METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation.
RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment.
CONCLUSIONS: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.
方法:在我们7名STAT1-GOF患者的队列中,我们调查了可能决定T淋巴细胞减少的机制,我们表征了干扰素基因标签(IGS),并分析了鲁索替尼在逆转免疫失调方面的作用.
结果:STAT1-GOF患者的T淋巴细胞凋亡增加,在静息状态下以及有丝分裂原和IFNα刺激下,通过膜联蛋白V/碘化丙啶测定通过流式细胞术评估。JAK抑制剂ruxolitinib显著降低IFNα诱导的STAT1过度磷酸化,并逆转刺激诱导的T细胞凋亡,在体外。在两名成人STAT1-GOF患者中,JAKinib治疗改善了慢性粘膜皮肤念珠菌病和淋巴细胞减少.大多数STAT1-GOF患者,特别是那些有自身免疫的人,在ruxolitinib治疗期间,2例患者的IGS增加,显著减少。
结论:在STAT1-GOF患者中,T淋巴细胞凋亡增加,和T淋巴细胞减少可能决定严重感染的高风险。应评估JAKinib靶向治疗以治疗严重的慢性念珠菌病和淋巴细胞减少症。并下调自身炎症或自身免疫表现患者的IFN。