Mass cytometry reveals global immune remodeling with multi-lineage hypersensitivity to Type I Interferon in Down syndrome
This project utilized an emerging new technology in the field of immunology called mass cytometry to complete the most in-depth mapping and characterization of the immune system in people with Down syndrome to-date. Key findings were then confirmed using flow cytometry, a well-established technique in the field. Our scientists measured 100 different types of immune cells in the blood of people enrolled in two research studies, including the Human Trisome Project, to create a scientific ‘map’ of the immune system. Then, they compared the immune system maps of people with Down syndrome to those without and found that, on average, people with Down syndrome have dysregulation in every detected branch of their immune system.
The immune system dysregulation observed in many ways looked similar to the dysregulation observed in the typical population with autoimmune or inflammatory conditions. For example, the scientists found that people with Down syndrome had more of a specific type of cell that expresses collagen, called ‘fibrocytes.’ Fibrocytes are associated with autoimmunity and fibrotic lung diseases. The increase in fibrocytes could help explain why people with Down syndrome have a higher risk of pulmonary hypertension.
Another interesting find was that people with Down syndrome had more cells that produce large quantities of antibodies during an immune response, called ‘plasmablasts.’ This increase in plasmablasts, along with other changes observed, could contribute to the development of self-reactive antibodies and autoimmunity. Other changes seen across the immune system are known to be involved in autoimmune conditions, Alzheimer’s disease, protection from solid tumors, and have even been associated with elevated risk of mortality from sepsis.
The scientists then measured a specific receptor for a family of cytokines on each of the 100 immune cell types, called IFNAR1, which acts to intercept and relay signals from a part of the immune system called the ‘interferon response.’ The interferon response is normally activated when your body is fighting an infection and leads to inflammation. However, people with Down syndrome naturally have higher levels of interferon signaling, even without any infections. The scientists found that IFNAR1 expression is significantly higher on nearly all of the 100 immune cell types measured in people with Down syndrome. They also showed that the immune systems of people with Down syndrome reacted more strongly to interferon signaling than those of typical controls. Notably, IFNAR1 is one of four interferon receptor genes located on chromosome 21, and thus people with Down syndrome have three copies of the gene instead of the typical two.
This research is important because it points to interferon-driven immune dysregulation as a likely contributor to many hallmarks of Down syndrome, including the well-recognized developmental features and the different disease spectrum. For example, people with Down syndrome have lower rates of certain medical conditions, such as most solid cancers, while being strongly predisposed to others, such as leukemias, various autoimmune disorders, pulmonary hypertension, and Alzhemier’s disease. Importantly, the immune system has been linked to protection (i.e. solid cancers) or promotion (i.e. autoimmunity and dementia) of these disease states in the typical population.
This study also lays the foundation for understanding if and how therapies that target interferon signaling could be beneficial for people with Down syndrome, especially those with health conditions tied to inflammation and autoimmunity (e.g. alopecia areata, hidradenitis suppurativa, celiac disease, etc.). Scientists at the Linda Crnic Institutes are now partnering with clinicians at the University of Colorado Anschutz to begin the first clinical trial of an immune-modulatory drug that could help normalize the immune dysregulation seen in this study.
Check out the full publication on PubMed.
Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down syndrome. Waugh KA, Araya P, Pandey A, Jordan KR, Smith KP, Granrath RE, Khanal S, Butcher ET, Estrada BE, Rachubinski AL, McWilliams JA, Minter R, Dimasi T, Colvin KL, Baturin D, Pham AT, Galbraith MD, Bartsch KW, Yeager ME, Porter CC, Sullivan KD, Hsieh EW, Espinosa JM. Cell Rep. 2019 Nov 12;29(7): 1893-1908.e4. PMID: 31722205. PMCID: PMC6871766.