Identification of new responsible gene for chronic mucocutaneous candidiasis disease. Analysis of molecular pathogenesis of STAT1 dysregulation.

2015 Fiscal Year Final Research Report

• Project/Area Number: 25713039
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: Okada Satoshi 広島大学, 医歯薬保健学研究院(医), 講師 (80457241)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: RORγT / STAT1 / CMC / MSMD

Outline of Final Research Achievements

We discovered bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγT resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+ CXCR3+ αβT cells. We thus discovered that both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγT in human （Okada S, et al. Science 349: 606-13, 2015).
We performed functional assay based on systematic alanine-scanning mutagenesis of human STAT1, which can be used to estimate the gain-of-function or loss-of-function status of nonsynonymous mutations (manuscript in preparation).

Free Research Field

小児免疫学