Lobo Pilar Blanco, Guisado-Hernández Paloma, Villaoslada Isabel, de Felipe Beatriz, Carreras Carmen, Rodriguez Hector, Carazo-Gallego Begoña, Méndez-Echevarria Ana, Lucena José Manuel, Aljaro Pilar Ortiz, Castro María José, Noguera-Uclés José Francisco, Milner Joshua D, McCann Katelyn, Zimmerman Ofer, Freeman Alexandra F, Lionakis Michail S, Holland Steven M, Neth Olaf, Olbrich Peter
Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Institute of Biomedicine of Seville (IBIS)/Universidad de Sevilla/CSIC, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Av Manuel Siurot s/n, 41013, Seville, Spain.
Pediatric Infectious Diseases and Immunodeficiency Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
J Clin Immunol. 2022 Aug;42(6):1193-1204. doi: 10.1007/s10875-022-01273-x. Epub 2022 May 4.
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.
信号转导和转录激活因子1（STAT1）功能获得性（GOF）综合征和显性负性（DN）STAT3综合征具有包括感染性和炎症性表现在内的共同临床表现。使用Janus激酶（JAK）抑制剂进行靶向治疗在治疗STAT1 GOF相关症状方面显示出有前景的结果，而DN STAT3患者的治疗主要是支持性的。我们在此评估了鲁索替尼对DN STAT3患者细胞中JAK-STAT1/3信号通路的影响。
我们使用流式细胞术、免疫印迹、定量聚合酶链反应（qPCR）和酶联免疫吸附测定（ELISA）技术，检测了在受到I/II型干扰素（IFN）或白细胞介素（IL）-6刺激后，从DN STAT3患者、STAT1 GOF患者和健康供体获得的细胞中基础STAT1和磷酸化STAT1（pSTAT1）的水平。我们还描述了鲁索替尼对这些患者细胞中细胞因子诱导的STAT1信号传导的影响。
DN STAT3和STAT1 GOF导致了相似的表型，其特征是在受到干扰素α（IFNα，CD3细胞）和干扰素γ（IFNγ，CD14单核细胞）刺激时，STAT1和pSTAT1水平升高。与健康对照相比，大多数DN STAT3患者在受到刺激后，STAT1下游基因表达和C-X-C基序趋化因子10分泌更高。使用JAK1/2抑制剂鲁索替尼进行体外治疗降低了细胞因子反应性，并使DN STAT3和STAT1 GOF患者细胞中的STAT1磷酸化恢复正常。此外，体外治疗在调节DN STAT3患者的STAT1下游信号传导方面是有效的。
鉴于目前针对自身免疫性高IgE综合征（AD-HIES）缺乏有效的靶向治疗选择，使用JAK抑制剂调节JAK/STAT1信号通路可能值得进一步探索，特别是在那些具有自身免疫和/或自身炎症表现的AD-HIES患者中。
