reg3γ significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3γ production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells.
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http://dx.doi.org/10.1084/jem.20162108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626396PMC
October 2017

Allergic airway inflammation: key players beyond the Th2 cell pathway.

Immunol Rev 2017 07;278(1):145-161

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Allergic asthma is characterized by eosinophilic airway inflammation, mucus hyperproduction, and airway hyperreactivity, causing reversible airway obstruction. Accumulating evidence indicates that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate these pathognomonic features of asthma. However, over the past decade, the understanding of asthma pathogenesis has made a significant shift from a Th2 cell-dependent, IgE-mediated disease to a more complicated heterogeneous disease. Recent studies clearly show that not only Th2 cytokines but also other T cell-related cytokines such as IL-17A and IL-22 as well as epithelial cell cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are involved in the pathogenesis of asthma. In this review, we focus on the roles of these players beyond Th2 pathways in the pathogenesis of asthma.
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http://dx.doi.org/10.1111/imr.12540DOI Listing
July 2017

Dectin-1 plays a critical role in HDM-induced PGE production in macrophages.

Allergol Int 2017 Sep 20;66S:S44-S46. Epub 2017 May 20.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

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http://dx.doi.org/10.1016/j.alit.2017.05.001DOI Listing
September 2017

Dectin-1 Plays an Important Role in House Dust Mite-Induced Allergic Airway Inflammation through the Activation of CD11b+ Dendritic Cells.

J Immunol 2017 01 16;198(1):61-70. Epub 2016 Nov 16.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;

It is well known that sensitization against fungi is closely associated with severity of asthma. Dectin-1 (gene symbol Clec7a), a C-type lectin receptor, recognizes the fungal cell wall component β-glucan, as well as some component(s) in house dust mite (HDM) extract. However, the roles of Dectin-1 in HDM-induced allergic airway inflammation remain unclear. In this study, we used Dectin-1-deficient (Clec7a) mice to examine whether Dectin-1 is involved in HDM-induced allergic airway inflammation. We found that HDM-induced eosinophil and neutrophil recruitment into the airways was significantly attenuated in Clec7a mice compared with that in wild-type mice. In addition, HDM-induced IL-5, IL-13, and IL-17 production from mediastinum lymph node cells was reduced in HDM-sensitized Clec7a mice. Dectin-1 was expressed on CD11b dendritic cells (DCs), an essential DC subset for the development of allergic inflammation, but not on CD103 DCs, plasmacytoid DCs, or lung epithelial cells. Transcriptome analysis revealed that the expression of chemokine/chemokine receptors, including CCR7, which is indispensable for DC migration to draining lymph nodes, was decreased in Clec7a DCs. In accordance with these results, the number of HDM-labeled CD11b DCs in mediastinum lymph nodes was significantly reduced in Clec7a mice compared with wild-type mice. Taken together, these results suggest that Dectin-1 expressed on CD11b DCs senses some molecule(s) in HDM extract and plays a critical role in the induction of HDM-induced allergic airway inflammation by inducing the expression of chemokine/chemokine receptors in DCs.
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http://dx.doi.org/10.4049/jimmunol.1502393DOI Listing
January 2017

T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production.

J Allergy Clin Immunol 2017 Apr 23;139(4):1355-1367.e6. Epub 2016 Sep 23.

Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address:

Background: Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and type 1 ILCs; however, the roles of T-bet in lung type 2 innate lymphoid cells (ILC2s) remain unknown.

Objective: We sought to determine the role of T-bet in ILC2-mediated airway inflammation.

Methods: The expression of T-bet in lung ILCs (defined as Thy1.2 Lin cells) was examined. The roles of T-bet in the development of lung ILC2s and airway inflammation induced by IL-33 administration were examined by using T-bet-deficient (T-bet) mice. Gene expression profiles of T-bet lung ILCs were analyzed by RNA sequencing.

Results: T-bet was expressed in lung ILC2s (defined as Thy1.2 Lin cells expressing ST2 or CD25) and IFN-γ enhanced its expression. Although the development of lung ILC2s at steady-state conditions was normal in T-bet mice, IL-33-induced accumulation of lung ILC2s and eosinophilic airway inflammation were exacerbated in T-bet mice. The exacerbated accumulation of ILC2s and eosinophilic airway inflammation by the absence of T-bet were evident even in a RAG2 background, suggesting that T-bet expressed in non-T/non-B population is involved in the suppression of IL-33-induced eosinophilic airway inflammation. Transcriptome analysis revealed that IL-9 expression in IL-33-stimulated lung ILCs was upregulated in T-bet mice compared with that in wild-type mice. Importantly, neutralization of IL-9 markedly attenuated IL-33-induced accumulation of lung ILC2s and eosinophilic inflammation in T-bet mice.

Conclusions: T-bet suppresses IL-9 production from lung ILC2s and thereby inhibits IL-33-induced eosinophilic airway inflammation.
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http://dx.doi.org/10.1016/j.jaci.2016.08.022DOI Listing
April 2017

Corticosteroid-sparing effect of tacrolimus in the initial treatment of dermatomyositis and polymyositis.

