Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody.

Heterozygous gain-of-function (GOF) mutations of STAT1 are responsible for chronic mucocutaneous candidiasis disease (CMCD), one of the primary immunodeficiency diseases characterized by susceptibility to mucocutaneous Candida infection. To date, 30 aa changes have been reported: 21 in the coiled-coil domain and 9 in the DNA-binding domain. In this study, we report two novel STAT1 GOF mutations of p.K278E in coiled-coil domain and p.G384D in DNA-binding domain in Japanese CMCD patients. Ectopic expression of these STAT1 mutants in HeLa cells was associated with increased phosphorylation of the mutant and the endogenous wild-type STAT1 due to impaired dephosphorylation, indicating heterodimers of the wild-type and mutant STAT1 cause impaired dephosphorylation, as did homodimers of the mutants. Because IL-17A production was not significantly reduced at least in one of the patients following PMA plus ionomycin stimulation, we further studied Th17-associated cytokines IL-17A, IL-17F, and IL-22 in response to more physiologically relevant stimulations. IL-17A and IL-22 production from PBMCs and CD4(+) cells was significantly reduced in four patients with STAT1 GOF mutations, including the previously reported R274Q in response to anti-CD3 plus anti-CD28 Abs or Candida stimulations. In contrast, IL-17F production was comparable to healthy controls in response to anti-CD3 plus anti-CD28 Abs stimulation. These results indicate impaired production of IL-17A and IL-22 rather than IL-17F was associated with the development of CMCD in these patients. Additionally, only the anti-IL-17F autoantibody was detected in sera from 11 of 17 patients with STAT1 GOF mutations, which may be useful as a marker for this disease.