研究者詳細 - 一宮　慎吾

論文 - 一宮　慎吾

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生体バリア機構とアレルギー疾患アレルギー性鼻炎に関連するエピイムノームの新機能

亀倉隆太, 矢部勇人, 重原克則, 高野賢一, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 68 ( 4-5 ) 320 - 320 2019年05月

鼻炎合併アトピー型喘息患者のダニ抗原SLIT施行における濾胞ヘルパー細胞と濾胞制御性T細胞の検討

重原克則, 亀倉隆太, 矢部隼人, 宇野英二, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 8 ( 増刊 ) 250 - 250 2019年03月

IL-10+ T follicular regulatory cells are associated with the pathogenesis of IgG4-related disease.

Ito F, Kamekura R, Yamamoto M, Takano K, Takaki H, Yabe H, Ikegami I, Shigehara K, Himi T, Takahashi H, Ichimiya S

Immunology letters ( Elsevier BV ) 207 56 - 63 2019年03月 [査読有り] [国際誌]

IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory disease characterized by elevation of serum IgG4 level as well as infiltration of IgG4+ plasma cells in various affected organs. The etiology of IgG4-RD is still not fully understood. Since IgG4-RD is more prevalent in the elderly, aging in itself is considered to be an important risk factor of IgG4-RD. However, the relationship between the pathogenesis of IgG4-RD and immunosenescence remains unknown. To clarify age-related features underlying IgG4-RD, we focused on T follicular regulatory (Tfr) cells, which share forkhead box P3 with regulatory T cells, since the percentage of Tfr cells is known to depend on age. Studies of blood specimens from patients with IgG4-RD and from healthy volunteers demonstrated a marked elevation of circulating Tfr (cTfr) cells in patients with IgG4-RD. Moreover, the percentage of cTfr cells was significantly correlated with various clinical parameters including the level of serum IgG4 and the number of involved organs in IgG4-RD patients. The percentages of tonsillar and blood Tfr cells were increased with aging in healthy volunteers, whereas the suppressive effect of cTfr cells on B cell function in elderly subjects was impaired in comparison with that in young subjects due to a defect in the production of a regulatory cytokine, IL-10. Given that the number of IL-10-producing cTfr cells in IgG4-RD patients was markedly increased compared with that in healthy elderly subjects, these findings suggest that an abnormal aging process of Tfr cells may be related to the pathogenesis of IgG4-RD.

DOI PubMed

Retroperitoneal Fibrosis Diagnosed as IgG4-related Disease after 35 Years.

Konno S, Matsuno Y, Ichimiya S, Nishimura M, Kawakami Y

Internal medicine (Tokyo, Japan) 58 ( 4 ) 609 - 613 2019年02月 [査読有り] [国内誌]

In 1982, we reported a case of retroperitoneal fibrosis (RPF) exhibiting various clinical manifestations. Our current understanding of immunoglobulin G4 (IgG4)-related disease led us to consider it as a possible diagnosis because all of the patient's clinical features could be explained by this disease entity. To confirm our hypothesis, were investigated the histopathological findings of resected specimens that had been stored for 35 years postoperatively. Typical pathological findings together with predominant IgG4+ plasma cell infiltration confirmed a potential diagnosis of IgG4-related RPF. Furthermore, we observed positive immunohistochemical staining for several molecules associated with T regulatory and T follicular helper cells.

DOI PubMed

A unique subset of PD-1(+)CXCR5(-)CD4(+) T cells is involved in immunological mechanisms of IgG4-related disease

Kamekura Ryuta, Yamamoto Motohisa, Yabe Hayato, Takaki Hiromi, Takano Kenichi, Takahashi Hiroki, Takahashi Hiroki, Himi Tetsuo, Ichimiya Shingo

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 143 ( 2 ) AB231 2019年02月 [査読有り]

DOI

Analysis of allergic reaction in IgG4-related disease.

Yamamoto M, Takano KI, Kamekura R, Aochi S, Suzuki C, Ichimiya S, Takahashi H

Modern rheumatology ( TAYLOR & FRANCIS LTD ) 29 ( 6 ) 1 - 3 2019年01月 [査読有り] [国際誌]

DOI PubMed

New insights into IgG4-related disease: emerging new CD4+ T-cell subsets.

