Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome

• Type of Material: Article
• Authors: Katherine A Waugh, University of Colorado; Paula Araya, University of Colorado; Ahwan Pandey, University of Colorado; Kimberly R Jordan, University of Colorado; Keith P Smith, University of Colorado; Ross E Granrath, University of Colorado; Santosh Khanal, University of Colorado; Eric T Butcher, University of Colorado; Belinda E Estrada, University of Colorado; Christopher Porter, Emory University
• Language: English
• Date: 2019-11-12
• Publisher: Cell Press
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2019.10.038
• Title of Journal or Parent Work: Cell Reports
• Volume: 29
• Issue: 7
• Start Page: 1893
• End Page: +
• Grant/Funding Information: This work was supported by NIH grants R01AI150305, R01AI145988, R01AI141662, T32CA190216, UL1TR002535, and P30CA046934.; Additional funding was provided by NSF grant MCB1817582, the Linda Crnic Institute for Down Syndrome, the Global Down Syndrome Foundation, the Anna and John J. Sie Foundation, the Human Immunology and Immunotherapy Initiative, the GI & Liver Innate Immune Program, and a Blumenthal Fellowship to K.A.W.
• Keywords: PLASMA-CELLS; Life Sciences & Biomedicine; T-CELLS; RISK; Science & Technology; CIRCULATING FIBROCYTES; MEMORY B-CELLS; AGE; ACCUMULATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DISEASE; Cell Biology; CHILDREN
• Research Categories: Health Sciences, Immunology; Biology, Molecular; Health Sciences, Pharmacology

Abstract

People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS.