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

Katherine A Waugh; Paula Araya; Ahwan Pandey; Kimberly R Jordan; Keith P Smith; Ross E Granrath; Santosh Khanal; Eric T Butcher; Belinda Enriquez Estrada; Angela L Rachubinski; Jennifer A McWilliams; Ross Minter; Tiana Dimasi; Kelley L Colvin; Dmitry Baturin; Andrew T Pham; Matthew D Galbraith; Kyle W Bartsch; Michael E Yeager; Christopher C Porter; Kelly D Sullivan; Elena W Hsieh; Joaquin M Espinosa

doi:10.1016/j.celrep.2019.10.038

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

Cell Rep. 2019 Nov 12;29(7):1893-1908.e4. doi: 10.1016/j.celrep.2019.10.038.

Authors

Katherine A Waugh¹, Paula Araya¹, Ahwan Pandey², Kimberly R Jordan³, Keith P Smith¹, Ross E Granrath¹, Santosh Khanal⁴, Eric T Butcher¹, Belinda Enriquez Estrada¹, Angela L Rachubinski⁵, Jennifer A McWilliams³, Ross Minter¹, Tiana Dimasi¹, Kelley L Colvin⁶, Dmitry Baturin⁷, Andrew T Pham¹, Matthew D Galbraith⁴, Kyle W Bartsch¹, Michael E Yeager⁶, Christopher C Porter⁸, Kelly D Sullivan⁹, Elena W Hsieh¹⁰, Joaquin M Espinosa¹¹

Affiliations

¹ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80302, USA.
³ Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁴ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁵ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁸ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁹ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
¹⁰ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
¹¹ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80302, USA. Electronic address: joaquin.espinosa@cuanschutz.edu.

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.

Trial registration: ClinicalTrials.gov NCT02864108.

Keywords: CyTOF; Down syndrome; JAK/STAT; autoimmunity; immune dysregulation; inflammation; interferon; mass cytometry; single cell; trisomy 21.

Publication types

Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Down Syndrome / immunology*
Down Syndrome / pathology
Female
Flow Cytometry
Humans
Interferon-alpha / immunology*
Male
Middle Aged

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

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