Understanding the Pathophysiology of STAT1 Gain-of-Function Mutations with a Focus on Th17 Differentiation Impairment and Autoimmune Disorders

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15865
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Hiroshima University
• Principal Investigator: SAKATA Sonoko 広島大学, 病院(医), 寄附講座助教 (50897907)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: STAT1機能獲得型変異 / Th17細胞 / サイトカイン / インターフェロノパチー

Outline of Final Research Achievements

【Elucidation of the Molecular Basis of Decreased Th17 Cell Count in Patients with STAT1 Gain-of-Function Mutations (STAT1-GOF)】When IFN-α, IFN-γ, and IL-27 were added to the differentiation culture of Th17 cells, differentiation and proliferation of Th17 cells were excessively inhibited in patients, and their differentiation and proliferation were restored by inhibiting these cytokines. This study identified the cytokines crucial for inhibiting the differentiation and proliferation of Th17 cells.
【Elucidation of the Molecular Basis of Autoimmune Diseases Focusing on Type I Interferonopathy】Using single-cell RNA-seq, it was found that in STAT1-GOF patients, a wide range of lymphocyte subsets exhibited an increase in gene expression induced by IFN-α and IFN-γ.

Free Research Field

免疫不全症

Academic Significance and Societal Importance of the Research Achievements

感染症や自己免疫疾患がコントールできないSTAT1機能獲得型変異（STAT1-GOF）重症例に対する治療法の開発のために、病態の解明を試みた。
Th17分化・増殖障害の鍵となるサイトカインの同定を行った。その成果はSTAT1-GOFがもたらす複雑な分子病態の理解に繋がり、同定されたサイトカインはTh17細胞の回復のための治療標的となる可能性があり、今後の発展性が期待される。
また、STAT1-GOF患者におけるI型インターフェロノパチーの分子病態を調査した。本成果は、自己免疫疾患合併STAT1-GOF患者に対するJAK阻害薬の有用性を議論するにあたって重要な意義があると考える。