JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function.
8 affiliations
- 1Advanced Disease Modelling, Targeted Drug Discovery and Gene Therapy (ADVANTAGE), Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine, KU Leuven, Leuven, Belgium.
- 2Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.
- 3Department of General Internal Medicine, Division of Allergy and Clinical Immunology, University Hospitals Leuven, Leuven, Belgium.
- 4Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
- 5Department of Hematology, University Hospitals Leuven and Laboratory of Experimental Transplantation, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
- 6Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
- 7Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium.
- 8Leuven Viral Vector Core, Group Biomedical Sciences, Faculty of Medicine, KU Leuven , Leuven, Belgium.
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.
Related
- Vaccination targeting the novel endogenous tumor-associated antigen Gpr149 induces protective immunity against checkpoint inhibitor-refractory SB28 glioblastoma
- Loss of ALN Function in Arabidopsis thaliana Induces Allantoin Accumulation and Enhances Antioxidant Enzyme Responses to Copper Toxicity
- Slc16a5 (MCT6) Knockout Induces Sex-Dependent Changes in Auditory Function, Hair Cell Viability and Cochlear Transcriptomic Programs in the Mouse
- Super-long-day treatment bypasses vernalization and induces flowering directly in Brassica rapaand Raphanus sativus
- Nitroxoline treatment of Balamuthia mandrillaris triggers genomic crisis, transcriptional collapse, and incomplete encystment via copper and iron chelation
BibTeX
@article{iglesiasherrero2026jakinhibitor,
title = {{JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function.}},
author = {Cecilia Iglesias-Herrero and Willem Roosens and Georgina Galicia and Jonathan Cremer and Pedro Elias Marques and Timothy Devos and Leen Moens and Isabelle Meyts and Rik Gijsbers and Rik Schrijvers},
journal = {Journal of human immunity},
year = {2026},
month = oct,
doi = {10.70962/jhi.20260009},
url = {https://europepmc.org/article/MED/42853149},
note = {CC BY},
}
RIS
TY - JOUR
TI - JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function.
AU - Cecilia Iglesias-Herrero
AU - Willem Roosens
AU - Georgina Galicia
AU - Jonathan Cremer
AU - Pedro Elias Marques
AU - Timothy Devos
AU - Leen Moens
AU - Isabelle Meyts
AU - Rik Gijsbers
AU - Rik Schrijvers
PY - 2026
DA - 2026/10/09
JO - Journal of human immunity
DO - 10.70962/jhi.20260009
UR - https://europepmc.org/article/MED/42853149
AB - 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.
SN - 3065-8993
ER -