Roles of CD226 in the pathogenesis of systemic lupus erythematosus

• Project/Area Number: 19K17887
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kyushu University
• Principal Investigator: Masahiro Ayano 九州大学, 医学研究院, 助教 (40773677)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CD226 / 全身性エリテマトーデス / ループス腎炎 / B細胞 / バイオマーカー

Outline of Research at the Start

全身性エリテマトーデス（SLE）の病態には過剰な自己への免疫応答が関与しており、多くの細胞の相互作用に関わる共刺激分子を標的とした治療戦略は有用と考えられる。CD226は近年SLEの新規疾患感受性遺伝子として報告された共刺激分子であり、CD226を標的とする治療はSLEの病態に関与する細胞を多面的に制御できる可能性がある。本研究は、SLEの病態形成におけるCD226の機能を明らかにし、CD226を標的とする治療法を確立することを目的として行う。

Outline of Final Research Achievements

This study aimed to reveal the involvement of CD226 in the pathogenesis of systemic lupus erythematosus (SLE) by assessing the relationship between CD226-expressing B cells or soluble CD226 and the disease activity, clinical manifestations, and prognosis of SLE. We demonstrated that the proportion of CD226+ B cells increased in SLE patients and could be associated with disease activity and prognosis. We also showed that serum soluble CD226 levels were elevated in active SLE patients and were associated with disease activity and flares. Thus, CD226+ B cells and soluble CD226 may be useful biomarkers for SLE, and its monitoring allows for more precise SLE management.

Academic Significance and Societal Importance of the Research Achievements

全身性エリテマトーデス（SLE）は治療薬や治療戦略の進歩に伴い長期予後は改善しつつあるが十分ではなく、依然として腎炎や中枢神経病変など難治性病態が残存している。本研究では、B細胞のCD226陽性率および血清可溶型CD226濃度がSLEの難治性病態および予後を反映しSLE診療における有用なバイオマーカーになり得ることを示した。これらを用いることでSLE診療の質の向上、長期予後の改善につながることが期待される。

