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Author Notes:

See publication for full list of authors.

Correspondence to joaquin.espinosa@cuanschutz.edu

Author contributions: J.M.E. conceived the study

J.M.E., K.A.W., E.W.H., and C.C.P. were in charge of overall direction and planning

K.A.W., K.R.J., K.P.S., R.E.G., J.A.M., P.A., R.M., T.D., K.L.C., M.E.Y., and D.B. designed and executed experiments

K.A.W., A.P., K.R.J., S.K., E.T.B., K.L.C., A.T.P., M.D.G., K.D.S., E.W.H., K.W.B., and J.M.E. contributed to the data analysis and interpretation

A.L.R., B.E.E., and E.T.B. recruited participants and collected clinical and demographics data

K.A.W. and J.M.E. wrote the manuscript

We thank members of the Sie Center for Down Syndrome, the Global Down Syndrome Foundation, the Clinical and Translational Research Center, the University of Colorado Cancer Center Flow Cytometry Shared Resource, and the Human Immune Monitoring Shared Resource for their assistance in various aspects of the project.

The authors declare no competing interests.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • SYSTEMIC-LUPUS-ERYTHEMATOSUS
  • MEMORY B-CELLS
  • T-CELLS
  • CIRCULATING FIBROCYTES
  • PLASMA-CELLS
  • DISEASE
  • CHILDREN
  • AGE
  • RISK
  • ACCUMULATION

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

Journal Title:

Cell Reports

Volume:

Volume 29, Number 7

Publisher:

, Pages 1893-+

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2019 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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