Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome
Open accessAbstract
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.
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Both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation, which could exacerbate the neuroinflammatory response.
“Notably, both individuals with DS and mouse models of DS experience constitutive hyperactivation of interferon (IFN) signaling with signs of chronic inflammation and immune dysregulation,30,31,32,33,34,35,36,37,38,39,40 that could exacerbate the neuroinflammatory response.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [35]
The Introduction reports global immune dysregulation and heightened IFN responsiveness in adults with Down syndrome; the Results report elevated baseline signaling and point to chronic IFN hyperactivity. The paper does not establish the same findings in mouse models of Down syndrome. The proposed exacerbation of neuroinflammation follows the citation and is not treated here as attributed to this source. Page numbers were unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPeople with DS present increased IFN signaling likely driven by triplication of four of the six IFN receptors encoded on HSA21, rather than by massive elevation of IFN ligands, and this has been associated with chronic immune dysregulation.
“people with DS present an increased IFN signaling likely driven by triplication of four of the six IFN receptors encoded on HSA21,36 rather than by massive elevation of the IFN ligands themselves as seen in interferonopathies,80 and this has been associated with chronic immune dysregulation.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [35]
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Self-citationDeep immune phenotyping reveals similarities between aging, Down syndrome, and autoimmunity
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Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype
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“75,79 35, Substantial evidence supports a pivotal role for neuroinflammation and neuronal cell loss in cognitive dysfunction in DS (E) Heatmap displaying NES from GSEA with Hallmark gene sets of transcriptome fold-changes for the indicated comparisons in the hippocampus, clustered hierarchically; *…”
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“They also serve as critical models for evaluating immunotherapies, vaccine responses, and disease-associated immune dysregulation (Sen et al. 2018; Waugh et al. 2019; David et al. 2020; Chew et al. 2022; Roser et al. 2023).”
- Authors
- Waugh, K. A., Araya, P., Pandey, A., Jordan, K. R., Smith, K. P., Granrath, R. E., Khanal, S., Butcher, E. T., Estrada, B. E., Rachubinski, A. L., McWilliams, J. A., Minter, R., Dimasi, T., Colvin, K. L., Baturin, D., Pham, A. T., Galbraith, M. D., Bartsch, K. W., Yeager, M. E., Porter, C. C., Sullivan, K. D., Hsieh, E. W., & Espinosa, J. M.
- Affiliations
- University of Colorado Anschutz (US)
- University of Colorado Boulder (US)
- Emory University (US)
- Corresponding author
- Espinosa, Joaquin M.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 29
- Issue
- 7
- Pages
- 1893-1908.e4
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6871766
- OpenAlex
- W2984925361
- Cited by
- 150
- References
- 81
- Citations by year
- 2026: 21 · 2025: 18 · 2024: 34 · 2023: 18 · 2022: 23 · 2021: 23 · 2020: 12 · 2018: 1
- FWCI
- 13.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation
- National Institutes of Health
- Global Down Syndrome Foundation
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- Down syndrome, immune dysregulation, type I interferon, IFNAR1, interferon receptor, chronic inflammation, myeloid cells, lymphoid cells, immune cell types, autoimmune disease susceptibility
- MeSH terms
- Adult, Down Syndrome, Female, Flow Cytometry, Humans, Male, Middle Aged, Interferon-alpha
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