Aging and Autoimmunity: Down Syndrome Gives a Master Class

Down syndrome (DS, trisomy 21) is the most common chromosomal abnormality. People with DS exhibit clinical and cellular features of advanced immune aging (inflammaging), especially increased predisposition to autoimmunity. To better define how immune architecture changes with age, we immunophenotyped 28 participants with DS across the lifespan using mass cytometry. We also included age- and sex-matched typical controls and, as a representative autoimmune disease, participants with type 1 diabetes. We built new analytic software (IMPACD, Iterative Machine-assisted Permutational Analysis of Cytometry Data) to execute rapid, exhaustive permutational analysis of immunophenotyping data. We found broad overlap between immune remodeling observed in DS and in many other autoimmune diseases. Further, we successfully used IMPACD’s highly granular data to build very accurate linear models of age using only immune subset data from typical control participants. These models allowed us to quantitatively demonstrate for the first time advanced immune aging in participants with DS of 5.2 to 16.9 years. These findings were supported by contemporaneous RNAseq studies, which pointed to heme metabolism and BACH2 as candidate drivers of immune aging. Notably, a DS-informed immune subset model suggested advanced immune aging in participants with T1D, the magnitude of which correlated with earlier age of onset of T1D. Inflammatory cytokines were also elevated in people with DS, supporting increased inflammaging. Together, these findings highlight novel relationships between immune dysregulation associated with DS, autoimmunity and immune aging. Elucidating these common underlying mechanisms is likely to advance therapeutic strategies for autoimmunity in people with and without DS.