Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

Abstract

Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.

Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease

“…In line with the experimental data observed in the M. canis mouse model, patients with mutations that lead to the gain of function in the transcription factor STAT1 (STAT1 GOF), that promote type I and type II IFN genes transcription, have reduced type 17 immunity and are susceptible to chronic mucocutaneous candidiasis (CMC) and dermatophytosis (96,97,(114)(115)(116)(117). Consistent with this, increased STAT1 responses to Th1 cytokines (IFN-g and IL-27) were shown to repress the differentiation of IL-17-producing T cells through mechanisms that are not yet completely understood (114,118).…”

“…However, much less is known about the skin T cell response during dermatophytosis. Deficiencies in type 17 immunity associated with susceptibility to widespread chronic dermatophytosis have been reported in patients with ATLL ( 67 ), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) ( 72 ), Dectin-1 mutations ( 39 ), loss-of-function mutations in STAT3 ( 62 ), autosomal gain-of-function mutations in STAT1 ( 96 , 97 ), and anti-IL-17 antibody treatment (secukinumab) ( 73 , 98 ). Furthermore, IL-17 impairment was also associated with inherited CARD9 deficiency and deep dermatophytosis ( 40 , 99 ).…”

An N-of-1 Trial of Itacitinib for a Patient with Aplastic Anemia Associated with a Gain-of-Function Variant in STAT1

“…4,6,8,9 GOF variants lead to hyper-phosphorylation of STAT1 in response to stimulation, increasing STAT1-dependent transcription. 7,10,11 The p.Ala267Val variant identified in our patient is absent from large population databases, but has been identified in more than 10 individuals in multiple families with chronic mucocutaneous candidiasis, and shown to have a GOF effect. 6,12 We thus considered the p.Ala267Val variant as causal for our patient's recurrent aphthous ulcers, thrush, and aplastic anemia.…”

“…4,5 More than 400 patients with more than 100 different STAT1 GOF variants have been reported. 4,6,7 Aplastic anemia has been described, as have numerous other autoimmune cytopenias, and severe aphthous stomatitis is frequent. 4,6,8,9 GOF variants lead to hyper-phosphorylation of STAT1 in response to stimulation, increasing STAT1-dependent transcription.…”

Successful Hematopoietic Stem Cell Transplantation for Autosomal Recessive STAT1 Complete Deficiency

“…Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates signal transduction via several factors, including interferon (IFN)-α/β and IFN-γ. Germline mutations in STAT1 cause the following four types of primary immunodeficiency disorders (PIDs): (1) autosomal recessive (AR) STAT1 complete deficiency, (2) AR STAT1 partial deficiency, (3) autosomal dominant (AD) STAT1 partial deficiency, and (4) STAT1 gain of function [1]. AR STAT1 complete deficiency is a rare form of PID, with only nine cases in seven families reported to date [2][3][4][5][6].…”