Oscillations of hyper- and hypo-response to the potent cytokine IFN-I in people with Down syndrome predispose to each decrease incidence of viral illness and elevated infection-related morbidity and mortality. Credit score: Immunity/Malle et al.
New findings reveal why people with Down syndrome have much less frequent, however extra extreme viral infections.
Folks with Down syndrome have less-frequent viral infections. Nevertheless, when current, these infections result in extra extreme illness. New analysis findings present that that is brought on by elevated expression of an antiviral cytokine kind I interferon (IFN-I), which is partially coded for by chromosome 21. Elevated IFN-I ranges result in hyperactivity of the immune response initially, however the physique overcorrects for this to scale back irritation, resulting in elevated vulnerability later within the viral assault. The discovering are printed at present (October 14) within the journal Immunity.
“We now have much more to do to utterly perceive the complexities of the immune system in Down syndrome.” — Louise Malle
“Often an excessive amount of irritation means autoimmune illness, and immune suppression normally means susceptibility to infections,” says senior research writer Dusan Bogunovic of the Icahn Faculty of Drugs at Mount Sinai. “What’s uncommon is that people with Down syndrome are each infected and immunosuppressed, a paradox of types. Right here, we found how that is doable.”
Down syndrome is usually brought on by the triplication of chromosome 21. This syndrome impacts a number of organ techniques, inflicting a blended scientific presentation that features mental incapacity, developmental delays, congenital coronary heart and gastrointestinal abnormalities, and Alzheimer’s disease in older individuals.
Down syndrome is the most common chromosomal disorder. According to the CDC, each year, about 6,000 babies are born with Down syndrome in the United States. 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 U.S. 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 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 (SARS-CoV-2) infections.
While people with Down syndrome show clear signs of immune disturbance, it has yet to be elucidated how a supernumerary chromosome 21 leads to dysregulation of viral defenses. To address this knowledge gap, the researchers compared fibroblasts and white blood cells derived from individuals with and without Down syndrome, at both 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 discovered that increased IFNAR2 expression was sufficient for the hypersensitivity to IFN-I observed in Down syndrome, independent of trisomy 21. But subsequently, the hyper-active IFN-I signaling cascade triggered excessive negative feedback via a protein called USP18, which is a potent IFNAR negative regulator. This process, in turn, suppressed further responses to IFN-I and antiviral responses. Taken together, the findings unveil oscillations of hyper- and hypo-responses to IFN-I in Down syndrome, predisposing to both lower incidence of viral disease and increased infection-related morbidity and mortality.
“We have a lot more to do to completely 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 severe viral disease, but this is only the tip of the iceberg.”
Reference: “Excessive Negative Regulation of Type I Interferon Disrupts Viral Control in Individuals with Down Syndrome” by Louise Malle, Marta Martin-Fernandez, Sofija Buta, Ashley Richardson, Douglas Bush and Dusan Bogunovic, 14 October 2022, Immunity.
DOI: 10.1016/j.immuni.2022.09.007
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