Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations

Pilar Blanco Lobo, Paloma Guisado-Hernández, Isabel Villaoslada, Beatriz de Felipe, Carmen Carreras, Hector Rodriguez, Begoña Carazo-Gallego, Ana Méndez-Echevarria, José Manuel Lucena, Pilar Ortiz Aljaro, María José Castro, José Francisco Noguera-Uclés, Joshua D. Milner, Katelyn McCann, Ofer Zimmerman, Alexandra F. Freeman, Michail S. Lionakis, Steven M. Holland, Olaf Neth, Peter Olbrich

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Purpose: STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients’ cells. Methods: Using flow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine-induced STAT1 signaling in these patients. Results: DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNγ (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient’ cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients. Conclusion: In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations.

Original languageEnglish
Pages (from-to)1193-1204
Number of pages12
JournalJournal of Clinical Immunology
Issue number6
StatePublished - Aug 2022


  • DN STAT3
  • JAK-STAT pathway
  • ruxolitinib


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