Mechanism of human B cell differentiation via amino-acid metabolism -Development of novel therapy for systemic lupus erythematosus-

• Project/Area Number: 19K08900
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Iwata Shigeru 産業医科大学, 医学部, 講師 (60389434)
• Co-Investigator(Kenkyū-buntansha): 田中 良哉 産業医科大学, 医学部, 教授 (30248562)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: SLE / B細胞 / 自己免疫疾患 / 免疫代謝 / mTOR / RA / mTORC1 / 必須アミノ酸 / 全身性エリテマトーデス / 免疫細胞代謝

Outline of Research at the Start

近年免疫代謝という概念が注目を集めている。本研究では、基礎医学分野では注目されるが、自己免疫疾患領域では未開拓である免疫代謝の研究を、古典的シグナル伝達経路との関連性、またエピゲノム解析など最先端研究分野と関連させ、SLE病態解明に繋げる点で、学術的特色・独創性を有する。また既存薬ではシグナル等の「阻害」が中心に行われてきたが、本研究では後述のように免疫代謝バランス異常を解明し、薬剤によるその「バランス異常の是正」を目指しており、有害事象リスクの軽減も期待される。また本研究は、感染症、癌治療、アレルギー疾患など他分野への応用も期待される。

Outline of Final Research Achievements

The mechanism of lymphocytes differentiation in rheumatoid arthritis (RA) and systemic lupus erythemtosus (SLE) were assessed in a view of immunometabolism. We found that effector Th1 cells overproducing IFN-γ were involved in refractory to conventional therapy in SLE. These cells showed metabolic abnormalities such as mTOR activation, enhancement of aerobic glycolysis and lipid metabolism. We also found that essential amino-acid methionine was involved in the pathogenesis of SLE via mTOR activation and plasmablast differentiation in B cells. In addition, we found that there were abnormality of mitochondrial membrane potential , and enhancement of mitochondrial function via glutaminolysis was important for plasmablast differentiation in B cells from SLE.

Academic Significance and Societal Importance of the Research Achievements

今回、SLE患者のリンパ球分化誘導機構を、本邦では依然未開拓な細胞内代謝システムの観点から一部解明することできた。これらの研究結果により、従来SLE患者で示されてきた古典的経路（B細胞受容体、共刺激分子: CD40など、Toll様受容体、サイトカインなどによるシグナル伝達経路）によるリンパ球活性化機序に加え、新たに免疫代謝機構の関与が明らかとなり、さらに疾患活動性や自己抗体産生、治療抵抗性など病態に深く関与することも示された。今後、より正確な分子生物学的評価方法の確立、新規治療へ繋げていくとともに、慢性ウイルス感染症 （ C型肝炎）、多発性硬化症、癌治療など他分野への応用も期待される。

