Girl with Down syndrome sitting with her mother
Credit: GabrielPevide/Getty Images

Investigators at the Icahn School of Medicine at Mount Sinai say they have identified specific cytokines and a B cell subtype that play a key role in the adaptive immune response that are likely contributors to autoimmune disease in people with Down syndrome.

Of particular note in the findings published today in Nature, was the discovery that people with Down syndrome are in a constant state of inflammation similar to people with Down syndrome in intensive care with an acute infection. These results, say the investigators, is a breaking of immune tolerance resulting in autoimmunity.

“Our findings could be used to test existing therapies not commonly used in persons with Down syndrome and to develop potential therapeutics to alleviate autoimmunity symptoms in individuals with the disorder,” said Dusan Bogunovic, PhD, professor at Icahn Mount Sinai’s Precision Immunology Institute and senior author of the study. “Available drugs such as tocilizumab and a variety of JAK inhibitors could potentially tame this inflammation. And in patients who have elevated autoimmune prone B cells, there is an opportunity to develop therapies targeting this cell type specifically.”

Down syndrome, typically caused by a trisomy in chromosome 21 is the most common genetic condition diagnosed at birth and comes with a host of other problems associated with the condition including autoimmunity, gastrointestinal problems, hypothyroidism, heart defects, and a higher incidence of leukemia, among others. It occurs across gender, racial, and socioeconomic classes and occurs in roughly one in every 700 live births.

“People with Down syndrome are an underserved population worldwide. They require the same level of dedication as all of us. We now have a better understanding of their health and are laying the groundwork to potentially use existing drugs and develop new ones, which could be transformative to their health,” noted first author Louise Malle, an MD/PhD candidate at  Icahn Mount Sinai. “We also need to keep in mind that, just like in the general population, not all individuals with the disorder are the same, and there is significant variability.”

The study adds to the team’s research published in October 2022 in the journal Immunity. Earlier research of individuals with Down syndrome versus non-Down syndrome controls showed people with Down syndrome were more protected against common infections including influenza A virus, upper respiratory infections, mononucleosis, Herpes zoster, and intestinal infections. However, despite this added protection, once infected, Down syndrome patients are likely to progress to severe disease. The earlier study identified the signaling pathway of pro-inflammatory cytokines that are essential for fighting against viral infections called IFN-Is.

Next steps for the Icahn team are to more thoroughly understand the root causes of autoimmunity associated with Down syndrome with an eye toward launching a placebo-controlled clinical trial to test currently available drugs as potential treatments. The team also seeks to more broadly add to the body of evidence detailing the unique characteristics of the condition.

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