Kamekura R, Takahashi H, Ichimiya S

Current opinion in rheumatology 31 ( 1 ) 9 - 15 2019年01月 [査読有り] [国際誌]

PURPOSE OF REVIEW: New insights into IgG4-related disease (IgG4-RD) have recently been obtained. A better understanding of the mechanisms underlying this disease is important for identification of therapeutic targets, which will lead to the development of specific strategies for treatment. RECENT FINDINGS: Infiltration of activated T follicular helper (Tfh) cells is observed in affected tissues of IgG4-RD. Such Tfh cells have a greater capacity than tonsillar Tfh cells to help B cells produce IgG4. Circulating PD-1CXCR5 peripheral T helper (Tph)-like cells are also increased in patients with IgG4-RD. Because Tph-like cells express high levels of chemokine receptors and granzyme A, they have the capacity to infiltrate affected tissues and exert a cytotoxic function. Tph-like cells can also produce CXCL13, and CXCR5 Tfh cells and B cells are therefore preferentially recruited to form ectopic lymphoid structures in the sites. Tph cells may have a role to ignite inflammation and maintain persistent fibroinflammation in collaboration with Tfh cells in lesions of IgG4-RD. SUMMARY: Recent advances in understanding the pathogenesis of IgG4-RD are remarkable. In this review, we summarize and discuss the possible pathologic role of CD4 T-cell subsets in IgG4-RD.

DOI PubMed

Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment.

Motohisa Yamamoto, Kenichi Takano, Ryuta Kamekura, Chisako Suzuki, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

Modern rheumatology ( TAYLOR & FRANCIS LTD ) 28 ( 6 ) 1004 - 1008 2018年11月 [査読有り] [国際誌]

OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.

DOI PubMed

ダニ舌下免疫療法における血液機能性リンパ球サブセットの経時的変化

亀倉隆太, 重原克則, 伊藤史恵, 高野賢一, 氷見徹夫, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 67 ( 4-5 ) 598 - 598 2018年05月

アトピー型喘息における治療前後の末梢血濾胞ヘルパーT細胞および制御性B細胞の変化

重原克則, 宮島さつき, 亀倉隆太, 矢部隼人, 高橋弘毅, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 67 ( 4-5 ) 637 - 637 2018年05月

「地域医療を支える人づくりプロジェクト事業」地域医療体験事業での教育手法の工夫

齊藤正樹, 神倫聡, 高野智史, 三瀬敬冶, 鈴木究, 田原勇人, 柴田亨, 橋本諭, 一宮慎吾, 下濱俊, 中村眞理子, 高橋弘毅

医療人育成センター紀要 ( 札幌医科大学医療人育成センター ) 9 ( 9 ) 9 - 14 2018年03月 [査読有り]

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Predicting therapeutic response in IgG4-related disease based on cluster analysis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Chisako Suzuki, Tetsuya Tabeya, Rieko Murakami, Saho Honda, Masaya Mukai, Masanori Nojima, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

Immunological medicine 41 ( 1 ) 30 - 33 2018年03月 [査読有り] [国際誌]

To bring the clinical practice of immunoglobulin (Ig)G4-related disease (IgG4-RD) close to personalized medicine, we classified the patient groups and clarified the therapeutic responses of each group. A total of 147 patients enrolled in our registry were classified into four groups by cluster analysis with the software. The therapeutic responses and prognosis of each group were examined. The cluster analysis classified the subjects into four groups: Cluster 1, patients who presented with prominent hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia; Cluster 2, patients who presented with eosinophilia, elevated concentrations of serum IgG, IgG4, and IgE, and in whom CRP tended to be positive; Cluster 3, patients with younger onset and serum levels of IgG, IgG4, and IgE and peripheral eosinophil counts lower than the other clusters; and Cluster 4, patients with elder onset and low peripheral eosinophil counts. The amounts of glucocorticoid for maintenance treatment were from 5 to 7 mg/d in all groups, but the amounts were significantly greater in Cluster 1 (patients with hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia) than in Cluster 4 (elder onset patients, relatively low concentrations of peripheral eosinophils). With regard to the use of immunosuppressants and the relapse rate, there were high frequencies in Cluster 1 and Cluster 3 (younger onset patients who presented with mild elevations of serum IgG and IgG4). On the other hand, Cluster 4 showed a low rate of relapse and often could discontinue steroids. The present results suggest that personalized medicine could be provided in IgG4-RD by classifying patients based on their clinical features.

