A novel pathogenesis of rheumatoid arthritis due to dysregulated super-enhancer in CD4-positive T cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08925
• 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: YAMAGATA KAORU 産業医科大学, 医学部, 講師 (80533786)
• 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
• Keywords: 関節リウマチ / CD4陽性T細胞 / スーパーエンハンサー / UBASH3A / BACH2 / eRNA / ChIP

Outline of Final Research Achievements

UBASH3A mRNA and protein expression was lower in CD4+ T cells from RA patients than in those from healthy donors. UBASH3A mRNA levels were reduced by eRNA_1 and eRNA_3 knockdown. In RA patients, BTB and CNC homology 2 (BACH2), the silencing transcription factor, accumulated at the UBASH3A loci in CD4+ T cells, whereas the SE-defining factor, mediator complex subunit 1 (MED1)/bromodomain 4 (BRD4), did not. However, opposite phenomena were observed in healthy donors. Although stimulation of TCRs expressed on CD4+ T cells from RA patients led to interleukin (IL)-6 production, UBASH3A over-expression significantly inhibited its production. In conclusion, we found that transcription of UBASH3A is suppressed via epigenetic regulation of SE in CD4+ T cells from RA patients. Decreased UBASH3A levels lead to excessive activation of TCR signaling, resulting in enhanced production of IL-6.

Free Research Field

リウマチ内科学

Academic Significance and Societal Importance of the Research Achievements

代表的な自己免疫疾患である関節リウマチ(RA)の患者においてT細胞が活性化しており、RA病態への機能的関与が予想されている。しかし、依然として病態の形成過程と進展過程を担う基盤について不明な点が多い。我々は、CD4+Ｔ細胞で高発現するUBASH3Aがリウマチで発現異常を示し、炎症と関わり、そしてRAの病態進展を担うことを解明した。