People with Down syndrome, or trisomy 21, a genetic condition caused by an extra copy of the human chromosome 21, experienced a dramatic increase in life expectancy during the 20th century. In the early 1900s, fewer than 20% of infants with Down syndrome survived beyond the age of 5. In the United States today, more than 90 percent of children with the condition live beyond the age of 10 and have a life expectancy of nearly 60 years. These increases were likely fueled by greater inclusion in society at large, disruption of institutionalization in psychiatric settings, and improved medical care.
Despite these advances, people with trisomy 21 experience an increased risk of many co-conditions, such as congenital heart defects, autoimmune conditions, autism spectrum disorders and Alzheimer’s disease. On the other hand, people with Down syndrome tend to have lower levels of high blood pressure and some cancers.
Understanding how an extra chromosome 21 causes these risks and resiliencies could advance the collective understanding of major medical conditions that also affect the general population. For example, the increased risk of Alzheimer’s disease among adults with Down syndrome may be explained in part by the presence of a gene on chromosome 21 that leads to overproduction of the beta-amyloid proteins and plaques characteristic of Alzheimer’s disease. ‘Alzheimer’s.
In our newly published research, my research group and I discovered that genes involved in the control of the immune system are central to the development of multiple hallmarks of Down syndrome. Our findings contribute to a growing body of research on the important role of the immune system in the appearance and severity of some of the adverse health effects of trisomy 21, supporting the idea that restoring immune balance could help improve the quality of the lives of people with this condition.
When too much of a good thing is bad
The genes we have identified, which encode so-called interferon receptors, are an important part of the antiviral defense of the immune system. These genes allow our cells to recognize a set of proteins called interferons, which virus-infected cells produce to alert the still uninfected cells around them of the presence of a virus during an infection.
While interferons trigger a beneficial immune response against viral infections, chronic interferon overactivity could have detrimental effects. Too much interferon signaling is known to be harmful in medical conditions such as systemic lupus erythematosus, a group of genetic disorders known as interferon diseases, and severe COVID-19.
Specifically, four of the six human interferon receptor genes are found on chromosome 21. Most people have only two copies of each chromosome and therefore would have only two copies of these genes. Because people with Down syndrome have three copies of chromosome 21, they also have three copies of the interferon receptor genes on it. This contributes to the overproduction of interferon receptors seen in those with Down syndrome.
Our team wanted to know whether this extra copy of the interferon receptor genes, compared to the approximately 200 other genes located on chromosome 21, contributed to the features of Down syndrome. To do this, we used a mouse model of Down syndrome. In this mouse model, a large region of its genome, equivalent to a large portion of human chromosome 21, is tripled to reproduce many features of Down syndrome.
Using CRISPR gene editing technology, we reduced the number of interferon receptor genes from three to the typical two, leaving all other triplicated genes intact. We found that correcting the number of interferon receptor genes significantly reduced abnormal gene expression patterns across multiple tissue types, both during embryonic development and in adult mice. These mice also had more regulated immune responses, normal cardiac development, reduced developmental delays, improved performance on memory and learning tasks, and even more typical cranial and facial morphology.
Overall, our results suggest that tripling of interferon receptor genes may cause a number of key Down syndrome traits.
Therapeutic implications and future directions
Our research indicates that many, though not all, aspects of Down syndrome may be associated with an overactive immune system response to interferon. He also supports the possibility of using drugs that blunt this response to treat some of the adverse health effects of trisomy 21.
Our team is currently conducting two clinical trials to test the safety and efficacy of one such drug, tofacitinib (Xeljanz). This drug belongs to a class of drugs known as JAK inhibitors used to treat autoinflammatory conditions. One study focuses on the most common autoimmune skin conditions in Down syndrome. The second study focuses on Down syndrome regression disorder, or DSRD, a rare but devastating neurological condition that can result in loss of speech, sleep disruptions, movement difficulties and hallucinations. There is evidence to suggest that a subset of DSRD cases may be caused by an immune dysregulation affecting the brain.
The results of our study also support further investigations into the effects of interferon overactivity on fetal development more generally. Two of the key traits of Down syndrome that we found were affected by the tripling of interferon receptors congenital heart disease and the shape of the skull and face as they develop in utero.
Although our research shows promise on the potential of JAK inhibitors and other drugs that modulate the immune system to improve health outcomes in Down syndrome, more research in people is needed to determine their safety and effectiveness.
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