Yoshimoto, Keiko

写真a

Affiliation

School of Medicine, Endowed Research Laboratory for the Promotion of Home Care Technology (Shinanomachi)

Position

Researcher (Non-tenured) / Project Researcher(Non-tenured)
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Other Affiliation 【 Display / hide 】

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

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Academic Degrees 【 Display / hide 】

  • 薬学博士, 名古屋市立大学, 1996.12

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Licenses and Qualifications 【 Display / hide 】

  • 薬剤師

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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

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Papers 【 Display / hide 】

  • Cytotoxic Tph subset with low B-cell helper functions and its involvement in systemic lupus erythematosus

    Seki N., Tsujimoto H., Tanemura S., Kojima S., Miyoshi F., Kikuchi J., Saito S., Akiyama M., Sugahara K., Yoshimoto K., Kaneko Y., Chiba K., Takeuchi T.

    Communications Biology (Communications Biology)  7 ( 1 )  2024.12

    　View Summary

    T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. However, the role of Tph subsets is not fully elucidated. Here, we investigate the immunological functions of Tph subsets and their involvement in systemic lupus erythematosus (SLE). We have defined four Tph subsets (Tph1: CXCR3+CCR6−, Tph2: CXCR3−CCR6−, Tph17: CXCR3−CCR6+, and Tph1-17: CXCR3+CCR6+) and performed RNA sequencing after cell sorting. Tph1 and Tph17 subsets express substantial levels of IL21, indicating B cell helper functions. However, Tph2 and Tph1-17 subsets express low IL21. Interestingly, we have found Tph2 subset express high levels of CX3CR1, GZMB, PRF1, GLNY, S1PR5, TBX21, EOMES, ZNF863, and RUNX3, indicating a feature of CD4+ cytotoxic T lymphocytes. In SLE patients, the frequency of Tph1 and Tph2 subsets are significantly increased and positively correlated with SLE disease activity indexes. Tph1 cells expansion has been observed in patients with cutaneous and musculoskeletal manifestations. On the other hand, Tph2 cell expansion has been found in patients with lupus nephritis in addition to the above manifestations. Our findings imply that Tph1 and Tph2 subsets exert distinct immunological functions and are contributed to the complexity of clinical manifestations in SLE.

  • Longitudinal analysis at pre- and post-flare of T peripheral helper and T follicular helper subsets in patients with systemic lupus erythematosus

    Seki N., Tsujimoto H., Tanemura S., Kikuchi J., Saito S., Sugahara K., Yoshimoto K., Akiyama M., Takeuchi T., Chiba K., Kaneko Y.

    Immunology Letters 269 2024.10

    ISSN  01652478

    　View Summary

    Objective: We focused to analyze the time-course changes at pre- and post-flare of T peripheral helper (Tph) cells and circulating T follicular helper (Tfh) cells in the blood of patients with systemic lupus erythematosus (SLE) with lupus low disease activity state (LLDAS) before flare. Methods: This study included inactive (n = 29) and active (n = 55) patients with SLE. Tph subsets, Tfh subsets, CD11chi B cells, and plasma cells in the blood were determined by flow cytometry. The blood levels of cytokines including interferons (IFNs) were measured by electrochemiluminescence assay or cytokine beads array. Results: Active SLE patients exhibited the increased frequency of Tph1, Tph2, Tfh1, and Tfh2 subsets when compared to inactive patients, but no clear changes in the other subsets. During the treatment with medications, Tph1, Tph2, and Tfh2 subsets were significantly reduced along with disease activity and Tph1 and Tph2 subsets were positively correlated with SLE disease activity index (SLEDAI). The time course analysis of patients at pre- and post-flare revealed that in the patients at LLDAS before flare, Tph subsets and Tfh subsets were relatively low levels. At the flare, Tph cells, particularly Tph1 and Tph2 subsets, were increased and correlated with SLEDAI. Furthermore, the blood levels of IFN-α2a, IFN-γ, and IFN-λ1 were low in the patients with LLDAS before flare but these IFNs, particularly IFN-λ1, were increased along with flare. Conclusion: Increased frequency of Tph1 and Tph2 subsets and elevated levels of serum IFN-λ1 are presumably critical for triggering of flare in SLE.

  • Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis

    Yoshida H., Magi M., Tamai H., Kikuchi J., Yoshimoto K., Otomo K., Matsumoto Y., Noguchi-Sasaki M., Takeuchi T., Kaneko Y.

    Rheumatology (United Kingdom) 63 ( 9 ) 2515 - 2524 2024.09

    ISSN  14620324

    　View Summary

    Objectives: Anti-IL-6 receptor antibodies are clinically efficacious in the management of RA with an associated increase in Tregs; however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyse the relationship between these Treg subsets and the clinical outcome of RA. Methods: We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. Results: The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. Conclusions: Blocking the IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favourable treatment course and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

  • Th17/IL-17A axis is critical for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc): SSc patients with high levels of serum IL-17A exhibit reduced lung functions and increased prevalence of PAH

    Seki N., Tsujimoto H., Tanemura S., Ishigaki S., Takei H., Sugahara K., Yoshimoto K., Akiyama M., Kaneko Y., Chiba K., Takeuchi T.

    Cytokine (Cytokine)  176 2024.04

    ISSN  10434666

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    Background: It is thought that systemic sclerosis (SSc) might be a T helper 17 (Th17) cell-driven autoimmune disease. Noticeably, pulmonary arterial hypertension (PAH) is a leading cause of death in patients with SSc. Here, we investigated the association between serum Th17-related cytokines and prevalence of PAH in SSc patients. Methods: This study included 72 SSc patients and 51 healthy controls (HC). We determined clinical manifestations, immunophenotypes including Th subsets in peripheral blood lymphocytes, and the serum levels of interleukin (IL)-17A, IL-17A/F, IL-17B. IL-17C, IL-17D. IL-1β, IL-6, IL-21, IL-22, and IL-23. Results: The frequency of Th17 cells was significantly increased in SSc patients compared to HC and was positively correlated with the modified Rodnan skin scores. Furthermore, the serum levels of IL-17A, IL-17D, IL-1β, and IL-6 were significantly increased in SSc patients compared to HC. SSc patients with detected IL-17A showed high levels of IL-17A/F, IL-1β, IL-6, and IL-22, and high frequency of Th17 cells. Interestingly, these patients exhibited the reduced lung functions and increased prevalence of PAH significantly compared to patients with undetected IL-17A. Similarly, SSc patients with detected IL-17A and high IL-6 (≥1.2 pg/mL) exhibited the decreased lung functions and increased prevalence of PAH compared to patients with undetected IL-17A and low IL-6. Conclusion: We found that SSc patients with high levels of serum IL-17A or both IL-17A and IL-6 show reduced lung functions and high prevalence of PAH. Consequently, it is highly probable that Th17/IL-17A axis is critical for the prevalence of PAH in SSc patients.

  • Clinical and immunological effects of hydroxychloroquine in patients with active rheumatoid arthritis despite antirheumatic treatment

    Takei H., Takanashi S., Otomo K., Hanaoka H., Kikuchi J., Yamaoka K., Yoshimoto K., Abe T., Takeuchi T., Kaneko Y.

    Modern Rheumatology (Modern Rheumatology)  34 ( 1 ) 50 - 59 2024.01

    ISSN  14397595

    　View Summary

    Objectives: To investigate the efficacy and safety of hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA). Methods: Patients with active RA, despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), were recruited. HCQ was administered for 24 weeks, in addition to prior treatment. The primary end-point was the proportion of patients achieving American College of Rheumatology (ACR) 20 at Week 24, compared to that of a propensity score–matched historical control group. Results: Sixty patients were enrolled and administered HCQ. We also identified 276 patients as candidates for the historical control group. Propensity score matching yielded 46 patients in each group. The proportion of patients achieving ACR20 at Week 24 was significantly higher in the HCQ group than in the control group (54.4% vs. 28.3%, P = .007). The proportion of patients achieving ACR50 and ACR70 at Week 24 were also higher in the HCQ group than in the control group (ACR50, 30.4% vs. 4.3%, P = .006; ACR70, 17.4% vs. 0%, P = .005). Neither HCQ retinopathy nor any new safety signal was observed during the study. Conclusion: The addition of HCQ to csDMARDs was effective, with no new safety signal in patients with RA.

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Reviews, Commentaries, etc. 【 Display / hide 】

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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 Sjögrens syndrome.

    2019.04
    -
    2022.03

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

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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
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