Yoshimoto, Keiko

写真a

Affiliation

School of Medicine, Department of Internal Medicine (Rheumatology) (Shinanomachi)

Position

Researcher (Non-tenured) / Project Researcher(Non-tenured)

Other Affiliation 【 Display / hide

  • School of Medicine, 内科学(リウマチ・膠原病), Research Associate

Academic Degrees 【 Display / hide

  • 薬学博士, 名古屋市立大学, 1996.12

Licenses and Qualifications 【 Display / hide

  • 薬剤師

 

Research Keywords 【 Display / hide

  • BAFF receptor (BR3)

  • B cell

  • B cell stimulationg factor (BAFF)

  • Sjogren's syndrome

  • systemic lupus erythematosus

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Research Themes 【 Display / hide

  • シェーグレン症候群の病態解析とBAFF受容体を標的としたSS治療薬の探索研究, 

    2012.04
    -
    Present

  • SLEおよびシェーグレン症候群(SS)の病態におけるB細胞活性化因子(BAFF)の関与に関する病態解析研究, 

    2006.04
    -
    Present

  • 全身性エリテマトーデス患者末梢血T細胞におけるT細胞受容体(TCR)の発現低下が及ぼすT細胞の機能異常に関する病態解析研究, 

    1997.05
    -
    Present

 

Papers 【 Display / hide

  • Identification of neutrophil β2-integrin LFA-1 as a potential mechanistic biomarker in ANCA-associated vasculitis via microarray and validation analyses

    Matsumoto K., Kurasawa T., Yoshimoto K., Suzuki K., Takeuchi T.

    Arthritis Research and Therapy (Arthritis Research and Therapy)  23 ( 1 )  2021.12

    ISSN  14786354

     View Summary

    Background: Leukocyte activation by anti-neutrophil cytoplasmic antibody (ANCA) and the subsequent leukocyte–endothelium interaction play a key role in the development of endothelial damage in ANCA-associated vasculitis (AAV). In contrast to that of leukocyte activation, the exact role of the leukocyte–endothelium interaction via integrin remains unclear. Here, we performed microarray and validation analyses to explore association between the expression levels of lymphocyte function-associated antigen-1 (LFA-1) and the clinical characteristics of patients with AAV. Methods: We performed gene set enrichment analysis (GSEA) to identify the functional gene sets differentially expressed between patients with AAV and other types of vasculitis and the healthy controls (HCs). Flow cytometry was performed to validate the GSEA results. Treatment-naïve patients were monitored until 24 weeks of treatment. To examine the role of LFA-1 in the neutrophil–endothelium interaction, we performed a leukocyte adhesion and transmigration assay using peripheral blood and human umbilical vein endothelial cells (HUVECs). Results: GSEA revealed that the molecular pathways involving integrin-related genes were significantly upregulated in patients with AAV compared to that in patients with other types of vasculitis and the HCs. Flow cytometry revealed that the percentage of neutrophils expressing LFA-1 was significantly higher in patients with AAV than in those with large-vessel vasculitis or polyarteritis nodosa and the HCs. LFA-1 levels in the neutrophils were higher in patients with MPO-ANCA-positive expression than in those with a positive PR3-ANCA expression and correlated with the peripheral eosinophil count, serum rheumatoid factor titre, serum C-reactive protein levels, and the vasculitis activity score of systemic and chest components. After 24 weeks of treatment, including prednisolone, cyclophosphamide, rituximab, azathioprine, methotrexate, and/or tacrolimus, neutrophil LFA-1 expression remained high in the non-responder patients, but decreased in the responder patients. The in vitro assay showed that leukocyte migration toward HUVECs was dependent on the interaction between LFA-1 and intercellular adhesion molecule-1 (ICAM1); the migration of leukocytes was inhibited by blocking the adhesion of LFA-1 to ICAM1. Conclusions: The expression of LFA-1 in neutrophils is increased in patients with AAV. Neutrophil LFA-1 levels correlate with the clinical features of AAV. Inhibiting the adhesion of LFA-1 and ICAM1 impedes the neutrophil–endothelium interaction and may have a therapeutic role in AAV.