Research Products

• [Journal Article] An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus (2022)
  • Author(s): Maiko Hajime Sumikawa, Shigeru Iwata, Mingzeng Zhang, Hiroko Miyata, Masanobu Ueno, Yasuyuki Todoroki, Atsushi Nagayasu, Ryuichiro Kanda, Koshiro Sonomoto, Keiichi Torimoto, Seunghyun Lee, Shingo Nakayamada, Kazuo Yamamoto, Yosuke Okada, Yoshiya Tanaka
  • Journal Title: Rheumatology Volume: - Issue: 7 Pages: 1-11
  • DOI: 10.1093/rheumatology/keab824
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Case of Simultaneous Onset of Highly Active Systemic Lupus Erythematosus and IgG4-Related Renal Disease (2022)
  • Author(s): Fujita Yuya、Iwata Shigeru、Nakano Kazuhisa、Nakayamada Shingo、Miyazaki Yusuke、Kawabe Akio、Korekoda-Yoshinari Hiroko、Nawata Aya、Tanaka Yoshiya
  • Journal Title: Modern Rheumatology Case Reports Volume: - Issue: 2 Pages: 178-182
  • DOI: 10.1093/mrcr/rxac002
  • Peer Reviewed / Open Access
• [Journal Article] Association of Viral Infection With the Development and Pathogenesis of Systemic Lupus Erythematosus (2022)
  • Author(s): Iwata Shigeru、Tanaka Yoshiya
  • Journal Title: Frontiers in Medicine Volume: 9
  • DOI: 10.3389/fmed.2022.849120
  • Peer Reviewed / Open Access
• [Journal Article] Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis. (2021)
  • Author(s): Iwata S, Zhang M, Hajime M, Ohkubo N, Sonomoto K, Torimoto K, Kitanaga Y, Trimova G, Todoroki Y, Miyata H, Ueno M, Nagayasu A, Kanda R, Nakano K, Nakayamada S, Sakata K, Tanaka Y.
  • Journal Title: Rheumatology (Oxford). Volume: in press Issue: 11 Pages: 5452-5462
  • DOI: 10.1093/rheumatology/keab229
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic perspectives on the metabolism of lymphocytes in patients with rheumatoid arthritis and systemic lupus erythematosus (2021)
  • Author(s): Shigeru Iwata, Yoshiya Tanaka
  • Journal Title: Expert Rev Clin Immunol. Volume: 17 Issue: 10 Pages: 1121-1130
  • DOI: 10.1080/1744666x.2021.1964957
  • Peer Reviewed
• [Journal Article] Neuropsychiatric systemic lupus erythematosus detected using extravascular spillage signal on dynamic magnetic resonance imaging (Ktrans) (2021)
  • Author(s): Fujita Yuya、Iwata Shigeru、Nakano Kazuhisa、Adachi Hiroaki、Tanaka Yoshiya
  • Journal Title: Rheumatology Volume: 61 Issue: SI Pages: SI102-SI104
  • DOI: 10.1093/rheumatology/keab757
  • Peer Reviewed / Open Access
• [Journal Article] mTOR activation in CD8+ cells contributes to disease activity of rheumatoid arthritis and increases therapeutic response to TNF inhibitors (2021)
  • Author(s): Zhang Mingzeng、Iwata Shigeru、Sonomoto Koshiro、Ueno Masanobu、Fujita Yuya、Anan Junpei、Miyazaki Yusuke、Ohkubo Naoaki、Sumikawa Maiko Hajime、Todoroki Yasuyuki、Miyata Hiroko、Nagayasu Atsushi、Kanda Ryuichiro、Hao He、Trimova Gulzhan、Lee Seunghyun、Nakayamada Shingo、Sakata Kei、Tanaka Yoshiya
  • Journal Title: Rheumatology Volume: - Issue: 7 Pages: 3010-3022
  • DOI: 10.1093/rheumatology/keab834
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of high-dose of mycophenolate mofetil compared with cyclophosphamide pulse therapy as induction therapy in Japanese patients with proliferative lupus nephritis (2021)
  • Author(s): Ohkubo Naoaki、Iwata Shigeru、Nakano Kazuhisa、Miyagawa Ippei、Hanami Kentaro、Fukuyo Shunsuke、Miyazaki Yusuke、Kawabe Akio、Nakayamada Shingo、Tanaka Yoshiya
  • Journal Title: Modern Rheumatology Volume: - Issue: 6 Pages: 1077-1085
  • DOI: 10.1093/mr/roab113
  • Peer Reviewed / Open Access
• [Journal Article] 自己免疫疾患におけるB細胞の役割と新規治療戦略 (2021)
  • Author(s): 岩田 慈, 田中 良哉
  • Journal Title: 医学のあゆみ Volume: in press
• [Journal Article] ヒトB細胞分化におけるアミノ酸を介した免疫代謝機構の解明～SLE新規治療の創出～ (2021)
  • Author(s): 岩田 慈, 田中 良哉
  • Journal Title: アレルギーの臨床. Volume: 41(2) Pages: 50-54
• [Journal Article] Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells (2020)
