ABSTRACT Type I interferonopathies represent a heterogeneous group of inborn errors of immunity (IEI), characterized by dysregulated and persistent activation of the Type I interferon pathway. These patients present a broad spectrum of clinical phenotypes involving the nervous system, skin, lungs, and haematopoietic system. Diagnosis is often challenging owing to overlap with other autoinflammatory and autoimmune conditions. In parallel with the expanding molecular spectrum of these disorders, their classification within IEI has continued to evolve. This review provides an updated synthesis of Type I interferonopathies in the context of the 2024 International Union of Immunological Societies (IUIS) classification, linking the underlying genetic defects and dysregulated interferon pathways to their characteristic and overlapping clinical phenotypes. Particular emphasis is placed on a practical diagnostic framework integrating clinical recognition, interferon‐based biomarkers, and molecular testing, as well as on the transition from conventional immunomodulation toward pathway‐directed therapies, including the growing clinical experience with Janus kinase inhibitors. This review integrates current knowledge on the pathogenesis, clinical features, diagnostic approaches, and treatment strategies in patients with Type I interferonopathies, providing an updated clinically oriented framework for their recognition, diagnosis, and management within the expanding spectrum of IEIs.
Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis, infections, autoimmunity, and immune dysregulation; however, mutation-level determinants of phenotypic variability remain incompletely defined. We aimed to describe the clinical, immunologic, and functional features of four patients with STAT1-GOF disease, including three related patients carrying a novel DNA-binding domain (DBD) variant associated with a mild phenotype. Clinical manifestations, immunologic findings, and immune deficiency and dysregulation activity scores were analysed. Whole-exome sequencing (WES) with Sanger confirmation was performed, and the functional activity of the novel p.Leu400Pro variant was assessed using a gamma-activated sequence luciferase reporter assay after interferon-gamma stimulation. All patients presented with early-onset chronic mucocutaneous candidiasis. Three related patients carrying p.Leu400Pro showed a mild, stable clinical course without severe infections or multisystem autoimmunity during a median follow-up of 8 years and had low disease activity scores. Functional analysis demonstrated increased IFN-gamma-induced transcriptional activity compared with wild-type STAT1, reaching levels comparable to the established R274Q GOF control under the experimental conditions used and supporting a GOF effect. In contrast, an unrelated patient with p.Glu353Lys developed severe multisystem autoimmunity, lymphoproliferation, and bronchiectasis with high disease activity scores. Ruxolitinib led to clinical improvement and was used as bridging therapy before haematopoietic stem cell transplantation (HSCT). These findings identify a novel, functionally validated DNA-binding domain STAT1-GOF variant associated with a mild phenotype, supporting mutation-level risk stratification and individualized management. Targeted Janus kinase inhibition may help stabilize severe disease before transplantation.
ABSTRACT Progesterone is an effective tool for the secondary prevention of spontaneous preterm birth. The aim of this prospective exploratory pilot study was to evaluate the effect of progesterone administration on the number of regulatory T cell (Treg) populations and on the concentrations of the immunoregulatory cytokines IL‐10 and TGF‐β1 during in vivo progesterone treatment in women at risk of preterm delivery. Pregnant women with a singleton pregnancy (22–30 weeks of gestation) who were at risk of spontaneous preterm delivery and required progesterone therapy were included ( n = 21). Peripheral blood was sampled before progesterone administration and twice thereafter during treatment. Seventeen women attended the second visit, while only seven attended the third visit. The control group consisted of prospectively recruited low‐risk women ( n = 8). Treg numbers were determined by flow cytometry, and plasma concentrations of TGF‐β1 and IL‐10 were measured by ELISA. In women at risk, plasma TGF‐β1 concentrations increased significantly between the first and second sampling ( p ≤ 0.01) and remained at a similar level at the third sampling. In contrast, TGF‐β1 levels in the control group remained low without statistically significant change. IL‐10 concentrations were generally low in both groups. This pilot study was associated with an increase in the immunoregulatory cytokine TGF‐β1 following progesterone administration. Although TGF‐β1 is produced by several cell types in addition to Tregs, our findings raise the possibility that progesterone reinforces an immunoregulatory pathway relevant to the maintenance of pregnancy in women at risk of preterm birth; however, the present study does not establish this mechanism.
