Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation–polyendocrinopathy–enteropathy–X-linked–like syndrome

Abstract

Background Mutations in STAT1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles), to mild disseminated mycobacterial disease (hypomorphic alleles), to chronic mucocutaneous candidiasis (hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity and squamous cell cancers. Objective To investigate the role of STAT1 gain of function mutations in phenotypes other than CMC. Methods We initially screened patients with chronic mucocutaneous candidiasis and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T cells. After our initial case identifications we explored two large cohorts of FOXP3WT IPEX-like patients for STAT1 mutations. Results We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis, reminiscent of IPEX syndrome, all but one had a variety of mucosal and disseminated fungal infections. All patients lacked FOXP3 mutations but had uniallelic STAT1 mutations [c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M (2 patients)]. STAT1 phosphorylation in response to IFN-γ, IL-6 and IL-21 was increased and prolonged. CD4+ IL-17 producing T cells were diminished. All patients had a normal percentage of regulatory T cells in the CD4+ T cell compartment and their function was intact in the two patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.. Conclusions Gain-of-function mutations in STAT1 can cause an IPEX-like syndrome with normal frequency and function of regulatory T cells.

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

“…[57][58][59] In addition to the mutations in FOXP3 that cause IPEX, 60,61 other components of the Treg activation pathway may be defective and may thus reduce the function and/or number of Tregs and lead to an IPEX-like syndrome (eg, deficiency of CD25 or STAT5b and gain-of-function mutations in STAT1). [62][63][64][65] Interestingly, the classical central T-cell tolerance defect, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome ([APECED] due to a defect of the autoimmune regulator transcription factor) is not typically associated with cytopenias. 66 Furthermore, immune dysregulatory processes such as hemophagocytosis or lymphoproliferation (and subsequent splenic sequestration of blood cells) may cause secondary cytopenia in critically ill patients.…”

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…Notably, gain-of-function STAT1 mutations in the DNA-binding and coiled-coil domains also predispose to severe disseminated infections by dimorphic fungi, such as coccidioidomycosis and histoplasmosis, with or without CMC Uzel et al 2013). In these patients, enhanced STAT1 phosphorylation, DNA binding, and transactivation results in initial increased IFN-g-induced gene expression but subsequent impaired responses to IFN-g re-stimulation, implicating IFN-g tachyphylaxis, but not impaired IL-17 immunity, as the underlying mechanism accounting for susceptibility to systemic fungal disease in STAT1 gain-of-function mutations.…”

Cardiovascular abnormalities in primary immunodeficiency diseases

“…Typically, Candida infections are limited to the mucocutaneous membranes and are not invasive, although patients may display T-cell deficiency, manifesting with increased susceptibility to cytomegalovirus and other viruses as well as disseminated coccidioidomycosis and histoplasmosis (Sampaio et al 2013). Some patients do not produce appropriate antibodies, resulting in increased frequency of sinopulmonary infections.…”