Abstract
Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency characterized by persistent or recurrent skin and mucosal surface infections with Candida species. Different gene mutations leading to CMC have been identified. These include various heterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) that are not only associated with infections but also with autoimmune manifestations. Recently, two STAT1 GOF mutations involving the Src homology 2 (SH2) domain have been reported, while so far, over 50 mutations have been described mainly in the coiled coil and the DNA-binding domains. Here, we present two members of a Dutch family with a novel STAT1 mutation located in the SH2 domain. T lymphocytes of these patients revealed STAT1 hyperphosphorylation and higher expression of STAT1 target genes. The clinical picture of CMC in our patients could be explained by diminished production of interleukin (IL)-17 and IL-22, cytokines important in the protection against fungal infections.
Highlights
Patient 1 (II-4) (Figures 1A,B) is a 24-year-old female who presented at age of 1 with a Streptococcus haemolyticus jaw abscess, with recurrent oral and esophageal Candida albicans infections from the age of 6 onward and an episode of Staphylococcus aureus pneumonia and cytomegalovirus (CMV) pneumonia at age of 7 years
She has experienced oral and vaginal ulcers which were found negative for bacterial, fungal, and viral microbes as determined by culture and/or PCR of oral and vaginal swabs and tissue biopsies from vaginal ulcers. Because of these ulcers, which were assumed to be autoimmune manifestations related to chronic mucocutaneous candidiasis (CMC), various immunosuppressive therapies have been initiated over time, including steroids, azathioprine, hydroxychloroquine, and mycophenolate mofetil, all with little benefit
The mutation identified in our patients is located in the signal transducer and activator of transcription 1 (STAT1) Src homology 2 (SH2) domain resulting in recurrent mucocutaneous C. albicans infections, which is one of the clinical hallmarks of CMC
Summary
Patient 1 (II-4) (Figures 1A,B) is a 24-year-old female who presented at age of 1 with a Streptococcus haemolyticus jaw abscess, with recurrent oral and esophageal Candida albicans infections from the age of 6 onward and an episode of Staphylococcus aureus pneumonia and cytomegalovirus (CMV) pneumonia at age of 7 years. Patient 2 (I-1) (Figures 1A,B) is the 50-year-old father of patient 1, with a medical history including aortic valve replacement at age 29 and surgical and antibiotic treatment for a culture-negative, frontal-lobe brain abscess at age 33 He presented for the first time at our outpatient clinic at the age of 49 because of very severe C. albicans infection in the oral cavity and esophagus. To evaluate the immunological phenotype associated with this mutation, STAT1 phosphorylation was studied by flow cytometry of fresh whole blood samples from patient 1 and an age-gender-race-matched healthy control. To study the kinetics of STAT1 phosphorylation in more detail, time-course stimulation experiments were performed with fresh whole blood samples from patients 1 and 2 along with age-gender-race-matched healthy controls. High mRNA levels were observed after IL-27 activation (P < 0.001) (Figure 3B)
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