Viral infections are less common but more severe in people with Down syndrome due to a fluctuating immune response
People with Down syndrome have less frequent viral infections, but when present, these infections lead to more severe disease. New results published on October 14 in the journal Immunity show that this is caused by increased expression of an antiviral interferon cytokine type I (IFN-I), which is partially encoded by chromosome 21. Elevated levels of IFN-I initially lead to an overactive immune response, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in viral attack.
“Usually too much inflammation means autoimmune disease, and immune suppression usually means susceptibility to infections,” says study lead author Dusan Bogunovic, of the Icahn School of Medicine at Mount Sinai. “What’s unusual is that people with Down syndrome are both inflamed and immunocompromised, sort of a paradox. Here we found out how that’s possible.”
Down syndrome is usually caused by triplication of chromosome 21. This syndrome affects multiple organ systems, resulting in a mixed clinical presentation that includes intellectual disability, developmental delays, congenital heart and gastrointestinal abnormalities, and disease Alzheimer’s in the elderly.
Recently, it has become clear that atypical antiviral responses are another prominent feature of Down syndrome. Increased rates of hospitalization of people with Down syndrome have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus infections (SARS-CoV-2).
While people with Down syndrome show clear signs of immune disruption, it remains to be elucidated how an extra chromosome 21 leads to dysregulation of viral defenses. To fill this knowledge gap, the researchers compared fibroblasts and white blood cells from individuals 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 the increase 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 via a protein called USP18, which is a potent negative regulator of IFNAR. This process, in turn, suppressed other responses to IFN-I and antiviral responses. Taken together, the results reveal oscillations in hyper- and hypo-responses to IFN-I in Down syndrome, predisposing both to a lower incidence of viral disease and to disease-related morbidity and mortality. increased infections.
“We still have a long way to go 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 here, in part, explained the susceptibility to serious viral illnesses, but that is only the tip of the iceberg.”
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