Clinical and immunological data of nine patients with chronic mucocutaneous candidiasis disease

Abstract

This paper describes the heterogeneous clinical phenotype of a cohort of nine patients diagnosed with heterozygous mutations in STAT1. We report data of extended immunophenotyping over time and we show lung damage in four patients. The increased phosphorylation of STAT1 in response to IFNγ and IFNα stimulation proves the gain-of-function nature of the defects. The data are supplemental to our original article concurrently published “Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease” [1], where additional results and interpretation of our research can be found.

Chronic mucocutaneous candidiasis due to gain‐of‐function mutation in STAT1

“…JAK1/2 inhibition inhibits STAT1‐mediated intracellular signalling, allowing restoration of STAT3 signalling and development of naïve T‐helper cells into a Th17 phenotype (Weinacht et al., ). Granulocyte colony‐stimulating factor or granulocyte monocyte colony‐stimulating factor may enhance Th17 cell differentiation and recovery from fungal infections (Dotta et al., ). Haematopoietic stem cell transplantation (HSCT) is another treatment option, but due to high rates of treatment‐related morbidity and mortality, it is reserved for the most severe CMC cases.…”

Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1

“…We showed that in-vitro treatment with Ruxolitinib significantly decreased the exaggerated cytokine-induced p-STAT1 response in CD4 + T cells of patient P1, suggesting that this therapeutic modality may be useful in case HSCT is unavailable. In addition, case reports with STAT1 GOF mutations have shown that treatment with either granulocyte-colony stimulating factor or granulocyte monocyte-colony stimulating factor may improve the generation of T H 17 cells and recovery from fungal infections (11). …”

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

“…Some of the patients had been previously screened for other mutations (ie, AIRE or CARD9) to rule out other causes of CMCD. In all patients described herein, we found heterozygous mutations in the coiled-coil or DNA-binding domains of STAT1: L283M in P1 and his mother P2, L351F in P3, L400V in P6, T837A in P8, 21,22 T385M in P4 and P5, 23 and A267V in P7. 4 Clinical data from patients were collected from medical records and are briefly summarized in Table I.…”

“…Fungal and bacterial infections were observed in all patients with CMCD, whereas viral infections were observed in patients P3 and P8. 21,22 More detailed information on the Methods used are reported in this article's Online Repository at www.jacionline.org.…”

“…13 Fungal infections constitute the most common manifestation of CMCD, but viral infections, including recurrent mucocutaneous infections caused by reactivation of varicella-zoster virus and herpes simplex viruses, debilitating orf infection, or severe invasive infection caused by chicken pox, cytomegalovirus, or EBV have also been reported. [16][17][18][19][20][21] The broad spectrum of infections observed in patients with CMCD suggests that susceptibility to pathogens is not entirely due to the lack of T H 17 cells, but other cell types, particularly NK cells, might play a role in the pathogenesis of CMCD. To define the role of NK cells in the susceptibility of patients with CMCD to intracellular pathogens and viruses, we have investigated NK functional activities and STAT1 and STAT5 signaling in response to cytokines in these patients.…”