People with Down syndrome have less frequent viral infections, but when they are present, these infections lead to more severe illness. New findings published Oct. 14 in the journal Immunity show that this is caused by increased expression of an antiviral cytokine interferon type I (IFN-I), which is partially encoded by chromosome 21. Elevated IFN-I levels lead to to an overactive immune response initially, but the body overcorrects this to reduce inflammation, leading to greater vulnerability later in the viral attack.
“Too much inflammation usually means autoimmune disease, and immune suppression usually means susceptibility to infection,” says the study’s senior author, Dusan Bogunovic, of the Icahn School of Medicine at Mount Sinai. “What’s unusual is that people with Down syndrome are inflamed and immunocompromised, something of a paradox. Here we find out how this is possible.”
Down syndrome is usually caused by the triplication of chromosome 21. This syndrome affects multiple organ systems, causing a mixed clinical presentation that includes intellectual disability, developmental delays, congenital heart and gastrointestinal abnormalities, and Alzheimer’s disease in older people.
Recently, it has become clear that atypical antiviral responses are another important feature of Down syndrome. Increased hospitalization rates of people with Down syndrome have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus (SARS-CoV-2) infections.
Although individuals with Down syndrome show clear signs of immune compromise, how a supernumerary chromosome 21 leads to dysregulation of viral defenses remains to be elucidated. To address this knowledge gap, the researchers compared fibroblasts and white blood cells derived from people with and without Down syndrome, both at the mRNA and protein levels. They focused on the potent antiviral cytokine IFN-I receptor subunits IFNAR1 and IFNAR2, which are located on chromosome 21.
The researchers found that increased IFNAR2 expression was sufficient for the IFN-I hypersensitivity seen in Down syndrome, independent of trisomy 21. But subsequently, the overactive IFN-I signaling cascade triggered excessive negative feedback. through a protein called USP18, which is a potent negative regulator of IFNAR. This process, in turn, suppressed more responses to IFN-I and antiviral responses. Taken together, the findings reveal oscillations of hyper- and hyporesponsiveness to IFN-I in Down syndrome, predisposing to both a lower incidence of viral disease and higher infection-related morbidity and mortality.
“We have much more to do to fully understand the complexities of the immune system in Down syndrome,” says first author Louise Malle of the Icahn School of Medicine at Mount Sinai. “We have explained here, in part, the susceptibility to severe viral disease, but this is only the tip of the iceberg.”
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