研究者詳細 - 一宮　慎吾

論文 - 一宮　慎吾

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Unraveling Novel Subsets of Lymphocytes Involved in Sac Expansion in the Tertiary Lymphoid Structure Within an Abdominal Aortic Aneurysm.

Itaru Hosaka, Ippei Ikegami, Takuma Mikami, Tatsuya Sato, Toshifumi Ogawa, Kei Mukawa, Marenao Tanaka, Keisuke Endo, Yukinori Akiyama, Akihito Ohkawa, Junji Nakazawa, Tsuyoshi Shibata, Tomohiro Nakajima, Yutaka Iba, Chikara Shiiku, Satoshi Sumino, Ryuji Koshima, Kenichi Takano, Shingo Ichimiya, Nobuyoshi Kawaharada, Masato Furuhashi

Journal of the American Heart Association e040279 2025年02月 [国際誌]

BACKGROUND: Chronic inflammation is involved in the development of abdominal aortic aneurysm (AAA). A tertiary lymphoid structure (TLS) within vascular lesions has recently been focused on for its role in modulation of inflammation in local tissues. We aimed to elucidate the relationships between TLS and pathophysiology of AAA. METHODS: Abdominal aortic samples obtained from 37 patients with AAA (men/women: 34/3, age: 72.8±9.9 years) and 15 autopsied patients who died from non-aortic events (men/women: 11/4, age: 65.5±9.8 years) were investigated. RESULTS: TLSs in AAA lesions were confirmed by focal infiltration of CD3-positive cells surrounding germinal center-like structures containing CD20-positive cells between the tunica adventitia and tunica media layers. The formation of a TLS was significantly more prevalent in AAA patients than in autopsied patients. The number of TLSs in AAA lesions was positively correlated with sac diameter (r=0.357, P=0.035) and the amount of intraluminal thrombosis (r=0.466, P=0.005). T cells and B cells were predominant cellular populations among CD45+ cells in AAA lesions. There was a significantly positive correlation between the proportions of interfollicular T follicular helper (CD3+CD4+CD45RA-CXCR5+PD-1+) cells and double negative B (CD3-CD19+IgD-CD27-) cells, and they were positively correlated with sac diameter, intraluminal thrombosis, and serum lipids. Deposited single-cell RNA-sequencing data for AAA showed that T follicular helper cells and double negative B cells were associated with lipid metabolism, T cell activation/proliferation and inflammation. CONCLUSIONS: The formation of a TLS in AAA lesions is associated with sac diameter and intraluminal thrombosis in connection with interfollicular T follicular helper cells and double negative B cells, which may contribute to the pathophysiology of AAA and might be novel therapeutic targets for the development of AAA.

DOI PubMed

Interleukin 9 mediates T follicular helper cell activation to promote antibody responses

Taiki Sato, Ippei Ikegami, Masahiro Yanagi, Takeshi Ohyu, Taiki Sugaya, Shotaro Shirato, Masanobu Tanemoto, Shiori Kamiya, Kohei Kikuchi, Yuka Kamada, Takehito Nakata, Ryuta Kamekura, Akinori Sato, Ken-ichi Takano, Masahiro Miyajima, Atsushi Watanabe, Shingo Ichimiya

Frontiers in Immunology ( Frontiers Media SA ) 15 2024年09月

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4^Cre/+Il9ra^fl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4^Cre/+Il9ra^fl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4^Cre/+Il9ra^fl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD⁺ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

DOI

Bob1 maintains T follicular helper cells for long-term humoral immunity.