Research Products

• [Journal Article] TNFR2 Signaling Enhances Suppressive Abilities of Human Circulating T Follicular Regulatory Cells (2022)
  • Author(s): Kawano Shotaro、Mitoma Hiroki、Inokuchi Shoichiro、Yamauchi Yusuke、Yokoyama Kana、Nogami Jumpei、Semba Yuichiro、Ayano Masahiro、Kimoto Yasutaka、Akahoshi Mitsuteru、Ono Nobuyuki、Arinobu Yojiro、Akashi Koichi、Horiuchi Takahiko、Niiro Hiroaki
  • Journal Title: The Journal of Immunology Volume: 208 Issue: 5 Pages: 1057-1065
  • DOI: 10.4049/jimmunol.2100323
  • Peer Reviewed
• [Journal Article] Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus (2021)
  • Author(s): Nakano Miki、Ayano Masahiro、Kushimoto Kazuo、Kawano Shotaro、Higashioka Kazuhiko、Inokuchi Shoichiro、Mitoma Hiroki、Kimoto Yasutaka、Akahoshi Mitsuteru、Ono Nobuyuki、Arinobu Yojiro、Akashi Koichi、Horiuchi Takahiko、Niiro Hiroaki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-95711-2
  • Peer Reviewed / Open Access
• [Journal Article] Increased proportion of CD226+ B Cells is associated with the disease activitiy and prognosis of systemic lupus erythematosus. (2021)
  • Author(s): 61.Nakano M, Ayano M, Kushimoto K, Kawano S, Higashioka K, Inokuchi S, Mitoma H, Kimoto Y, Akahoshi M, Ono N, Arinobu Y, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Front Immunol Volume: 12 Pages: 713225-713225
  • DOI: 10.3389/fimmu.2021.713225
  • Peer Reviewed / Open Access
• [Journal Article] Hydroxychloroquine versus tacrolimus for the treatment of persistently active systemic lupus erythematosus (2021)
  • Author(s): Ayano Masahiro、Kimoto Yasutaka、Mitoma Hiroki、Akahoshi Mitsuteru、Ono Nobuyuki、Arinobu Yojiro、Akashi Koichi、Horiuchi Takahiko、Niiro Hiroaki
  • Journal Title: Modern Rheumatology Volume: 32 Issue: 2 Pages: 345-350
  • DOI: 10.1093/mr/roab010
  • Peer Reviewed / Open Access
• [Journal Article] HLA-B52 allele in giant cell arteritis may indicate diffuse large-vessel vasculitis formation: retrospective study. (2021)
  • Author(s): 64.Kushimoto K, Ayano M, Nishimura K, Nakano M, Kimoto Y, Mitoma H, Ono N, Arinobu Y, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Arthritis Res Ther Volume: 23 Issue: 1 Pages: 238-238
  • DOI: 10.1186/s13075-021-02618-4
  • Peer Reviewed / Open Access
• [Journal Article] Predictive factors of fetal and maternal pregnancy outcomes in Japanese patients with systemic lupus erythematosus. (2021)
  • Author(s): Irino K, Arinobu Y, Ayano M, Kawano S, Kimoto Y, Mitoma H, Akahoshi M, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Lupus Volume: 30 Issue: 10 Pages: 1637-1643
  • DOI: 10.1177/09612033211031989
  • Peer Reviewed
• [Journal Article] Type 1 helper T cells generate CXCL9/10-producing T-bet + effector B cells potentially involved in the pathogenesis of rheumatoid arthritis (2021)
  • Author(s): Nakayama T, Yoshimura M, Higashioka K, Miyawaki K, Ota Y, Ayano M, Kimoto Y, Mitoma H, Ono N, Arinobu Y, Kikukawa M, Yamada H, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Cell Immunol. Volume: 360 Pages: 104263-104263
  • DOI: 10.1016/j.cellimm.2020.104263
  • Peer Reviewed
• [Journal Article] Activation of caspase-1 is mediated by stimulation of interferon genes and NLR family pyrin domain containing 3 in monocytes of active systemic lupus erythematosus (2021)
  • Author(s): Inokuchi S, Mitoma H, Kawano S, Ayano M, Kimoto Y, Akahoshi M, Arinobu Y, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Clin Exp Rheumatol. Volume: -
  • Peer Reviewed
• [Journal Article] Human PD-1 hi CD8 + T Cells Are a Cellular Source of IL-21 in Rheumatoid Arthritis (2021)
  • Author(s): Higashioka K, Yoshimura M, Sakuragi T, Ayano M, Kimoto Y, Mitoma H, Ono N, Arinobu Y, Kikukawa M, Yamada H, Horiuchi T, Akashi K, Niiro H.
  • Journal Title: Front Immunol. Volume: 12 Pages: 654623-654623
  • DOI: 10.3389/fimmu.2021.654623
  • Peer Reviewed / Open Access
• [Journal Article] Shoulder ultrasound and serum lactate dehydrogenase predict inadequate response to glucocorticoid treatment in patients with polymyalgia rheumatica. (2020)
  • Author(s): Ayano M, Arinobu Y, Tsukamoto H, Ota SI, Misaki K, Nishimura K, Kimoto Y, Mitoma H, Akahoshi M, Akashi K, Horiuchi T, Niiro H.
  • Journal Title: Rheumatology International Volume: - Issue: 7 Pages: 1101-1109
  • DOI: 10.1007/s00296-020-04512-9
  • Peer Reviewed / Open Access
• [Journal Article] Homeostatic Milieu Induces Production of Deoxyribonuclease 1-like 3 from Myeloid Cells. (2020)
  • Author(s): Inokuchi S, Mitoma H, Kawano S, et. al.
  • Journal Title: J Immunol. Volume: 204 Issue: 8 Pages: 2088-2097
  • DOI: 10.4049/jimmunol.1901304
  • Peer Reviewed / Open Access
• [Journal Article] Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease. (2020)
  • Author(s): Higashioka K, Ota Y, Maehara T, et. al.
  • Journal Title: BMC Immunol. Volume: 21 Issue: 1 Pages: 31-31
  • DOI: 10.1186/s12865-020-00361-0
  • Peer Reviewed / Open Access
• [Journal Article] Generation of a novel CD30 + B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis (2020)
  • Author(s): Higashioka K, Kikushige Y, Ayano M, Kimoto Y, Mitoma H, Kikukawa M, Akahoshi M, Arinobu Y, Horiuchi T, Akashi K, Niiro H.
  • Journal Title: Clin Exp Immunol. Volume: 201 Issue: 3 Pages: 233-243
  • DOI: 10.1111/cei.13477
  • Peer Reviewed
• [Journal Article] Methotrexate Enhances Apoptosis of Transmembrane TNF-Expressing Cells Treated With Anti-TNF Agents (2020)
  • Author(s): Wang Q, Oryoji D, Mitoma H, Kimoto Y, Koyanagi M, Yokoyama K, Ayano M, Akahoshi M, Arinobu Y, Niiro H, Akashi K, Horiuchi T.
  • Journal Title: Front Immunol. Volume: 14 Pages: 2042-2042
  • DOI: 10.3389/fimmu.2020.02042
  • Peer Reviewed / Open Access
• [Journal Article] CCR6+ group 3 innate lymphoid cells accumulate in inflamed joints in rheumatoid arthritis and produce Th17 cytokines (2019)
  • Author(s): Takaki-Kuwahara Ayako、Arinobu Yojiro、Miyawaki Kohta、Yamada Hisakata、Tsuzuki Hirofumi、Irino Kensuke、Ayano Masahiro、Kimoto Yasutaka、Mitoma Hiroki、Akahoshi Mitsuteru、Tsukamoto Hiroshi、Horiuchi Takahiko、Niiro Hiroaki、Akashi Koichi
  • Journal Title: Arthritis Research & Therapy Volume: 21 Issue: 1 Pages: 198-198
  • DOI: 10.1186/s13075-019-1984-x
  • Peer Reviewed / Open Access
• [Presentation] 全身性エリテマトーデスに対するヒドロキシクロロキンのステロイド減量効果：タクロリムスとの比較検討 (2019)
  • Author(s): 綾野 雅宏、赤星 光輝、木本 泰孝、三苫 弘喜、 有信 洋二郎、赤司 浩一、堀内 孝彦、新納 宏昭
  • Organizer: 第63回日本リウマチ学会総会・学術集会
• [Presentation] 全身性エリテマトーデス患者における血清可溶型CD226濃度の臨床的意義 (2019)
  • Author(s): 中野 未来、綾野 雅宏、久志本 和郎、河野 正太郎、木本 泰孝、三苫 弘喜、赤星 光輝、有信 洋二郎、赤司 浩一、堀内 孝彦、新納 宏昭
  • Organizer: 第63回日本リウマチ学会総会・学術集会
• [Presentation] 全身性強皮症に対する自家造血幹細胞移植の長期成績 (2019)
  • Author(s): 綾野 雅宏、三苫 弘喜、塚本 浩、柏戸 佑介、 木本 泰孝、赤星 光輝、有信 洋二郎、 赤司 浩一、堀内 孝彦、新納 宏昭
  • Organizer: 第63回日本リウマチ学会総会・学術集会