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Autoimmunity in Down Syndrome Arises From Rapid Immune Aging

trisomy 21 karyotype
Down syndrome, sometimes called trisomy 21, affects approximately 1 in 800 births in the United States. | Dr_Microbe/ iStock

People living with Down syndrome have a much higher risk of autoimmune diseases such as type 1 diabetes, but the nature of this connection had long remained a mystery to scientists.

Now, a research team has found that the high risk of autoimmunity in Down syndrome might arise because of an accelerated aging of the immune system. Their new study, which included data from 81 patients and healthy volunteers, was published in the January 12 issue of Science Translational Medicine.

"Our findings may help explain the many shared clinical immune features between people with Down syndrome and older individuals without Down syndrome, [such as] increased autoimmunity and impaired vaccine response," said Bernard Khor, a physician-scientist at Benaroya Research Institute in Seattle, WA and senior author of the new study.

Although more work is needed, Khor also suggested these immune features could be partly responsible for the shorter life expectancy often seen in people with Down syndrome who come down with respiratory infections such as influenza and COVID-19.

Autoimmunity as a major burden in Down syndrome

Down syndrome is one of the most common congenital conditions, and affects approximately 1 in 800 births in the United States, according to a recent estimate.

People with Down syndrome can show a range of symptoms and severity, with some having only mild intellectual disability and others being severely disabled. However, most people with Down syndrome deal with a range of health complications , including birth defects in the heart, eye problems, and issues with hearing.

Down syndrome also tends to disrupt the body's immune defenses, leaving individuals more vulnerable to infections and weakening their responses to protective vaccines. These disruptions also mean people with Down syndrome have a much higher risk of autoimmune disorders, or diseases caused by the body's own immune system.

Autoimmune conditions, which include diseases like type 1 diabetes, are usually lifelong and can severely impact quality of life. They therefore represent an ever-growing burden on the Down syndrome population, especially as lifespans in Down syndrome have drastically grown in recent decades.

"Immune dysregulation is an emerging clear and present threat to the health of people with Down syndrome," said Khor. "Conversely, understanding the underlying pathophysiology will allow us to better treat and prevent autoimmunity in people with Down syndrome."

Katharina Lambert, a postdoctoral researcher at Benaroya and lead author of the new study, Khor, and colleagues set out to demystify the link between Down syndrome and autoimmunity.

The research team began by recruiting 28 individuals with Down syndrome of varying ages (2-55 years old), 25 individuals with type 1 diabetes, and 28 healthy volunteers. Using a combination of lab techniques, the scientists then probed the characteristics of each participant's immune cells.

One key tool in their search was a new analytical platform that they developed called IMPACD. This algorithm allowed them to rapidly look for any shared changes in the immune systems of the people with Down syndrome and those with type 1 diabetes.

Lambert's team combined IMPACD with three models of immune aging known as "immune clocks," which estimated how "old" the immune system was in each of the study participants.

Study reveals rapid immune aging in Down syndrome

Taken together, the modeling experiments revealed that the immune system in the individuals with Down syndrome or type 1 diabetes seemed to age more quickly than expected.

The participants with type 1 diabetes showed an immune age around 3.9 years older on average than the healthy individuals, according to one of the models. The same model predicted that people with Down syndrome had even faster immune aging, with an immune system almost 15 years older than the healthy individuals.

People with Down syndrome showed shifts in their populations of T cells that would usually be seen in older people, which the study authors attributed to an immune signaling molecule called interleukin-6.

Furthermore, the participants with Down syndrome displayed classic signs of "inflammaging," a form of low-grade inflammation often seen in the elderly. Lambert's team noted that inflammaging was apparent even in the youngest members of the Down syndrome group.

"One of our findings was that even in the absence of any autoimmunity, [Down syndrome] already reshapes the immune system to look in many ways like the immune system of people with autoimmunity," Khor said.

"Our models also show that [Down syndrome] reshapes the immune system to look like that of older individuals without Down syndrome," he added.

The scientists speculate that therapeutics might be able to restrain autoimmunity and inflammaging in both Down syndrome and the general population. Khor said that research into therapeutics is a key goal for his group. He also believes that treatments for people with Down syndrome might benefit certain patients without Down syndrome who live with autoimmune disorders.

The researchers also speculate these findings may help explain other observed clinical differences in Down syndrome, such as a higher risk of severe COVID-19 infections. A 2021 study previously showed that mortality rates from COVID-19 begin to sharply rise after age 40 in people with Down syndrome, compared with after age 60 in the general population.

"We want to better understand what drives immune aging and immune dysfunction in people with Down syndrome, in order to guide optimal therapeutic selection for people with Down syndrome and develop novel therapies for people both with and without Down syndrome," said Khor.