Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition.
Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition.
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DOI：
10.1126/sciadv.adg6218
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发表时间：
2023-06-28
期刊：
影响因子：
13.6
通讯作者：
Espinosa, Joaquin M.
中科院分区：
文献类型：
--
作者：
Galbraith, Matthew D.;Rachubinski, Angela L.;Smith, Keith P.;Araya, Paula;Waugh, Katherine A.;Enriquez-Estrada, Belinda;Worek, Kayleigh;Granrath, Ross E.;Kinning, Kohl T.;Eduthan, Neetha Paul;Ludwig, Michael P.;Hsieh, Elena W. Y.;Sullivan, Kelly D.;Espinosa, Joaquin M.
唐氏综合征（DS）患者表现出干扰素信号的慢性过度激活。然而，干扰素活性过高对退行性椎体滑移的临床影响尚不明确。在这里，我们描述了一个多组学研究干扰素信号在数百个人与退行性痴呆。利用来自全血转录组的干扰素评分，我们定义了与DS患者干扰素过度活跃相关的蛋白质组学、免疫、代谢和临床特征。干扰素过度活跃与明显的促炎表型和主要生长信号和形态发生途径的失调有关。干扰素活性最高的个体表现出最强的外周免疫系统重构，包括细胞毒性T细胞增加、B细胞耗竭和单核细胞活化。干扰素过度活跃伴随着关键的代谢变化，最突出的是色氨酸分解代谢失调。高干扰素信号使先天性心脏病和自身免疫发生率升高的亚群分层。最后，一项纵向病例研究表明，JAK抑制使干扰素信号正常化，对退行性痴呆有治疗益处。总之，这些结果证明了在退行性椎体滑移中测试免疫调节疗法是正确的。干扰素过度活跃形成唐氏综合征的病理生理，并通过JAK抑制而减弱。
Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS. Interferon hyperactivity shapes the pathophysiology of Down syndrome and is attenuated by JAK inhibition.
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影响因子：
3.7
作者：
Finck, Rachel;Simonds, Erin F.;Jager, Astraea;Krishnaswamy, Smita;Sachs, Karen;Fantl, Wendy;Pe'er, Dana;Nolan, Garry P.;Bendall, Sean C.
通讯作者：
Bendall, Sean C.
影响因子：
3.5
作者：
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通讯作者：
Piccione M
影响因子：
6.4
作者：
EPSTEIN, LB;EPSTEIN, CJ
通讯作者：
EPSTEIN, CJ
影响因子：
5.4
作者：
Gold, Larry;Walker, Jeffrey J.;Williams, Stephen
通讯作者：
Williams, Stephen
影响因子：
14.3
作者：
Espinosa, Joaquin M.
通讯作者：
Espinosa, Joaquin M.