Authors
Cecilia Iglesias-Herrero, Willem Roosens, Georgina Galicia, Jonathan Cremer, Pedro Elias Marques, Timothy Devos, Leen Moens, Isabelle Meyts, Rik Gijsbers, Rik Schrijvers
Published in
Journal of human immunity. Volume 2. Issue 6. Nov 02, 2026. Epub Oct 09, 2026.
Abstract
Autosomal dominant STAT1 gain-of-function (GOF) is an inborn error of immunity characterized by chronic mucocutaneous candidiasis and variable immune dysregulation. JAK inhibitors are a promising therapy, but their efficacy in STAT1 GOF remains variable. We longitudinally evaluated the clinical and molecular impact of JAK inhibitors in two STAT1 GOF patients, harboring p.R321S and p.T385M mutations, using Cellular Indexing of Transcriptomes and Epitopes by sequencing, flow cytometry, cytokine measurement, and allele-specific expression analysis in peripheral blood mononuclear cells and serum. Rapid yet incomplete immune reconstitution was observed as early as 1 week after treatment initiation. T cells rebalanced to a more homeostatic status and TCR repertoire diversity increased rapidly. However, some immune defects remained, including natural killer deficiency in one patient. The pronounced transcriptional dysregulation in monocytes was not explained by an unbalanced mutant STAT1 expression but improved with JAK-inhibitor treatment. JAK inhibitors provided significant clinical and immunological benefits to STAT1 GOF patients but did not fully restore immune homeostasis. These findings highlight the therapeutic potential and limitations of JAK inhibitors in STAT1 GOF.
PMID:
42853149
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.
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