DOI PubMed

COPD患者における喘息患者との対比を含めた末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

重原克則, 亀倉隆太, 川田耕司, 宮島さつき, 矢部勇人, 高橋弘毅, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 7 ( 増刊 ) 219 - 219 2018年03月

COPD患者における喘息患者との対比を含めた末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

重原克則, 亀倉隆太, 宮島さつき, 矢部勇人, 高橋弘毅, 一宮慎吾

日本内科学会雑誌 ( (一社)日本内科学会 ) 107 ( Suppl. ) 215 - 215 2018年02月

Unique profiles of lesional T follicular helper cells in the pathogenesis of IgG4-related disease

Kamekura Ryuta, Yabe Hayato, Takano Kenichi, Yamamoto Motohisa, Ikegami Ippei, Ito Fumie, Takahashi Hiroki, Himi Tetsuo, Ichimiya Shingo

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 141 ( 2 ) AB284 2018年02月 [査読有り]

Circulating PD-1+CXCR5-CD4+ T cells underlying the immunological mechanisms of IgG4-related disease.

Kamekura R, Yamamoto M, Takano K, Yabe H, Ito F, Ikegami I, Takaki H, Shigehara K, Suzuki C, Himi T, Takahashi H, Ichimiya S

Rheumatology advances in practice ( Oxford University Press (OUP) ) 2 ( 2 ) rky043 2018年 [査読有り] [国際誌]

OBJECTIVE: The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1+CXCR5-CD4+) in IgG4-related disease (IgG4-RD). METHODS: PD-1+CXCR5-CD4+ T cells in the blood of patients with IgG4-RD (n = 53), patients with SS (n = 16) and healthy volunteers (n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed. RESULTS: The percentage and absolute number of PD-1+CXCR5- cells within total CD4+ T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1+CXCR5-CD4+ T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA)+ cells were enriched in PD-1+CXCR5-CD4+ T cells, and the percentage and absolute number of GZMA+PD-1+CXCR5-CD4+ T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4+ T cells, the percentage and absolute number of PD-1+CXCR5-CD4+ T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids. CONCLUSION: In IgG4-RD, circulating CD4+ T-cell populations were composed of PD-1+CXCR5- cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA+PD-1+CXCR5-CD4+ T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

DOI PubMed

Mucosal Immune Response in Nasal-Associated Lymphoid Tissue upon Intranasal Administration by Adjuvants.

Takaki H, Ichimiya S, Matsumoto M, Seya T

Journal of innate immunity ( KARGER ) 10 ( 5-6 ) 515 - 521 2018年 [査読有り] [国際誌]

The nasal administration of vaccines directed against diseases caused by upper respiratory tract infections of pathogens, such as the influenza virus, mimics the natural infection of pathogens and induces immunoglobulin A (IgA) production in the nasal cavity to effectively protect viral entry. Therefore, the development of a nasally administered vaccine is a research objective. Because the antigenicity of influenza split vaccines is low, nasal inoculation with the vaccine alone does not induce strong IgA production in the nasal cavity. However, the addition of adjuvants activates the innate immune response, enhancing antigen-specific IgA production and the T-cell response. Although the development of suitable adjuvants for nasal vaccinations is in progress, the mechanism by which adjuvants promote the immune response is still unclear. In this review, we discuss the mucosal immune response, especially in the nasal-associated lymphoid tissue, induced in response to the intranasal inoculation of an influenza vaccine and adjuvants in animal models.