Masahiro Yanagi, Ippei Ikegami, Ryuta Kamekura, Tatsuya Sato, Taiki Sato, Shiori Kamiya, Kosuke Murayama, Sumito Jitsukawa, Fumie Ito, Akira Yorozu, Miho Kihara, Takaya Abe, Hiromi Takaki, Koji Kawata, Katsunori Shigehara, Satsuki Miyajima, Hirotaka Nishikiori, Akinori Sato, Noritsugu Tohse, Ken-Ichi Takano, Hirofumi Chiba, Shingo Ichimiya

Communications biology 7 ( 1 ) 185 - 185 2024年02月 [国際誌]

Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

DOI PubMed

Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases

Katsunori Shigehara, Ryuta Kamekura, Ippei Ikegami, Hiroshi Sakamoto, Masahiro Yanagi, Shiori Kamiya, Kentaro Kodama, Yuichiro Asai, Satsuki Miyajima, Hirotaka Nishikiori, Eiji Uno, Keisuke Yamamoto, Kenichi Takano, Hirofumi Chiba, Hirofumi Ohnishi, Shingo Ichimiya

Frontiers in Immunology ( Frontiers Media SA ) 14 2023年11月

The relationships between T follicular helper (Tfh) cells and antigen-specific immunoglobulins (sIgs) in patients with allergic respiratory diseases who are receiving antigen immunotherapy (AIT) have not been fully clarified. Therefore, we started to perform house dust mite sublingual immunotherapy (HDM-SLIT) for 20 patients with atopic asthma comorbid with allergic rhinitis (AA+AR) who were already receiving ordinary treatments including inhaled corticosteroid (ICS). We examined percentages of circulating T follicular helper (cTfh) and regulatory (cTfr) cells and percentages of circulating regulatory T (cTreg) and B (cBreg) cells by FACS and we examined levels of Der-p/f sIgs by ELISA. Based on the symptom score (asthma control questionnaire: ACQ) and medication score ((global initiative for asthma: GINA) treatment step score) in patients with AA, the patients were divided into responders and non-responders. The percentage of cTfh2 cells significantly decreased and the percentage of cTfh1 cells significantly increased within the first year. Der-p/f sIgEs decreased after a transient elevation at 3 months in both groups. Notably, the percentage of cTfh2 cells and the ratio of cTfh2/cBreg cells and Der-p/f sIgEs greatly decreased in responders from 6 months to 12 months. The percentages of cTfr and cTreg cells showed significant negative correlations with the percentage of cTfh2 cells. The percentage of IL-4⁺ cTfh cells were significantly decreased and the percentage of IFN-γ⁺ cTfh cells were increased before treatment to 24 months in 6 patients examined (4 responders and 2 non-responders). We performed multi plelogistic regression analysis based on these results, the ratios of cTfh2/cTfr cells and cTfh2/cBreg cells at the start of therapy were statistically effective biomarkers for predicting the response to HDM-SLIT in patients with AA+AR.

DOI

通年性アレルギー性鼻炎・各種鼻炎:治療・管理・診断ダニ舌下免疫療法の新しい効果発現のメカニズムの解明

亀倉隆太, 重原克則, 山本圭佑, 一宮慎吾, 高野賢一

アレルギー ( (一社)日本アレルギー学会 ) 72 ( 6-7 ) 872 - 872 2023年08月

原発性肺癌浸潤CD4陽性T細胞組成と浸潤メカニズムの解析

佐藤太軌, 石井大智, 大湯岳, 千葉慶宜, 鶴田航大, 高橋有毅, 槙龍之輔, 高瀬貴章, 宮島正博, 渡辺敦, 池上一平, 一宮慎吾

肺癌 ( (NPO)日本肺癌学会 ) 63 ( 2 ) 130 - 130 2023年04月

Immunohistochemical analysis of arachidonate 5-lipoxygenase expression in B-cell lymphomas: Implication for B cell differentiation and its analogy with lymphomagenesis.

Terufumi Kubo, Tomoki Kikuchi, Masahiko Obata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Shingo Ichimiya, Naoya Nakamura, Toshihiko Torigoe

Pathology, research and practice 242 154328 - 154328 2023年02月 [国際誌]

