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
Affiliations
Katherine A. Waugh
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Paula Araya
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ahwan Pandey
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
Kimberly R. Jordan
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Keith P. Smith
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ross E. Granrath
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Santosh Khanal
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Eric T. Butcher
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Belinda Enriquez Estrada
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Angela L. Rachubinski
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
Jennifer A. McWilliams
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Ross Minter
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Tiana Dimasi
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kelley L. Colvin
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
Dmitry Baturin
Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Andrew T. Pham
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Matthew D. Galbraith
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Kyle W. Bartsch
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Michael E. Yeager
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
Christopher C. Porter
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
Kelly D. Sullivan
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
Elena W. Hsieh
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
Joaquin M. Espinosa
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; Corresponding author
Summary: 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. : Waugh et al. undertook deep mapping of the immune system in adults with trisomy 21, revealing global immune dysregulation reminiscent of inflammatory states, concurrent with widespread hypersensitivity to IFN-α. These data highlight immune dysregulation and IFN hyperactivity as contributors to the comorbidities more common in people with Down syndrome. Keywords: Down syndrome, trisomy 21, mass cytometry, CyTOF, immune dysregulation, single cell, interferon, JAK/STAT, autoimmunity, inflammation
