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.
Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes.Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes.Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of “Primary Immune Deficiency (PID—related) genes.”Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified.Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.
Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8+ T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8+STAT5+ T cells with lytic potential infiltrated the skin, even though FOXP3+ Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.
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