Arachidonate 5-lipoxygenase (ALOX5) is a cardinal enzyme in the synthesis of leukotrienes, which are powerful immune-regulating lipid mediators. We previously reported that ALOX5 is preferentially expressed in B lymphocytes in the mantle zone of human lymphoid tissue. In the context of physiological relevance, the loss of the Alox5 gene in mice significantly impairs the development of follicular B helper T cells and antibody production. However, ALOX5 expression in B-cell lymphomas has not been investigated in detail. In this study, we examined ALOX5 expression in representative B-cell lymphomas and non-neoplastic lymphoid tissues by immunohistochemistry with a commercially available anti-ALOX5 antibody that can be used on formalin-fixed paraffin-embedded specimens. Interestingly, 22/22 cases of mantle cell lymphoma, 7/7 cases of chronic lymphocytic leukemia/small cell lymphoma, and 20/20 cases of follicular lymphoma expressed ALOX5. A small proportion of extranodal marginal zone lymphoma/mucosa-associated lymphoid tissue lymphoma or nodal marginal zone lymphoma cases were positive for ALOX5 (2/13 or 1/3, respectively). In contrast, no cases with diffuse large B-cell lymphoma, regardless of germinal center B cell (GCB) or non-GCB type, expressed ALOX5 (0/25 cases). These findings suggest that ALOX5 may be a novel marker for identifying the cell of origin of B-cell lymphoma. Further investigation is required to clarify the biological significance of ALOX5 expression in lymphoma cells.

DOI PubMed

Functional Interplay between IL-9 and Peptide YY Contributes to Chronic Skin Inflammation.

Shiori Kamiya, Ippei Ikegami, Masahiro Yanagi, Hiromi Takaki, Ryuta Kamekura, Taiki Sato, Keiju Kobayashi, Takafumi Kamiya, Yuka Kamada, Takaya Abe, Ken-Ichi Inoue, Tokimasa Hida, Hisashi Uhara, Shingo Ichimiya

The Journal of investigative dermatology 142 ( 12 ) 3222 - 3231 2022年12月 [国際誌]

Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14CRE/ERTIl9raΔ/Δ mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14CRE/ERTIl9raΔ/Δ mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14WTIl9rafl/fl mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14CRE/ERTIl9raΔ/Δ epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.

DOI PubMed

アレルゲン・抗原・免疫療法・検査法ダニ舌下免疫療法における濾胞Tヘルパー細胞と特異的Igの2年間解析

重原克則, 亀倉隆太, 柳昌弘, 錦織博貴, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 71 ( 6-7 ) 817 - 817 2022年08月

CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions.

Kosuke Murayama, Ippei Ikegami, Ryuta Kamekura, Hiroshi Sakamoto, Masahiro Yanagi, Shiori Kamiya, Taiki Sato, Akinori Sato, Katsunori Shigehara, Motohisa Yamamoto, Hiroki Takahashi, Ken-Ichi Takano, Shingo Ichimiya

Frontiers in immunology 13 941385 - 941385 2022年 [国際誌]

T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.

DOI PubMed

アレルギー性炎症疾患の病態形成における免疫系の役割細胞傷害性Tph細胞のオリゴクローナルな増殖がIgG4関連疾患の病態形成に関与する

亀倉隆太, 村山公介, 山本圭佑, 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 ) 70 ( 6-7 ) 817 - 817 2021年08月

免疫療法鼻炎合併喘息患者におけるダニ舌下免疫療法の濾胞ヘルパー及び濾胞制御性T細胞を中心とした解析

重原克則, 亀倉隆太, 池上一平, 柳昌弘, 山本圭佑, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 70 ( 6-7 ) 789 - 789 2021年08月

Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease

Hayato Yabe, Ryuta Kamekura, Motohisa Yamamoto, Kosuke Murayama, Shiori Kamiya, Ippei Ikegami, Katsunori Shigehara, Hiromi Takaki, Hirofumi Chiba, Hiroki Takahashi, Kenichi Takano, Hiroki Takahashi, Shingo Ichimiya

Modern Rheumatology ( Informa UK Limited ) 31 ( 1 ) 249 - 260 2021年01月 [国際誌]

OBJECTIVES: The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5-CD4+ T) cells in IgG4-related disease (IgG4-RD). METHODS: Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. RESULTS: Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. CONCLUSION: CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.

DOI PubMed

Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A-Induced Production of IL-36γ in Tonsillar Epithelial Cells.

