Due to oscillations in the immune response, viral infections are less common in people with Down syndrome, but more severe

Individuals with Down syndrome have a lower frequency of viral infections, but when these infections appear, they can lead to more severe disease
.
The new findings, published Oct.
14 in the journal Immunology, suggest that this is caused by increased expression of an antiviral cytokine type I interferon (IFN-I), which is encoded
in part by chromosome 21.
Initially, elevated IFN-I levels lead to an overactive immune response, but the body overcorrects this to reduce inflammation, leading to increased vulnerability
in subsequent viral attacks.

Dussaint Bogunovich, senior study author at the Icahn School of Medicine at Mount Sinai, said: "Typically, too much inflammation means an autoimmune disease, and immunosuppression usually means susceptibility to infection
.
" "It's an extraordinary paradox
that people with Down syndrome are both inflamed and immunosuppressed.
Here we discover how this is achieved
.
”

Down syndrome is usually caused
by triploiding of chromosome 21.
The syndrome affects multiple organ systems, resulting in mixed clinical manifestations, including intellectual disability, developmental delay, congenital heart disease and gastrointestinal abnormalities, and Alzheimer's disease
in older adults.

Recently, it has become clear that atypical antiviral reactions are another important feature of
Down syndrome.
Increased
hospitalizations for people with Down syndrome have been recorded due to influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome caused by coronavirus (SARS-CoV-2) infection.

While people with Down syndrome show clear signs of immune disturbance, how the extra chromosome 21 contributes to viral defenses has yet to be elucidated
.
To bridge this knowledge gap, the researchers compared mRNA and protein levels
in fibroblasts and white blood cells from people with Down syndrome and those with and without Down syndrome.
They focused on IFNAR1 and IFNAR2
, the potent antiviral cytokine IFN-I receptor subunits located on chromosome 21.

The researchers found that the increase in IFNAR2 expression was enough to make people with Down syndrome allergic to IFN-I, independent of trisomy 21
.
But then, the overactive IFN-I signaling cascade triggered excessive negative feedback through a protein called USP18, a potent negative regulator of
IFNAR.
This process, in turn, inhibits further and antiviral responses
to IFN-I.
Taken together, these findings reveal that the oscillations of high and low response to IFN-I in Down syndrome predispose to reducing the incidence of viral diseases and increasing infection-related morbidity and mortality
.

Lead author Louise Malle of the Icahn School of Medicine at Mount Sinai said, "We still have a lot of work to do
to fully understand the complexity of the immune system of people with Down syndrome.
" "We explain susceptibility to serious viral diseases to some extent, but that's just the tip
of the iceberg.
"

Journal Reference:

1. Louise Malle, Marta Martin-Fernandez, Sofija Buta, Ashley Richardson, Douglas Bush, Dusan Bogunovic.
   Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome.
   Immunity, 2022; DOI: 10.
   1016/j.
   immuni.
   2022.
   09.
   007