KEIO RESEARCHERS INFORMATION SYSTEM

Other Affiliation 【 Display / hide 】

Other Affiliation 【 Display / hide 】

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

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• 薬学博士, 名古屋市立大学, 1996.12

Licenses and Qualifications 【 Display / hide 】

Licenses and Qualifications 【 Display / hide 】

• 薬剤師

Research Keywords 【 Display / hide 】

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 】

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 】

Papers 【 Display / hide 】

• CX3CR1+ age-associated CD4+ T cells contribute to synovial inflammation in late-onset rheumatoid arthritis

  Akiyama M., Wakasugi S., Yoshimoto K., Saito K., Ishigaki S., Inukai R., Matsuno Y., Alshehri W., Kondo Y., Kaneko Y.

  Inflammation and Regeneration 45 ( 1 )  2025.12

  　View Summary

  Background: Recent evidence suggests that clonally expanded cytotoxic T cells play a role in various autoimmune diseases. Late-onset rheumatoid arthritis (LORA) exhibits unique characteristics compared to other RA forms, suggesting distinct immunological mechanisms. This study aimed to examine the involvement of cytotoxic T cells in LORA. Methods: Fresh peripheral blood samples were collected from 78 treatment-naïve active RA patients, 12 with difficult-to-treat RA, and 16 healthy controls. Flow cytometry was employed to measure the proportions of CX3CR1⁺cytotoxic CD4⁺ and CD8⁺ T cells in these samples. Additionally, immunohistochemical staining was performed on lymphoid node and synovial biopsy samples from patients with RA. Results: CX3CR1⁺cytotoxic CD4⁺ T cells were specifically increased in untreated, active patients with LORA, displaying features of CXCR3^mid age-associated T helper cells known as “ThA”. CX3CR1⁺CD4⁺ T cells were identified as a cytotoxic ThA subset, as nearly all of these cells specifically expressed granzyme B. These cells were observed in enlarged lymph nodes and were found to infiltrate synovial tissues from patients with LORA. The proportions of CX3CR1⁺CD4⁺ T cells positively correlated with arthritis activity in LORA. The number of cells decreased after treatment with methotrexate, tumor necrosis factor inhibitors, and interleukin-6 inhibitors, whereas T-cell activation modulators did not affect them. Moreover, PD-1⁺CD38⁺CX3CR1⁺CD4⁺ T cells were identified as a treatment-resistant T cell subset that was characteristically increased in difficult-to-treat RA. CX3CR1⁺CD8⁺ T cells showed no significant difference between RA patients and healthy individuals, and no correlation with disease activity was observed. However, a correlation with age was observed in RA patients. Conclusions: Our findings suggest that the immunopathogenesis of RA differs by age of onset, with CX3CR1⁺ age-associated cytotoxic CD4⁺ T cells playing a significant role in LORA. Additionally, the presence of a specific CX3CR1⁺ T cell subset may be linked to treatment resistance.

  • Access to Document (DOI)

• Cytotoxic CX3CR1+ T cells drive vascular inflammation in giant cell arteritis but not in Takayasu’s arteritis

  Inukai R., Akiyama M., Yoshimoto K., Wakasugi S., Matsuno Y., Ishigaki S., Alshehri W., Saito K., Kaneko Y.

  Clinical and Experimental Rheumatology 43 ( 4 ) 630 - 635 2025.04

  ISSN  0392856X

  　View Summary

  Objective To compare the involvement of cytotoxic CX3CR1+ T cell subsets between giant cell arteritis (GCA) and Takayasu’s arteritis (TAK). Methods We examined the proportions of CX3CR1+ CD4+ and CD8+ T cells in whole blood freshly obtained from 30 treatment-naive patients with active large-vessel vasculitis (GCA, n=22 and TAK, n=8) and 16 healthy controls (HC). Infiltration of CX3CR1+ T cells into the affected arteries was assessed using immunohistochemical staining. Furthermore, CX3CR1+ CD4+ and CD8+ T cells were followed up after glucocorticoid treatment for longitudinal assessment of both diseases. Results The proportion of CX3CR1+ CD4+ T cells was significantly higher in GCA than in HC but not in TAK. No differences were observed in the proportions of CX3CR1+ CD8+ T cells among the GCA, TAK, and HC groups. The increased proportion of CX3CR1+ CD4+ T cells in GCA strongly correlated with the severity of systemic inflammation, whereas no significant correlation was found in TAK. Compared to TAK, CX3CR1+ CD4+ T cells from GCA patients showed significantly higher expression of granzyme B and perforin. The inflamed temporal arterial tissues of the GCA were infiltrated by numerous CX3CR1+ T cells, contributing to inflammation, disruption of the elastic lamina, and intimal hyperplasia. In contrast, no infiltration of CX3CR1+ T cells was observed in the aortitis lesions of TAK. Longitudinal analysis of post-glucocorticoid treatment showed a reduction in CX3CR1+ T cells in GCA, whereas no significant change was observed in TAK. Conclusion Differences in immune mechanisms between GCA and TAK highlight cytotoxic CX3CR1+ T cells as potential drivers for GCA-related inflammation and vessel damage but not for TAK.