Keiju Kobayashi, Ryuta Kamekura, Junji Kato, Shiori Kamiya, Takafumi Kamiya, Kenichi Takano, Shingo Ichimiya, Hisashi Uhara

The Journal of investigative dermatology 141 ( 6 ) 1533 - 1541 2020年11月 [国際誌]

Palmoplantar pustulosis (PPP) is characterized by sterile pustules on the palms and soles. A strong association between PPP and tobacco smoking has been reported, and it has been speculated that the IL-17A pathway may play an important role in PPP. Recent studies have suggested that IL-36 plays a pivotal role in the pathogenesis of psoriasis and its subtypes. The relationships among IL-36, smoking, and PPP have not been examined. Here, we investigated the relationships among the smoking index, severity of the clinical condition of PPP, and in vitro dynamics of IL-36 in human tonsillar epithelial cells under the condition of exposure to a cigarette smoke extract. The results demonstrated that the Palmoplantar Pustulosis Area and Severity Index was strongly and positively correlated with the smoking index in female patients. Immunohistochemical examinations showed that IL-36γ was highly expressed in tonsillar epithelial cells from patients with PPP but not in those from patients with recurrent tonsillitis without PPP. The in vitro study revealed that IL-17A synergistically induced a release of IL-36γ under cigarette smoke extract exposure. These results suggest that local production of IL-36γ by epithelial cells induced by cigarette smoke exposure plays an important role in the pathogenesis of PPP.

DOI PubMed

ダニSLIT中のアレルギー性鼻炎合併喘息における末梢血濾胞ヘルパーT細胞の検討

重原克則, 亀倉隆太, 矢部隼人, 針生寛之, 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 ) 9 ( 増刊 ) 324 - 324 2020年08月

Activated circulating T follicular helper cells and skewing of T follicular helper 2 cells are down-regulated by treatment including an inhaled corticosteroid in patients with allergic asthma

Satsuki Miyajima, Katsunori Shigehara, Ryuta Kamekura, Hiromi Takaki, Hayato Yabe, Ippei Ikegami, Yuichiro Asai, Hirotaka Nishikiori, Hirohumi Chiba, Eiji Uno, Hiroki Takahashi, Shingo Ichimiya

Allergology International ( Elsevier BV ) 69 ( 1 ) 66 - 77 2020年01月 [国際誌]

BACKGROUND: CXCR5+ T follicular helper (TFH) cells primarily promote B cells to produce an antigen-specific antibody through germinal centers (GCs). TFH cells exist in circulation, and circulating(c) TFH2 cells, a subset of cTFH cells, are able to help naïve B cells produce IgE in healthy individuals. Conversely, IL-10-producing regulatory B (Breg) cells inhibit an accelerated immune response. METHODS: We investigated the roles of cTFH cells and cBreg cells based on a TH2 response in patients with atopic asthma (AA). Thirty-two patients with AA and 35 healthy volunteers (HV) were enrolled. We examined cTFH cells including their subsets, their expression of ICOS and PD-1, and cBreg cells by flow cytometry and their associations with clinical biomarkers. Plasma levels of CXCL13, which is a counterpart of CXCR5, were also measured using ELISA. RESULTS: In patients with AA, cTFH2 cells were increased and cTFH1 cells were decreased compared with those in HV. The expression levels of ICOS on cTFH and their subset cells were elevated and Breg cells were greatly decreased. The plasma levels of CXCL13 in patients with AA were significantly elevated and correlated well with the cTFH2/cBreg ratio. These cells were examined in 10 patients AA before and after inhaled corticosteroid (ICS) treatment. Interestingly, the percentages and numbers of TFH2 and ICOS+ cTFH cells declined after ICS treatment together with improvements in symptoms and clinical biomarkers. CONCLUSIONS: The percentages and numbers of cTFH2 and ICOS+ cTFH cells might be useful as biomarkers of TH2 typed airway inflammation in patients with AA.

DOI PubMed

Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis.

