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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 解糖系 / IL-6産生 / 新規病原性B細胞 / 治療層別化

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.

Free Research Field

リウマチ膠原病

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。