SOD1 at the Crossroads: Co-Overexpression of Canonical Antioxidant Response and Noncanonical Hydrogen Sulfide Generation Pathways in Down Syndrome, With Immune Cell Implications

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, serum transcriptomic and 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. SOD1 mRNA overexpression was also associated with decreased M2-polarized macrophages, increased resting-memory CD4 + T cells, elevated serum interleukin-16 levels and interferon-γ protein levels, indicative of pathological pro-inflammatory immune dysregulation. SOD1 mRNA was co-overexpressed with glutathione and thioredoxin-dependent pathways, both are integral to the antioxidative responses and the generation of hydrogen sulfide (H ₂ S). Although H ₂ S overproduction in DS has been attributed to the overexpression 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 noncanonical 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.