Yuichiro Asai, Hirofumi Chiba, Hirotaka Nishikiori, Ryuta Kamekura, Hayato Yabe, Shun Kondo, Satsuki Miyajima, Katsunori Shigehara, Shingo Ichimiya, Hiroki Takahashi

Respiratory research 20 ( 1 ) 244 - 244 2019年11月 [国際誌]

BACKGROUND: T follicular helper (Tfh) cells have been identified as a new category of helper T cells, which express CXCR5 on their surface and induce the production of antigen-specific antibodies. Many investigations have found morbid proliferation and/or activation of Tfh cells in systemic autoimmune and allergic diseases. It is also known that Tfh cells are regulated by regulatory B (Breg) cells in the deteriorating such diseases. Recently, CXCL13, a ligand of CXCR5, has been reported to increase in the peripheral blood and lungs of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the involvement of Tfh cells and Breg cells in IPF. METHODS: Peripheral blood samples were obtained from 18 patients with IPF. We isolated heparinized peripheral blood mononuclear cells and investigated the proportions of Breg cells, Tfh cells, PD-1+ICOS+ Tfh cells (activated form of Tfh cells), and the Tfh-cell subsets by flow cytometry. These cell profiles were compared with those of 21 healthy controls. Furthermore, we investigated the correlations between profiles of lymphocytes and lung physiology. RESULTS: The median proportions of Tfh cells per total CD4+ T cells and of PD-1+ICOS+ proportion of Tfh cells per total Tfh cells was significantly more in the IPF patients (20.4 and 5.2%, respectively) compared with healthy controls (15.4 and 2.1%, respectively; p = 0.042 and p = 0.004, respectively). The proportion of Tfh2 cells per total Tfh cells was significantly higher and the proportion of Tfh17 was smaller in the IPF patients than healthy controls. The percentage of Breg cells to total B cells was significantly decreased in the IPF patients (median, 8.5%) compared with that in the controls (median, 19.7%; p < 0.001). The proportion of Breg cells was positively correlated with the annual relative change in diffusing capacity of the lungs for carbon monoxide in the IPF patients (r = 0.583, p = 0.018). CONCLUSION: Proliferation and activation of Tfh cells and a decrease in Breg cells were observed in the peripheral blood of patients with IPF. The profile of the Tfh-cell subset also changed. Specific humoral immunity aberration would likely underlie complicated pathophysiology of IPF.

DOI PubMed

Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Satsuki Aochi, Chisako Suzuki, Shingo Ichimiya, Hiroshi Nakase, Tetsuo Himi, Hiroki Takahashi

Modern rheumatology ( TAYLOR & FRANCIS LTD ) 29 ( 5 ) 856 - 860 2019年09月 [査読有り] [国際誌]

Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.

DOI PubMed

Bob1 enhances RORγt-mediated IL-17A expression in Th17 cells through interaction with RORγt.

Ikegami I, Takaki H, Kamiya S, Kamekura R, Ichimiya S

Biochemical and biophysical research communications ( Elsevier BV ) 514 ( 4 ) 1167 - 1171 2019年07月 [査読有り] [国際誌]

POU domain class 2-associating factor 1 (also called Bob1), which is mainly expressed in B cells, regulates B cell homeostasis and controls humoral immune responses. Although Bob1 is known to function reliably in T cell subsets including follicular helper T cells, Th1 cells and Th2 cells, it is unknown whether Bob1 functions in other T cell subsets. In this study, we found that Bob1 knock out (KO) mice are resistant to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide and that Bob1 KO T cells are defective in Th17 differentiation. Importantly, Bob1 interacts with retinoid acid receptor-related orphan receptor (ROR) gamma t (RORγt), a signature transcription factor for Th17 cells, through the ligand-binding domain of RORγt, thereby enhancing IL-17A transcription activity. IL-17A induction by Bob1 requires the ability for its formation of a DNA-Oct1-Bobl ternary complex. Thus, our findings demonstrate that Bob1 enhances IL-17A expression in vivo and in vitro by interacting with RORγt in Th17 cells, suggesting that Bob1 plays a pivotal role in Th17-mediated autoimmune disease.

DOI PubMed

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年05月

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