Pilar Blanco-Lobo, Paula Gilabert-Prieto, Beatriz de Felipe, David Moreno-Fuentes, Paloma Guisado Hernández, Ana Ortiz-Ramírez, Anna Mensa-Vilaró, Juan I. Aróstegui, Natalia Palmou, Valle Velasco Gonzalez, Ángela Deyà Martinez, Jan Ramakers, José Ivorra-Cortés, Cristina Roca, Elisa Cordero, Inmaculada Guillen, Nicolás Valerdiz Menéndez, José Manuel Lucena, Mirella Gaboli, Peter Olbrich, Olaf Neth
IBiS/Hospital Universitario Virgen del Rocío and CSIC/Universidad de Sevilla. Instituto de Salud Carlos III. Universitat de Barcelona and Hospital Clínic Barcelona. Institut d’Investigacions Biomèdiques August Pi i Sunyer. Hospital Universitario Marqués de Valdecilla. Canary Islands University Teaching Hospital. Sant Joan de Déu-Hospital Clínic de Barcelona. Hospital Universitari Son Espases. Balearic Island Health Research Institute. Hospital Universitari I Politècnic La Fe.
Spain
Journal of Clinical Immunology
J Clin Immunol 2025; 45:
DOI: 10.1007/s10875-025-01957-0
Abstract
Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates inflammatory responses, posing additional management challenges. Two patients (P1 and P2) were studied: P1, with DS and a heterozygous p.P326S STAT1 variant, and P2, with the STAT1 p.P326S variant only. Individuals with isolated DS or STAT1 GOF served as controls. IFN receptor subunits (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ stimulation were analyzed using flow cytometry and RT-PCR. Whole blood type I IFN signature and serum cytokines were evaluated using NanoString and Luminex assays. P1 experienced recurrent infections, chronic mucocutaneous candidiasis, interstitial pneumonitis, and pulmonary hypertension. P2 presented with esophageal candidiasis, dysphagia, and stenosis. The p.P326S variant led to increased STAT1/pSTAT1 levels in response to IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1’s key biomarkers (STAT1 levels, IFN signature, TNFα, IL-6) remained altered, indicating persistent inflammation despite clinical improvement. This first report of a STAT1 GOF variant in DS provides a unique “experiment of nature”, offering insights into the interplay between trisomy 21 and STAT1-mediated immune dysregulation. Although ruxolitinib demonstrated clinical benefits, the persistent inflammation observed in P1 highlights the need for further strategies to achieve complete immune resolution. These findings emphasize the importance of comprehensive genetic and immunological assessments in individuals with DS, particularly when immune dysfunction is suspected.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes