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Rebalancing immune hyperactivity in Down’s syndrome

Written by Charlotte Harrison, Science Writer 

People with Down’s syndrome have chronic hyperactivation of interferon signalling, meaning they are at higher risk of autoimmune conditions. A new study by scientists from the University of Colorado provides the largest characterization of immune dysregulation in Down’s syndrome to date.

The findings provide proof of concept that immune balance can be restored in Down’s syndrome using repurposed drugs.

A vastly different immune system

The researchers derived so called interferon scores from whole blood transcriptome data from over 500 individuals with Down’s syndrome. These scores were then used to define the proteomic, immune, metabolic and clinical features associated with interferon hyperactivity. The results showed that interferon hyperactivity was linked to a proinflammatory phenotype as well as dysregulation of growth signalling pathways.

People that had the highest interferon scores had strong remodelling of the peripheral immune system, including increased levels of cytotoxic T cells, B cell depletion and monocyte activation.

“We observed that interferon hyperactivity really shapes the biology of Down syndrome across the lifespan. Those with the highest interferon activity display … a vastly different immune system,” said the authors in a press release.

JAK inhibition

Because interferon signalling uses the Janus-activated kinase (JAK)1 pathway for signal transduction, the authors hypothesised that JAK inhibitors would halt the deleterious effects of interferon over-activity. 

In a mouse model, a JAK inhibitor blocked the expression of inflammatory gene signatures that were relevant to Down’s syndrome pathophysiology. Examples included genes involved in extracellular matrix remodelling in the heart, mTORC1 signalling in the lung, complement and coagulation factors in the liver and oxidative phosphorylation genes in the brain.

To determine if their findings translated to patients, the researchers  evaluated interferon signalling in an individual who was taking the JAK inhibitor tofacitinib to treat a form of hair loss that is common in people with Down’s syndrome.

Commenting on this result: “We observed a remarkable normalisation of interferon hyperactivity when the participant was taking the JAK inhibitor. Consistently, her interferon metrics and other biomarkers of inflammation dropped from the abnormally high levels seen in Down’s syndrome down to the range observed in the general population,” said the authors.

Based on the findings of the current study, the researchers have initiated a new clinical trial of tofacitinib in a rare form of Down’s syndrome (NCT05662228).

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Down's syndrome