Details of a Researcher - KAMEKURA Ryuta

Papers - KAMEKURA Ryuta

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舌下免疫療法ダニ舌下免疫療法中の喘息合併アレルギー性鼻炎患者における濾胞ヘルパーT細胞を中心とした検討

重原克則, 亀倉隆太, 矢部勇人, 高木宏美, 宇野英二, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 68 ( 4-5 ) 503 - 503 2019.05

Potential utility of core needle biopsy in the diagnosis of IgG4-related dacryoadenitis and sialadenitis

Kenichi Takano, Tsuyoshi Okuni, Keisuke Yamamoto, Ryuta Kamekura, Ryoto Yajima, Motohisa Yamamoto, Hiroki Takahashi, Tetsuo Himi

Modern Rheumatology ( Taylor and Francis Ltd ) 29 ( 2 ) 393 - 396 2019.03

DOI PubMed

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 207 56 - 63 2019.03 [Refereed] [International journal]

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

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 2019.03

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 2019.02 [Refereed]

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 29 ( 6 ) 1 - 3 2019.01 [Refereed] [International journal]

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 2019.01 [Refereed] [International journal]

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 28 ( 6 ) 1004 - 1008 2018.11 [Refereed] [International journal]

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 2018.05

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 2018.03

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

Yamamoto M, Takano KI, Kamekura R, Suzuki C, Tabeya T, Murakami R, Honda S, Mukai M, Nojima M, Ichimiya S, Himi T, Nakase H, Takahashi H

Immunological medicine 41 ( 1 ) 30 - 33 2018.03 [Refereed]

DOI PubMed

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 2018.02 [Refereed]

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 [Refereed]

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 2017.11 [Refereed]

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

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 2017.11 [Refereed]

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 Delta Np73 regulating thymic stromal lymphopoietin production via NF-kappa B

Ayako Kumagai, Terufumi Kubo, Koji Kawata, Ryuta Kamekura, Keiji Yamashita, Sumito Jitsukawa, Tomonori Nagaya, Yasuyuki Sumikawa, Tetsuo Himi, Toshiharu Yamashita, Shingo Ichimiya

JOURNAL OF DERMATOLOGICAL SCIENCE ( ELSEVIER IRELAND LTD ) 88 ( 2 ) 175 - 183 2017.11 [Refereed]

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

Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease

Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Katsunori Shigehara, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Akinori Sato, Noriko Ogasawara, Chieko Tsubomatsu, Hiroki Takahashi, Hiroshi Nakase, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 199 ( 8 ) 2624 - 2629 2017.10 [Refereed]

IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1 hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.

DOI PubMed

Deterioration of regulatory B cells and activation of follicular helper T cells in idiopathic interstitial pneumonias patients

Asai Yuichiro, Chiba Hirofumi, Kondoh Syun, Nishikiori Hirotaka, Takahashi Mamoru, Kuronuma Koji, Otsuka Mitsuo, Yamada Gen, Kamekura Ryuta, Ichimiya Shingo, Takahashi Hiroki

EUROPEAN RESPIRATORY JOURNAL 50 2017.09 [Refereed]

DOI

Functional RNAs control T follicular helper cells

Shingo Ichimiya, Ryuta Kamekura, Koji Kawata, Motonari Kamei, Tetsuo Himi

JOURNAL OF HUMAN GENETICS ( NATURE PUBLISHING GROUP ) 62 ( 1 ) 81 - 86 2017.01 [Refereed]

T follicular helper cells (Tfh cells), which are a prototypic subset of effector CD4(+) T cells, regulate the production of high-affinity antibodies by controlling B cells at initial and recall phases. Since the discovery of Tfh cells in human tonsils, many notable studies focusing on Tfh cells have clarified mechanisms underlying Tfh-cell-related physiological and pathological settings. Results of these studies revealed a chief regulatory function of BCL6 in Tfh cells and the involvement of Tfh cells in the pathogenesis of various disorders including autoimmune diseases, allergies and cancers. Further, accumulating evidence has revealed microRNAs (miRNAs) of functional noncoding RNAs (ncRNAs) to be cardinal regulators of Tfh cells during the processes of development, differentiation and plasticity. In this review article, we summarize and discuss the results of recent studies about miRNAs operating Tfh-cell function and their relationships in diseases. Through the window of such functional ncRNAs, the functional significance of Tfh cells in CD4(+) T-cell biology is becoming apparent. Studies to determine the complex background of the genetic program of Tfh cells operated by functional RNAs should lead to an understanding of the manifestations of Tfh cells with unidentified pathophysiological relevance.

DOI PubMed

Lipid mediators foster the differentiation of T follicular helper cells

Tomonori Nagaya, Koji Kawata, Ryuta Kamekura, Sumito Jitsukawa, Terufumi Kubo, Motonari Kamei, Noriko Ogasawara, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

IMMUNOLOGY LETTERS ( ELSEVIER SCIENCE BV ) 181 51 - 57 2017.01 [Refereed]

Lipid mediators such as leukotrienes and lipoxines broadly regulate innate and acquired immunity, and their dysfunction causes various immune -mediated disorders. We previously reported a salient feature of arachidonate 5-lipoxyganase (Alox5), which is responsible for the production of such lipid mediators, in the regulation of high affinity antibodies in vivo. The aim of this study was to determine the functional significance of Alox5-related lipid mediators during the processes of acquired humoral responses. The results of in vitro experiments using lymphocytes in tonsils and blood specimens showed that lipoxin A4 (LXA4) and leukotriene B4 (LTB4) have the capacity to differentiate naive CD4(+) T cells into T follicular helper (Tfh) cells, which activate naive B cells to form germinal centers. Such a function of LXA4 was further supported by results of in vitro studies using BML-111 and BOC-2, which are an agonist and an antagonist, respectively, of FPR2 of an LXA4-specific cell-surface receptor. The results suggest that such lipid mediators have a potential role in the development of lymphoid follicles through the regulation of Tfh cell differentiation. (C) 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

DOI PubMed

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Papers - KAMEKURA Ryuta