Mod Rheumatol 2015 30;25(6):888-92. Epub 2015 Apr 30.

a Department of Allergy and Clinical Immunology , Chiba University Hospital , Chiba , Japan.

Objective: In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment of PM/DM.

Methods: We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1 mg/kg/day (Conventional Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8 mg/kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected.

Results: There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination Group was significantly lower than that in the Conventional Monotherapy Group during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients, except one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate was comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy.

Conclusion: This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM.
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http://dx.doi.org/10.3109/14397595.2015.1029239DOI Listing
September 2016

Helios Enhances Treg Cell Function in Cooperation With FoxP3.

Arthritis Rheumatol 2015 Jun;67(6):1491-502

Chiba University Graduate School of Medicine, Chiba, Japan.

Objective: Helios+FoxP3+CD4+ (Helios+) Treg cells are believed to be involved in the regulation of various autoimmune diseases; however, the regulatory mechanisms underlying the development of Helios+ Treg cells remain uncertain. This study was undertaken to elucidate the regulatory mechanisms of Helios expression in CD4+ T cells and its roles in transforming growth factor β (TGFβ)-induced Treg cell function.

Methods: We examined the expression of Helios in CD4+ T cells in patients with rheumatoid arthritis by DNA microarray analysis before and after treatment with biologic agents. We also examined the effect of interleukin-6 (IL-6) and TGFβ on Helios expression in CD4+ T cells in humans and mice. The effect of forced expression of Helios on murine induced Treg cell function was also examined. The role of FoxP3 in the induction and function of Helios was assessed by using CD4+ T cells from FoxP3-deficient scurfy mice.

Results: Tocilizumab, but not tumor necrosis factor (TNF) inhibitors or abatacept, increased Helios expression in CD4+ T cells in patients with a good response. IL-6 inhibited the TGFβ-induced development of Helios+ induced Treg cells in both humans and mice. Both cell-intrinsic FoxP3 expression and TGFβ signaling were required for Helios induction in murine induced Treg cells. The forced expression of Helios enhanced the expression of various Treg cell-related molecules and the suppressive function in murine induced Treg cells. Helios-mediated enhancement of the suppressive function of induced Treg cells was obvious in FoxP3-sufficient CD4+ T cells but not in FoxP3-deficient CD4+ T cells.

Conclusion: Our findings indicate that Helios enhances induced Treg cell function in cooperation with FoxP3.
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http://dx.doi.org/10.1002/art.39091DOI Listing
June 2015

Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3.

J Exp Med 2014 Aug 29;211(9):1857-74. Epub 2014 Jul 29.

Department of Allergy and Clinical Immunology and Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

Stat3 signaling is essential for the induction of RORγt and subsequent Th17 cell differentiation. However, the downstream targets of Stat3 for RORγt expression remain largely unknown. We show here that a novel isoform of Sox5, named Sox5t, is induced in Th17 cells in a Stat3-dependent manner. In vivo, T cell-specific Sox5-deficient mice exhibit impaired Th17 cell differentiation and are resistant to experimental autoimmune encephalomyelitis and delayed-type hypersensitivity. Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 cell differentiation even in Stat3-deficient CD4(+) T cells but not in RORγt-deficient CD4(+) T cells, indicating that Sox5 and c-Maf induce Th17 cell differentiation as downstream effectors of Stat3 and as upstream inducers of RORγt. Moreover, Sox5 physically associates with c-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5 together with c-Maf directly activates the promoter of RORγt in CD4(+) T cells. Collectively, our results suggest that Sox5 and c-Maf cooperatively induce Th17 cell differentiation via the induction of RORγt as downstream targets of Stat3.
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http://dx.doi.org/10.1084/jem.20130791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144730PMC
August 2014

Dectin-2 promotes house dust mite-induced T helper type 2 and type 17 cell differentiation and allergic airway inflammation in mice.

Am J Respir Cell Mol Biol 2014 Aug;51(2):201-9

1 Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

The fact that sensitization against fungi is closely related to the severity of asthma suggests that immune systems recognizing fungi are involved in the pathogenesis of severe asthma. Recently, Dectin-2 (gene symbol, Clec4n), a C-type lectin receptor, has been shown to function as not only a major pattern-recognition receptor for fungi, but also a receptor for some components of house dust mite (HDM) extract, a major allergen for asthma. However, the roles of Dectin-2 in the induction of HDM-induced allergic airway inflammation remain largely unknown. Our objective was to determine the roles of Dectin-2 in HDM-induced allergic airway inflammation. We examined the roles of Dectin-2 in the induction of HDM-induced T helper (Th) 2 and Th17 cell differentiation and subsequent allergic airway inflammation by using Clec4n-deficient (Clec4n(-/-)) mice. We also investigated Dectin-2-expressing cells in the lung and their roles in HDM-induced allergic airway inflammation. Clec4n(-/-) mice showed significantly attenuated HDM-induced allergic airway inflammation and decreased Th2 and Th17 cell differentiation. Dectin-2 mRNA, together with Dectin-3 and Fc receptor-γ mRNAs, was expressed in CD11b(+) dendritic cells (DCs), but not in CD4(+) T cells or epithelial cells in the lung. CD11b(+) DCs isolated from Clec4n(-/-) mice expressed lower amounts of proinflammatory cytokines and costimulatory molecules, which could lead to Th2 and Th17 cell differentiation than those from wild-type mice. HDM-pulsed Clec4n(-/-) DCs were less efficient for the induction of allergic airway inflammation than HDM-pulsed wild-type DCs. In conclusion, Dectin-2 expressed on CD11b(+) DCs promotes HDM-induced Th2 and Th17 cell differentiation and allergic airway inflammation.
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http://dx.doi.org/10.1165/rcmb.2013-0522OCDOI Listing
August 2014

Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in clinical remission: high predictive values of total gray-scale and power Doppler scores that represent residual synovial inflammation before discontinuation.

Arthritis Care Res (Hoboken) 2014 Oct;66(10):1576-81

Objective: This prospective study aimed to determine whether the comprehensive ultrasonographic assessment of synovial inflammation predicts relapse after discontinuation of treatment with a biologic agent in patients with rheumatoid arthritis (RA) in clinical remission.

Methods: RA patients in clinical remission (Disease Activity Score in 28 joints [DAS28] <2.6) receiving treatment with a biologic agent who agreed to discontinue the treatment were recruited. Patients underwent a comprehensive ultrasound scan on 134 synovial sites in 40 joints and were prospectively followed up for 6 months. Physicians who evaluated the patients during the study period were blinded to the baseline ultrasound findings.

Results: Forty-two patients receiving either a tumor necrosis factor antagonist or tocilizumab were enrolled. Using the optimal cutoff values determined by receiver operating characteristic curve analysis, relapse rates were significantly higher in patients whose total ultrasound scores at discontinuation were high than in those whose total ultrasound scores were low (P < 0.001 for both total gray-scale and power Doppler scores), whereas the difference between high and low DAS28 was not statistically significant (P = 0.158 by log rank test). Positive and negative predictive values were 80.0% and 73.3% for the total gray-scale score and 88.9% and 74.2% for the total power Doppler score, respectively.

Conclusion: In RA patients in clinical remission receiving treatment with a biologic agent, residual synovial inflammation determined by comprehensive ultrasound assessment predicted relapse within a short term after discontinuation of the treatment. Our data provide a rationale and groundwork to conduct a large-scale study for establishment of ultrasound-based strategies to optimize the period of treatment with a biologic agent.
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http://dx.doi.org/10.1002/acr.22303DOI Listing
October 2014

Clinical characteristics of Nocardia infection in patients with rheumatic diseases.

Clin Dev Immunol 2013 19;2013:818654. Epub 2013 Sep 19.

Department of Allergy and Clinical Immunology, Chiba University Hospital, 1-8-1 Inohana, Chiba, Chiba City 260-8677, Japan.

Although Nocardiosis has considerable recurrence and mortality rates, characteristics and risk factors of Nocardia infection have not been assessed in patients with rheumatic diseases. Here, we examined the characteristics and risk factors of Nocardia infection in rheumatic disease patients in our hospital. Ten rheumatic disease patients who developed Nocardia infection were identified by retrospectively reviewing the medical records. Possible predisposing factors for Nocardia infection were high-dose glucocorticoid treatment, concomitant use of immunosuppressants, preexisting pulmonary diseases, and diabetes mellitus. All patients had pulmonary Nocardiosis, and six of them had disseminated Nocardiosis when their pulmonary lesions were identified.
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http://dx.doi.org/10.1155/2013/818654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792524PMC
June 2014

Th2-type inflammation instructs inflammatory dendritic cells to induce airway hyperreactivity.

Int Immunol 2014 Feb 22;26(2):103-14. Epub 2013 Oct 22.

Department of Allergy and Clinical Immunology and.

Dendritic cells (DCs) play critical roles in determining the fate of CD4⁺ T cells. Among DC sub-populations, monocyte-derived inflammatory DCs (iDCs) have been shown to play an important role in the induction of adaptive immune responses under inflammatory conditions. Although previous studies have shown that DCs have an indispensable role in the induction of allergic airway inflammation and airway hyperreactivity (AHR) in murine asthma models, the precise roles of iDCs in the asthmatic responses remain largely unknown. We show here that T(h)2 cell-mediated inflammation in murine asthma models induces the expression of some markers of alternatively activated macrophage such as arginase 1 and resistin-like molecule-α in iDCs by a mechanism depending on the intrinsic expression of STAT6. In contrast, T(h)1 cell-mediated inflammation induces iDCs to express TNF-α and inducible nitric oxide synthase (iNOS), markers of TNF-α- and iNOS-producing DCs. Moreover, we show that iDCs under a T(h)2 environment play an important role in the induction of AHR, independently of allergic airway inflammation. Our results thus indicate the importance of iDCs in the induction of AHR as downstream effector cells in T(h)2 cell-mediated asthmatic responses.
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http://dx.doi.org/10.1093/intimm/dxt047DOI Listing
February 2014
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