Oscillations of hyper- and hypo-responsiveness to the potent cytokine IFN-I in people with Down syndrome predispose both to a lower incidence of viral disease and to higher infection-related morbidity and mortality. Credit: Immunity/Malle et al.
New findings reveal why people with Down syndrome have less frequent but more severe viral infections.
People with Down syndrome have less frequent viral infections. However, when present, these infections lead to more severe disease. New research findings 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 initially lead to hyperactivity of the immune response, but the body overcorrects so that this reduces inflammation, leading to greater vulnerability later in the viral attack. The findings are published today (October 14) in the journal Immunity.
“We have a lot more to do to fully understand the complexities of the immune system in Down syndrome.” — Louise Malle
“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 is 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 cardiac and gastrointestinal abnormalities, and
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Down syndrome is the most common chromosomal disorder. According to the CDC, about 6,000 babies with Down syndrome are born in the United States each year. This is about 1 in every 700 babies born. Between 1979 and 2003, the number of babies born with Down syndrome increased by about 30% in the US Older mothers are more likely to have a baby affected by Down syndrome than younger mothers.
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 (
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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 scientists 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 here, in part, explained susceptibility to severe viral illness, but this is just the tip of the iceberg.”
Reference: “Type I Interferon Upregulation Alters Viral Control in People With Down Syndrome” by Louise Malle, Marta Martin-Fernandez, Sofija Buta, Ashley Richardson, Douglas Bush, and Dusan Bogunovic, Oct 14, 2022, Immunity .
DOI: 10.1016/j.immune.2022.09.007
Source: news.google.com