  • Platelet CXCL4 mediates neutrophil extracellular traps formation in ANCA-associated vasculitis

    Matsumoto K., Yasuoka H., Yoshimoto K., Suzuki K., Takeuchi T.

    Scientific Reports (Scientific Reports)  11 ( 1 )  2021.12

     View Summary

    Neutrophils form neutrophil extracellular traps (NETs), which are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Recent reports suggest that platelets stimulated via toll-like receptor (TLR) pathways can induce NETs formation. However, the mechanism underlying the involvement of platelets in NETs formation in AAV is unknown. We investigated the role of platelets in the pathogenesis of AAV. Platelets from AAV patients and healthy controls (HCs) were co-cultured with peripheral neutrophils, and NETs formation was visualized and quantified. The expression levels of TLRs on platelets were examined by flow cytometry. Platelets were treated with a TLR agonist, platelet-derived humoral factor, CXCL4 (platelet factor 4: PF4), and/or anti-CXCL4 antibody to investigate the effects of TLR–CXCL4 signaling on NETs formation. Platelets from AAV significantly upregulated NETs formation in vitro. Flow cytometric analysis revealed that the proportion of TLR9 positive platelets was significantly higher in AAV than HCs. CXCL4 released from TLR9 agonist-stimulated platelets was significantly enhanced in AAV, which subsequently increased NETs formation. Further, neutralizing anti-CXCL4 antibody significantly inhibited NETs formation enhanced by platelets from AAV. TLR9 signaling and CXCL4 release underlie the key role that platelets play in NETs formation in the pathogenesis of AAV.

  • Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease

    Akiyama M., Suzuki K., Yoshimoto K., Yasuoka H., Kaneko Y., Takeuchi T.

    Frontiers in Immunology (Frontiers in Immunology)  12 2021.04

     View Summary

    Objectives: Multiple studies suggest that interleukin (IL)-21 plays a pivotal role in the differentiation of B cells and activation of cytotoxic T cells and is involved in the pathogenesis of IgG4-related disease (IgG4-RD). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a new marker of T follicular helper (Tfh) cells, yet its significance remains unknown. The objective of this study was to investigate whether TIGIT expression could detect high IL-21-producing peripheral Tfh populations and their association with disease activity in IgG4-RD. Methods: TIGIT expression in peripheral CD4+T cell subsets was comprehensively analyzed by multi-color flow cytometry. Single cell mapping was performed by t-SNE method, and IL-21 production was compared in TIGIT+ and TIGIT-T cells. The effect of OX40 signal on cytokine expression was analyzed by RNA-sequencing. Clinical significance of TIGIT+ and TIGIT- peripheral T cells was analyzed in active patients with IgG4-RD, both at baseline and after 12 weeks of glucocorticoid treatment. Results: Unbiased single cell mapping revealed two high IL-21-producing peripheral T cell populations; TIGIT+ Tfh and TIGIT-T helper cells. OX40 signal was associated with high IL-21 production in TIGIT+ Tfh and TIGIT-T helper cells. IL-21 production in Tfh cells correlated with the proportion of TIGIT+ cells in Tfh cells, serum IgG4 level, and scores of disease activity. Furthermore, the skewing toward peripheral TIGIT+ Tfh cells, particularly TIGIT+Tfh2 subset correlated with disease activity and was corrected by glucocorticoid treatment in IgG4-RD. Conclusions: OX40 is associated with high IL-21 production in peripheral TIGIT+ Tfh cells, and the increase in peripheral TIGIT+ Tfh cells reflects disease activity in IgG4-RD.

  • Lymphadenopathy in IgG4-related disease: A phenotype of severe activity and poor prognosis, with eotaxin-3 as a new biomarker

    Takanashi S., Kikuchi J., Sasaki T., Akiyama M., Yasuoka H., Yoshimoto K., Seki N., Sugahara K., Chiba K., Kaneko Y., Takeuchi T.

