RT Journal Article
T1 Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations.
A1 Blanco-Lobo, Pilar
A1 Guisado-Hernandez, Paloma
A1 Villaoslada, Isabel
A1 de-Felipe, Beatriz
A1 Carreras, Carmen
A1 Rodriguez, Hector
A1 Carazo-Gallego, Begoña
A1 Mendez-Echevarria, Ana
A1 Lucena, Jose Manuel
A1 Ortiz-Aljaro, Pilar
A1 Castro, Maria Jose
A1 Noguera-Ucles, Jose Francisco
A1 Milner, Joshua D
A1 McCann, Katelyn
A1 Zimmerman, Ofer
A1 Freeman, Alexandra F
A1 Lionakis, Michail S
A1 Holland, Steven M
A1 Neth, Olaf
A1 Olbrich, Peter
K1 DN STAT3
K1 JAK-STAT pathway
K1 STAT1 GOF
K1 Ruxolitinib
AB 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. 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. 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. 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.
PB Springer
YR 2022
FD 2022-05-04
LK http://hdl.handle.net/10668/20631
UL http://hdl.handle.net/10668/20631
LA en
NO Lobo PB, Guisado-Hernández P, Villaoslada I, de Felipe B, Carreras C, Rodriguez H, et al. Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations. J Clin Immunol. 2022 Aug;42(6):1193-1204
DS RISalud
RD Apr 8, 2025