  • Author(s): Iwata Shigeru、Zhang Mingzeng、Hao He、Trimova Gulzhan、Hajime Maiko、Miyazaki Yusuke、Ohkubo Naoaki、Satoh Kanda Yurie、Todoroki Yasuyuki、Miyata Hiroko、Ueno Masanobu、Nagayasu Atsushi、Nakayamada Shingo、Sakata Kei、Tanaka Yoshiya
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 593103-593103
  • DOI: 10.3389/fimmu.2020.593103
  • Peer Reviewed / Open Access
• [Journal Article] Methionine commits cells to differentiate into plasmablasts through epigenetic regulation of BTB and CNC homolog 2 by the methyltransferase enhancer of zeste homolog 2. (2020)
  • Author(s): Zhang M, Iwata S, Hajime M, Ohkubo N, Todoroki Y, Miyata H, Ueno M, Hao H, Zhang T, Fan J, Nakayamada S, Yamagata K, Tanaka Y.
  • Journal Title: Arthritis Rheumatol. Volume: － Issue: 7 Pages: 1143-1153
  • DOI: 10.1002/art.41208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The relevance of mTOR activation in CD8+ cells to disease activity and therapeutic response to TNF inhibitor in patients with rheumatoid arthritis (2021)
  • Author(s): Shigeru Iwata, Mingzeng Zhang, Koshiro Sonomoto, Masanobu Ueno, Yuya Fujita, Naoaki Ohkubo, Maiko Hajime, Yasuyuki Todoroki, Hiroko Miyata, Atsushi Nagayasu, Ryuichiro Kanda, Gulzhan Trimova, Shingo Nakayamada, and Yoshiya Tanaka
  • Organizer: 第49回日本免疫学会
• [Presentation] 自己免疫疾患における免疫代謝機構を介したリンパ球分化・機能発現と病態への関与 (2021)
  • Author(s): 岩田慈、田中良哉
  • Organizer: 第49回臨床免疫学会総会
• [Presentation] Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)の新規評価法確立に向けた取り組み～LOOPS registryから～ (2021)
  • Author(s): 岩田慈, 藤田悠哉, 秀瀬真輔, 石渡小百合, 園本格士朗, 大久保直紀 中野和久, 中山田真吾, 服部功太郎, 功刀浩, 吉村玲児, 田中良哉
  • Organizer: 2021年日本生物学的精神医学会/日本神経精神薬理学会(合同年会)
• [Presentation] RA患者におけるmTOR活性化CD8+細胞の病態への関与と生物学的製剤が与える影響 (2021)
  • Author(s): 岩田慈、張明増、上野匡庸、藤田悠哉、隅川舞子、 大久保直紀、轟泰幸、宮田寛子、永安敦、神田龍一郎、中野和久、中山田真吾、阪田圭、田中良哉
  • Organizer: 第65回日本リウマチ学会
• [Presentation] 全身性エリテマトーデス (SLE)におけるリンパ球免疫代謝異常と病態への関与 (2020)
  • Author(s): 岩田慈、田中良哉
  • Organizer: 第48回日本臨床免疫学会
  • Invited
• [Presentation] The relevance of mTORC1-phosphorylated CXCR3+ memory B cells to the pathogenesis of rheumatoid arthritis (2020)
  • Author(s): Shigeru Iwata, Mingzeng Zhang, Maiko Hajime, Naoaki Ohkubo, Yukihiro Kitanaga, Gulzhan Torimova, Kazuhisa Nakano, Shingo Nakayamada, Kaoru Yamagata, Kei Sakata and Yoshiya Tanaka
  • Organizer: 第64回日本リウマチ学会
• [Presentation] Role of amino acid cystine in cytotoxic effects of CD8+ cells and the relevance to pathological processes of rheumatoid arthritis (2020)
  • Author(s): Shigeru Iwata, Mingzeng Zhang, Maiko Hajime, Naoaki Ohkubo, Yasuyuki Todoroki, Hiroko Miyata, Kazuhisa Nakano, Shingo Nakayamada, Kaoru Yamagata, Kei Sakjata and Yoshiya Tanaka
  • Organizer: 第64回日本リウマチ学会
• [Presentation] Methionine commits immunometabolism and epigenetic regulation of BACH2 loci in B cells, resulting in biases toward plasmablast differentiation in the pathogenesis of SLE (2019)
  • Author(s): Mingzeng Zhang, Shigeru Iwata, Maiko Hajime, Naoaki Ohkubo, Yasuyuki Todoroki, Hiroko Miyata, Jie Fan, Shingo Nakayamada, Kaoru Yamagata and Yoshiya Tanaka
  • Organizer: American college of rheumatology 2019
  • Int'l Joint Research
• [Presentation] 必須アミノ酸メチオニンによるEZH2発現を介した形質芽細胞分化誘導とSLE病態への関与 (2019)
  • Author(s): 張明増、岩田慈、元舞子、大久保直紀、轟泰幸、宮田 寛子、中山田真吾、 山形薫、田中良哉
  • Organizer: 日本臨床免疫学会 2019
• [Presentation] Role of methionine and its transporter CD98 in human B cell differentiation and the relevance to pathological processes of SLE (2019)
  • Author(s): Mingzeng Zhang, Shigeru Iwata, Maiko Hajime, Naoaki Ohkubo, Yasuyuki Todoroki, Hiroko Miyata, Jie Fan, Shingo Nakayamada, Kaoru Yamagata and Yoshiya Tanaka
  • Organizer: EAGOR 2019
  • Int'l Joint Research
• [Presentation] Role of methionine in human B cell differentiation and the relevance to pathological processes of SLE (2019)
  • Author(s): 張明増、岩田慈、元舞子、大久保直紀、轟泰幸、宮田 寛子、中山田真吾、 山形薫、田中良哉
  • Organizer: 日本免疫毒性学会 2019