    Rheumatology (United Kingdom) (Rheumatology (United Kingdom))  60 ( 2 ) 967 - 975 2021.02

    ISSN  14620324

     View Summary

    Objective: To clarify relevant proteins and clinical characteristics of a phenotype of IgG4-related disease (IgG4-RD) with lymphadenopathy. Methods: We enrolled patients newly diagnosed with IgG4-RD in our department between January 2000 and June 2018 and performed proteomic analysis to measure serum concentrations of 1305 proteins. We extracted proteins overexpressed in patients with IgG4-RD with lymphadenopathy by comparing between those with lymphadenopathy, those without lymphadenopathy and healthy controls. We further reviewed all the patients with IgG4-RD in our institution and investigated the characteristics and prognosis of the patients with IgG4-RD with lymphadenopathy. Results: Eighty-five patients with IgG4-RD were enrolled, of which, 55% had lymphadenopathy. Proteomic analysis in 31 patients with IgG4-RD and 6 healthy controls revealed that eotaxin-3 was a potential serum biomarker in the patients with lymphadenopathy versus those without lymphadenopathy and healthy controls. A cohort of 85 patients with IgG4-RD demonstrated that patients with lymphadenopathy showed a significantly higher serum IgG4, IgG4:IgG ratio, IgG4-RD responder index and eosinophilia (P < 0.001 for all), irrelevant of the extent to which organ involvement developed. Patients with lymphadenopathy treated with glucocorticoid alone relapsed with significantly higher rates than those without lymphadenopathy (P = 0.03). Conclusion: Lymphadenopathy in IgG4-RD represents a phenotype associated with high disease activities, eosinophilia and relapsing disease. Eotaxin-3 is a novel biomarker related to IgG4-RD with lymphadenopathy.

  • Milk fat globule epidermal growth factor 8 (MFG-E8) on monocytes is a novel biomarker of disease activity in systemic lupus erythematosus

    Ushikubo M., Saito S., Kikuchi J., Takeshita M., Yoshimoto K., Yasuoka H., Yamaoka K., Seki N., Suzuki K., Oshima H., Takeuchi T.

    Lupus (Lupus)  30 ( 1 ) 61 - 69 2021.01

    ISSN  09612033

     View Summary

    Background: Milk fat globule epidermal growth factor (MFG-E8) is related secreted protein which links phosphatidylserine on apoptotic cells and integrin αvβ3/5 on phagocytes. To clarify the clinical significance of MFG-E8 in SLE, we analyzed the correlation between expression level of MFG-E8 in circulating phagocytic leukocytes and clinical parameters of patients. Methods: The study was conducted under a multi-center, prospective cohort design. Patients with one or both BILAG A or B, or SLEDAI- 2 K ≥ 4 with clinical symptoms were defined as the active SLE group. Expression of MFG-E8 on monocytes and concentration in serum were measured by FACS and ELISA, respectively. Results: 96 subjects were enrolled. The absolute number and proportion of MFG-E8-positive monocytes to total monocytes were significantly higher in the active SLE group (p < 0.01). Importantly, the proportion was also significantly correlated with SLEDAI-2K, clinical SLEDAI, as well as serum levels of anti-ds-DNA antibody and complement and C1q. In addition, the proportion of MFG-E8-positive monocytes to total monocytes was significantly decreased from baseline in active SLE patients after 6 months’ treatment and increased concordantly with disease activity in 6 refractory cases. Further, in receiver operating characteristic curve analysis for discrimination between active and inactive SLE, the AUC of the proportion of MFG-E8 was 0.854, which was equivalent to classical activity markers such as anti-ds DNA antibody (0.776), complement (0.897) and C1q (0.815) Conclusions: The proportion of MFG-E8-positive monocytes to total monocytes in peripheral blood was positively associated with disease activity in SLE and may be a novel biomarker of disease activity.

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Reviews, Commentaries, etc. 【 Display / hide

Presentations 【 Display / hide

  • Possible involvement of the voltage-gated sodium channel 1.7 in activation of BAFF signaling in monocytes of patients with primary Sjögren’s syndrome.

    Keiko Yoshimoto, Katsuya Suzuki, Yumi Ikeda, Eriko Takei, Tsutomu Takeuchi

    The 50th annual meeting of Japanese Society for Immunology , 

    2021.12

    Poster presentation

  • Signal transduction via BAFF receptor, BR3, is involved in activation of monocytes through NF-kB pathways in primary Sjögren’s syndrome.

