Waugh, Katherine AAraya, PaulaPandey, AhwanJordan, Kimberly RSmith, Keith PGranrath, Ross EKhanal, SantoshButcher, Eric TEstrada, Belinda EnriquezRachubinski, Angela LMcWilliams, Jennifer AMinter, RossDimasi, TianaColvin, Kelley LBaturin, DmitryPham, Andrew TGalbraith, Matthew DBartsch, Kyle WYeager, Michael EPorter, Christopher CSullivan, Kelly DHsieh, Elena WEspinosa, Joaquin M
Summary
The spectrum of diseases that people with Down syndrome tend to face are different from the general population. These differences include fewer solid masses and tumors and a higher incidence of both neurological and autoimmune conditions. The researchers on this project used a method called deep mapping to study the immune system in adults with DS. They observed immune dysregulation consistent with chronic inflammation, and changes to myeloid and lymphoid cell compartments. The results point to interferon receptors, encoded on chromosome 21 and responsible for initiating the inflammatory response, as the mechanism behind these disparities. Researchers report interferon-driven immune dysregulation as a likely contributor to the hallmarks of DS.
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.
Conditions
Cancer, Hypersensitivity, Inflammation