Transcriptomic and proteomic evidence for noncanonical hydrogen sulfide metabolism and immune dysregulation in Down Syndrome

Accelerated immune cell aging is well-recognized feature of Down Syndrome (DS), a condition caused by trisomy of human chromosome 21 ( Hsa21 ). DS predisposes individuals to recurrent infections, autoimmunity, low bone mass and leukemia. To investigate potential connections between immune cell dysfunction or disruption in DS, transcriptomic and plasma proteomic datasets from DS and euploid individuals were examined. High DS superoxide dismutase 1 ( SOD1 ) mRNA expression was consistently found and was strongly associated with an increased odds of inflammatory co-occurring conditions such as pharyngitis. Higher SOD1 mRNA expression was also associated with increased resting-memory CD4 + T cells, elevated plasma interleukin-16 levels and interferon-γ protein levels, indicative of pathological pro-inflammatory immune dysregulation. Higher SOD1 mRNA was correlated with increased expression of glutathione and thioredoxin-dependent pathways, both integral to antioxidative responses and the generation of hydrogen sulfide (H 2 S). Although H 2 S overproduction in DS has been attributed to higher expression of cystathionine-β-synthase ( CBS ), no consistent CBS mRNA elevation was observed in this study. Conversely, the increased expression of a thioredoxin-dependent cysteine catabolism pathway suggests a noncanonical route for H 2 S overproduction in DS distinct from CBS . Our findings highlight the unexpected relationship between oxidative stress homeostasis and H 2 S overproduction in DS, extending beyond Hsa21 trisomy.