Glycolysis controls the differentiation of naïve B cells to T-bet+CD11c+ B cells in SLE

• Project/Area Number: 21K20884
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Todoroki Yasuyuki 産業医科大学, 医学部, 助教 (40746814)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 解糖系 / IL-6産生 / 新規病原性B細胞 / 治療層別化 / T-bet+CD11c+ B細胞 / 活動性腎炎 / 全身性エリテマトーデス / 細胞内代謝 / 免疫細胞内代謝

Outline of Research at the Start

全身性エリテマトーデス(SLE)においてB細胞は重要な役割を担う。近年、T-bet+CD11c+B細胞はSLEの病態形成に重要な細胞集団として注目されつつあるが、その分化機構および機能の詳細は不詳である。本研究では、①基礎実験において、特に免疫細胞分化に影響をもたらす細胞内代謝に着目しT-bet+CD11c+B細胞の分化機構・機能を解明し、さらに②患者さん毎の特性(末梢血リンパ球に占める同細胞の割合)を事前に把握しその特性に沿った適切かつ戦略的な薬剤選択(precision medicine)に繋げる事を目的としている。

Outline of Final Research Achievements

In vitro, T-bet+ B cells were well-induced when naive B cells cultured under the combination of B cell receptor + CD40 ligand+IL-21 + TLR9 ligand +IFN-γ. And in the culture medium, IL-6 were excessively produced from naive B cell-derived T-bet+ cells. The differentiation process showed a metabolic bias toward glycolytic system. In contrast, differentiation into plasmablasts depend on OXPHOS-dominant metabolic bias. Glycolytic　inhibitors suppressed the proliferation and IL-6 production of these cells. On the other hand, OXPHOS inhibitors showed a limited effect.
In SLE patients, T-bet+ B cells (%) were associated with active nephritis and resistance to treatment and positively correlated with serum IL-6 concentration. Glycolytic enzymes GLUT1/3, HK2, and GAPDH were upregulated in these cells.

Academic Significance and Societal Importance of the Research Achievements

本研究はSLEの病態形成において重要な役割を果たすT-bet+CD11c+B細胞の分化機構や機能を細胞内代謝の観点から検討を行った。解糖系阻害が難治性SLEの新たな治療標的となる可能性とともに症例毎にT-bet+CD11c+B細胞の割合を事前に把握することで、多くの合併症を誘発しうる副腎皮質ステロイド剤とは異なる作用機序の効率的かつ有害事象の少ない治療法を提供するというprecision medicineの実践にも応用可能である事が示唆された。その実現により、SLE患者の労働生産性の改善、療養・就労両立支援への貢献が可能となる点で社会的意義が高いと考える。

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
• [Presentation] Increased IL-21 receptor expression level via glycolysis in B cells and its potential as a trigger for exacerbation of disease activity in SLE (2022)
  • Author(s): Masanobu Ueno, Shigeru Iwata, Kaoru Yamagata, Koshiro Sonomoto, Yasuyuki Todoroki, Jyunpei Anan, Kentaro Hanami, Yusuke Miyazaki, Akio Kawabe, Hiroko Miyata, Atsushi Nagayasu, Ryuichiro Kanda, Takafumi Aritomi, Shingo Nakayamada, Yoshiya Tanaka
  • Organizer: 第66回 日本リウマチ学会
• [Presentation] SLE患者B細胞における初期解糖系亢進とIL-21シグナルを介した疾患増悪への関与 (2022)
  • Author(s): 上野匡庸、岩田慈、山形薫、園本格士朗、轟泰幸、阿南純平、宮崎佑介、永安敦、神田龍一郎、有冨貴史、中山田真吾、田中良哉
  • Organizer: 第50回日本臨床免疫学会