Down Syndrome Tied to Accelerated Immune System Aging, Higher Risk of Autoimmune Disorders

By Marilynn Larkin

January 20, 2022

NEW YORK (Reuters Health) - Individuals with Down syndrome (DS) show accelerated aging of their immune systems, putting them at higher risk of autoimmune disorders, researchers say.

"Studying immune dysregulation in people with DS is important because immune-mediated diseases like autoimmunity are emerging as a clear and present threat to the health and well-being of people with DS," Dr. Bernard Khor of Benaroya Research Institute at Virginia Mason in Seattle told Reuters Health by email. "Also, understanding the basis of immune dysregulation in people with DS has implications for precision therapy in people without DS, as our work begins to demonstrate."

As reported in Science Translational Medicine, Dr. Khor and colleagues used mass cytometry to immunophenotype peripheral blood mononuclear cells from 28 individuals with DS, ages 2 to 55, but mostly without autoimmune disease (two had Hashimoto's disease); 25 age- and sex-matched individuals without DS but with type 1 diabetes as a representative autoimmune disease; and 28 age- and sex-matched controls without DS or diabetes.

The team built an analytical software, IMPACD (Iterative Machine-assisted Permutational Analysis of Cytometry Data), that enabled them to identify features of immune dysregulation in DS shared with other autoimmune diseases.

They found quantitative and qualitative dysregulation of naïve CD4+ and CD8+ T cells in individuals with DS - specifically, decreased naïve T cells, increased CD11c+ B cells, and increased IL-6, and identified IL-6 as the likely driver of these changes (a new finding).

The changes are emblematic of inflammaging (remodeling of the immune system during aging, leading to inflammation), and on the basis of the findings, they built three linear models of inflammaging, called "immune clocks," trained control participants.

All three immune clocks showed advanced immune aging in individuals with DS. One clock, informed by DS-relevant biology, also showed advanced immune aging in individuals with type 1 diabetes.

Further, orthologous RNA sequencing-derived immune clocks also showed advanced immune aging in individuals with DS.

The authors conclude, "Together, our findings demonstrate an approach to studying immune aging in Down syndrome that may have implications in other autoimmune diseases."

Going forward, Dr. Khor said, "We want to better understand the mechanisms driving advanced immune aging, using studies both in humans and in murine models. We want to understand whether thinking of DS as a disease of immune aging is a useful clinical paradigm (i.e., do therapies designed for older typical individuals improve outcomes in people with DS - and vice versa?)."

"We expect this work to help identify therapeutically tractable targets driving immune aging in DS, and help identify which individuals both with and without DS may benefit from related therapies," Dr. Khor concluded.

Dr. Dusan Bogunovic, Director of the Center for Inborn Errors of Immunity at Icahn School of Medicine at Mount Sinai and Associate Professor at the Precision Immunology Institute, Mindich Child Health and Development Institute, Icahn Genomics Institute, commented by email. "The authors elegantly show premature aging in individuals with DS."

"Clinically and epidemiologically, our community has been documenting for a while that individuals with DS indeed have clear signs and features of those who are significantly older than they are, at times, decades," he said. "This is true in terms of susceptibility to infectious diseases, autoimmunity and dementia onset, at the very least."

"Here, the authors show that immune system features are also indicative of premature aging, perhaps with 'inflammaging' being the driver - a notion we also see in individuals with DS we follow," Dr. Bogunovic concluded.

SOURCE: https://bit.ly/33z7fJZ Science Translational Medicine, online January 12, 2022.

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