Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition

被引:16
作者
Galbraith, Matthew D. [1 ,2 ]
Rachubinski, Angela L. [1 ,3 ]
Smith, Keith P. [1 ]
Araya, Paula [1 ]
Waugh, Katherine A. [1 ,2 ]
Enriquez-Estrada, Belinda [1 ]
Worek, Kayleigh [1 ]
Granrath, Ross E. [1 ]
Kinning, Kohl T. [1 ]
Eduthan, Neetha Paul [1 ]
Ludwig, Michael P. [1 ]
Hsieh, Elena W. Y. [4 ,5 ]
Sullivan, Kelly D. [1 ,6 ]
Espinosa, Joaquin M. [1 ,2 ]
机构
[1] Univ Colorado, Linda Crn Inst Syndrome, Anschutz Med Campus, Aurora, CO 80309 USA
[2] Univ Colorado, Dept Pharmacol, Anschutz Med Campus, Aurora, CO 80309 USA
[3] Univ Colorado, Dept Pediat, Sect Dev Pediat, Anschutz Med Campus, Aurora, CO USA
[4] Univ Colorado, Dept Immunol & Microbiol, Anschutz Med Campus, Aurora, CO USA
[5] Univ Colorado, Dept Pediat, Div Allergy Immunol, Anschutz Med Campus, Aurora, CO USA
[6] Univ Colorado, Dept Pediat, Sect Dev Biol, Anschutz Med Campus, Aurora, CO USA
关键词
I-INTERFERON; IMMUNE; EXPRESSION; METABOLISM; PREGNANCY; MODELS; GROWTH;
D O I
10.1126/sciadv.adg6218
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:22
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