DOI PubMed

Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression

Sumito Jitsukawa, Ryuta Kamekura, Koji Kawata, Fumie Ito, Akinori Sato, Hiroshi Matsumiya, Tomonori Nagaya, Keiji Yamashita, Terufumi Kubo, Tomoki Kikuchi, Noriyuki Sato, Tadashi Hasegawa, Hiroshi Kiyonari, Yoshiko Mukumoto, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF PATHOLOGY ( WILEY ) 243 ( 3 ) 342 - 353 2017年11月 [査読有り] [国際誌]

Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well-differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5-deficient (Snx5(-/-)) mice. In comparison to wild-type (Snx5(+/+)) mice, Snx5(-/-) mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular-shaped vacuoles. Snx5(-/-) thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid-stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5(-/-) thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5(-/-) thyrocytes were also confirmed by results showing that Snx5(-/-) mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti-thyroidal agent revealed that Snx5(-/-) mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI PubMed

Keratinocytes in atopic dermatitis express abundant ΔNp73 regulating thymic stromal lymphopoietin production via NF-κB.

Kumagai A, Kubo T, Kawata K, Kamekura R, Yamashita K, Jitsukawa S, Nagaya T, Sumikawa Y, Himi T, Yamashita T, Ichimiya S

Journal of dermatological science ( ELSEVIER IRELAND LTD ) 88 ( 2 ) 175 - 183 2017年11月 [査読有り]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that often cannot be completely controlled by modern medicine. Since multiple factors are intricately involved in the pathogenesis of AD, wide-ranging research is required for further advancement of AD treatment. Epidermal keratinocytes are the forefront to the external environment and play a pivotal role in the initiation of immune reaction against exogenous invasion. Objective: Thymic stromal lymphopoietin (TSLP) is a keratinocyte-derived cytokine that induces differentiation and activation of type 2 helper T cells and innate lymphoid cells, cardinal effectors in pathophysiology of AD. We previously reported that Delta Np63, a p53-related molecule, regulates the expression of TSLP receptors and suggested the entity of a potential TSLP autocrine loop in the AD epidermis. In this study, we further explored the significance of p53 family transcription factors in TSLP production from human keratinocytes. Method: Expression profile of p73, a p53-related molecule, was evaluated in human AD tissue by immunohistochemistry. In addition, the function of p73 in producing TSLP was investigated with in vitro cultured keratinocytes via molecular biological analysis. Results: Delta Np73 was abundantly expressed in the AD epidermis and increased the release of TSLP via NF-kappa B activation. Furthermore, the Toll-like receptor 3 signal enhanced Delta Np73 expression and thereby induced TSLP expression. Conclusion: Our results indicate that Delta Np73 is an additional participant in the mechanism of TSLP production. Amending the aberrant state of keratinocytes, represented by overexpression of ANp73, can be a novel therapeutic target of AD. (C) 2017 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI PubMed

High frequency of Bob1(1o) T follicular helper cells in florid reactive follicular hyperplasia

Hiroshi Matsumiya, Koji Kawata, Ryuta Kamekura, Chieko Tsubomatsu, Sumito Jitsukawa, Takamasa Asai, Syunsuke Akasaka, Motonari Kamei, Keiji Yamashita, Fumie Ito, Terufumi Kubo, Noriyuki Sato, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

IMMUNOLOGY LETTERS ( ELSEVIER SCIENCE BV ) 191 23 - 30 2017年11月 [査読有り]

Florid reactive follicular hyperplasia (FRFH), which is characterized by large germinal centers (GCs) within normal lymphoid follicles, is often observed in benign lesions of lymph nodes and other tissues. Because of the histologic similarity of FRFH to tumorous lesions such as follicular lymphoma, careful pathological examination is required to evaluate such lesions; however, little is known about the mechanism underlying the development of FRFH. In this study, we investigated T follicular helper (Tfh) cells in hyperplastic tonsils of patients with obstructive sleep apnea syndrome (OSA), which frequently exhibits typical FRFH. When we analyzed tonsils of OSA and recurrent tonsillitis (RT) as a control, tonsils of OSA were found to harbor Tfh cells with a nearly 3-fold higher ratio in total CD4(+) T cells than that in tonsils of RT. Further analysis showed that, in comparison to Tfh cells of RT tonsils, Tfh cells of OSA tonsils were relatively tolerant to CD3-mediated activation-induced cell death (AICD) and also expressed lower levels of a Bob1 transcription coactivator and IL-4, which fosters the development of GC-B cells. Given that Bob1 controls the proliferative activity in response to CD3 stimulation and has been suggested to have a role in the production of IL-4 in Tfh cells, the unique structure of FRFH is possibly associated with the function of Bob1(lo) Tfh cells.

DOI PubMed

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