    Keiko Yoshimoto, Katsuya Suzuki, Yumi Ikeda, Eriko Takei, Tsutomu Takeuchi

    APLAR 2021, 

    2021.08

    Oral presentation (general)

  • The crosstalk between BAFF-signaling and sodium channel is involved in activation of monocytes of patients with primary Sjogren’s syndrome.

    Keiko Yoshimoto, Katsuya Suzuki, Yumi Ikeda, Eriko Takei, Tsutomu Takeuchi

    第65回日本リウマチ学会総会・学術集会, 

    2021.04

    Oral presentation (general)

  • Possible involvement of Fractalkine/CX3CR1 axis in peripheral CD14++CD16+ monocytes in disease development of patients with systemic lupus erythematosus.

    Keiko Yoshimoto, Katsuya Suzuki, Noriyasu Seki, Shuntaro Saito, Jun Kikuchi, Tsutomu Takeuchi

    ACR 2020, 

    2020.11

    Oral presentation (general)

  • Elevated expression of BAFF receptor, BR3, in peripheral monocytes is involved in B cell activation and clinical features of patients with primary Sjögren’s syndrome.

    Keiko Yoshimoto, Katsuya Suzuki, Eriko Takei, Yumi Ikeda, Tsutomu Takeuchi

    第64回日本リウマチ学会総会・学術集会, 

    2020.08

    Oral presentation (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • B細胞機能制御作用を有する低分子化合物を用いたSLE新規治療標的分子の探索

    2022.04
    -
    2025.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 基盤研究(C), Principal investigator

  • Elucidation of the regulatory mechanisms of the crosstalk between BAFF signaling and Nav channel in monocytes aiming at development of radical therapy for Sj&ouml;grens syndrome.

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Intellectual Property Rights, etc. 【 Display / hide

  • 炎症性疾患の予防及び/又は治療剤

    Date applied: JP2015541587A  2014.10 

    Patent, Joint

  • ピロロピリミジン誘導体を有効成分とするBAFFの結合阻害剤

    Date applied: JP2010266369A  2010.11 

    Date issued: JP5628647B2  2014.11

    Patent, Joint

  • BAFF抑制剤又は阻害剤のスクリーニング法

    Date applied: JP2006535161A  2005.09 

    Date issued: JP4907353B2  2012.03

    Patent, Joint

  • BAFF抑制剤又は阻害剤のスクリーニング法

    Date applied: US11662795  2005.09 

    Date issued: US8017329B2  2011.09

    Patent, Joint

  • BAFF抑制剤又は阻害剤のスクリーニング法

    Date applied: EP20050783483  2005.09 

    Date issued: EP1801231B1  2011.11

    Patent, Joint

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Awards 【 Display / hide

  • 第34回日本臨床免疫学会総会 優秀演題賞

    吉本桂子, 2006.10, 日本臨床免疫学会, ヒトT細胞BAFF産生制御機構におけるMMPの関与

  • 第41回日本臨床免疫学会総会 優秀演題賞

    吉本桂子, 2013.11, 日本臨床免疫学会, B細胞活性化因子(BAFF)による末梢単球活性化機構にはNF-kB経路が関与している

  • 第35回日本炎症再生医学会総会 優秀演題賞

    吉本桂子, 2014.07, 日本再生医学会, 一次性シェーグレン症候群患者末梢単球機能異常の抗体産生機構への関与

  • 第27回日本シェーグレン症候群学会学術集会優秀演題賞

    吉本桂子, 2018.09, 日本シェーグレン症候群学会, 原発性シェーグレン症候群患者末梢血単球活性化におけるBAFFとMMP-9の関与

  • 第27回日本シェーグレン症候群学会学術集会優秀演題賞

    吉本桂子, 2018.09, 日本シェーグレン症候群学会, 原発性シェーグレン症候群患者末梢血単球活性化におけるBAFFとMMP-9の関与

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Memberships in Academic Societies 【 Display / hide

  • The Japanese Society of Inflammation and Regeneration, 

    2011
    -
    Present
  • Japanese Society for Clinical Immunology, 

    2004
    -
    Present
  • American Society of Immunologists, 

    1999
    -
    Present
  • Japan College of Rheumatology, 

    1998
    -
    Present
  • Japanese Society for Immunology, 

    1997
    -
    Present