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 STAT1-dependent 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.

2011 年在慢性粘膜皮肤念珠菌病 (CMC) 和甲状腺功能减退症患者中发现了STAT1杂合子功能获得 (GOF) 突变。 CMC 是念珠菌真菌引起的复发性或持续性皮肤粘膜感染，甲状腺功能减退症由自身免疫性甲状腺炎引起。患有这些疾病的患者会发展其他传染病，包括病毒、细菌和真菌疾病，以及其他自身免疫表现，包括小肠结肠炎、免疫性血细胞减少症、内分泌疾病和系统性红斑狼疮。状态1-GOF 突变具有高度外显性，发病时的中位年龄为 1 岁，并且通常是常染色体显性特征的基础。全世界 400 多名患者中已经报道了多达 72 个残基的 105 个突变，包括 65 个复发突变。GOF 机制涉及细胞核中 STAT1 的去磷酸化受损。患者细胞对 I 型和 II 型干扰素 (IFN) 和 IL-27 的 STAT1 依赖性反应增强。这会损害导致 CMC 的 Th17 细胞发育。与其他 I 型干扰素病一样，自身免疫的发病机制可能涉及增强的 I 型干扰素反应。其他感染的发病机制，尤其是由巨噬细胞内细菌和真菌引起的感染，在 II 型 IFN 免疫力减弱的患者中可见，仍然是个谜。患有和不患有严重疾病（侵袭性感染、癌症和/或有症状的动脉瘤）的患者在 60 岁时的累积生存率分别为 31% 和 87%。严重的自身免疫性也会使预后恶化。患者的治疗患有严重感染性和自身免疫性表现的STAT1 -GOF 突变依赖于造血干细胞移植和/或口服 JAK 抑制剂。