  • Access to Document (DOI)

• CCR4+Tfh2 cells specifically produce IL-4 driving the pathological reaction in IgG4-related disease

  Akiyama M., Yoshimoto K., Yasuoka H., Ishigaki S., Takanashi S., Takeuchi T., Kaneko Y.

  Clinical and Experimental Rheumatology 43 ( 3 ) 435 - 443 2025.03

  ISSN  0392856X

  　View Summary

  Objective Human T follicular helper (Tfh) cells are classified into three subsets: Tfh1, Tfh2, and Tfh17 cells. Among them, Tfh2 cells are defined as CXCR3-negative and CCR6-negative, and may contain diverse cell populations. We examined whether CCR4 serves as a marker for identifying Tfh2 cells that produce interleukin (IL)-4 and its involvement in IgG4-related disease (IgG4-RD). Methods Single cell analysis of IL-4-producing Tfh subset was performed using multi-colour flow cytometry and t-SNE method. Blood samples were obtained from 23 treatment-naïve patients with active IgG4-RD. CCR4+Tfh2 cells were also assessed in affected tissues of IgG4-RD by flow cytometry and immunohistochemical staining. Results Tfh2 cells expressing CCR4 were identified as Tfh cells that specifically produce IL-4. CCR4+Tfh2 cells showed higher expression of GATA-3 and ICOS than CCR4-Tfh2 cells, while there was no difference in the expression of BCL-6 and FOXP3. The proportion of CCR4+Tfh2 cells in peripheral blood was increased in IgG4-RD compared to healthy controls, and even more CCR4+Tfh2 cells infiltrated into the affected lesions. CCR4+GATA-3+Tfh2 cells diffusely infiltrated tertiary lymphoid tissues and storiform fibrosis lesions. The proportion of CCR4+Tfh2 cells showed a significant correlation specifically with serum IgG4 levels among clinical indicators. Glucocorticoid therapy did not correct the increased proportion of CCR4+Tfh2 cells. Conclusion CCR4 serves as a marker for identifying Tfh2 cells that specifically produce IL-4. CCR4+Tfh2 cells are a widely present T cell population that infiltrates tertiary lymphoid tissues and storiform fibrosis of IgG4-RD. Glucocorticoid fails to effectively target CCR4+Tfh2 cells that may contribute to a high relapse rate during glucocorticoid tapering in this disease.

  • Access to Document (DOI)

• Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial

  Tamai H., Ikeda K., Miyamoto T., Taguchi H., Kuo C.F., Shin K., Hirata S., Okano Y., Sato S., Yasuoka H., Kuwana M., Ishii T., Kameda H., Kojima T., Nishi Y., Mori M., Miyagishi H., Toshima G., Sato Y., Tsai W.C., Takeuchi T., Kaneko Y., Izumi K., Kondo Y., Yoshimoto K., Gono T., Park S.H., Baek H.J., Lee Y.J., Choi I.A., Kim J., Hsu P.N., Huang C.M., Weng M.Y., Sung W.Y., Cheng T.T.

  Annals of the Rheumatic Diseases 84 ( 1 ) 41 - 48 2025.01

  ISSN  00034967

  　View Summary

  Objectives: The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial. Methods: The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety. Results: The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index. Conclusions: The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX. Trial registration number: NCT03505008.

  • Access to Document (DOI)

• 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.

  • Access to Document (DOI)

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Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• CC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4-related disease

  Akiyama M., Yasuoka H., Yoshimoto K., Takeuchi T.

  Annals of the Rheumatic Diseases (Annals of the Rheumatic Diseases)  77 ( 9 ) 1386 - 1387 2018.09

  ISSN  00034967

  • Access to Document (DOI)

Presentations 【 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 】

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

Intellectual Property Rights, etc. 【 Display / hide 】

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 】

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 】

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