Mass-cytometry reveals global immune remodeling with multi-lineage hypersensitivity to Type I Interferon in Down syndrome

• DOI: 10.4049/jimmunol.202.supp.52.1
• Publication Date: 2023-01-01T11:44:13Z
• Authors: Katherine A Waugh; Ahwan Pandey; Kimberly R Jordan; Keith P Smith; Ross E Granrath; Santosh Khanal; Eric T Butcher; Angela L Rachubinski; Jennifer A McWill...; Paula Araya; Ross Minter; Tiana Dimasi; Kelley L Colvin; Dmitry Baturin; Andrew T Pham; Matthew D Galbraith; Michael E Yeager; Kelly D Sullivan; Christopher C Porter; Elena W Hsieh; Joaquin M Espinosa
• Keywords: Mass cytometry; Immune Dysregulation

Abstract People with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (chr21), have an altered disease spectrum. For example, adults DS are largely protected from solid tumors while predisposed to various autoimmune disorders, early-onset Alzheimer’s disease, and severe respiratory infection. While immune system is known play a key role in these comorbidities among disomic population, there dearth studies DS. Here, we applied single-cell, systems-level approach mass-cytometry, or Cytometry Time-Of-Flight (CyTOF), broadly define phenotypic functional alterations homeostasis that relevant potentiation associated T21. We developed innovative strategy analyze CyTOF data, incorporating techniques commonly used genomics even topography eliminate batch bias efficiently resolve ~100 cell types. This revealed global dysregulation reminiscent inflammatory states enriched older individuals population. Upon stimulation directly ex vivo Type I Interferon (IFN) simultaneous detection diverse phosphorylation events across lymphoid myeloid lineages, all subsets T21 were hyper-responsive, but degree response signaling pathways varied specific Notably, 4 6 IFN receptor subunits for Types I, II, III IFNs encoded on chr21. Altogether, results establish critical foundation pursue hyperactivity as driver spectrum