A Trisomy 21 Lung Cell Atlas

Abstract

Trisomy 21 (T21), resulting in Down Syndrome (DS), is the most prevalent chromosomal abnormality worldwide. While pulmonary disease is a major cause of morbidity and mortality in DS, the ontogeny of pulmonary complications remains poorly understood. We recently demonstrated that T21 lung anomalies, including airway branching and vascular lymphatic abnormalities, are initiated in utero. Here, we aimed to describe molecular changes at the single cell level in prenatal T21 lungs. Our results demonstrate differences in the proportion of cell populations and detail changes in gene expression at the time of initiation of histopathological abnormalities. Notably, we identify shifts in the distribution of alveolar epithelial progenitors, widespread induction of key extracellular matrix molecules in mesenchymal cells and hyper-activation of IFN signaling in endothelial cells. This single cell atlas of T21 lungs greatly expands our understanding of antecedents to pulmonary complications and should facilitate efforts to mitigate respiratory disease in DS.

JAK inhibition decreases the autoimmune burden in Down syndrome

“…In mouse models, triplication of four IFNR genes contributes to multiple hallmarks of DS 48,56 and JAK inhibition attenuates global dysregulation of gene expression 42 while rescuing key phenotypes, such as lethal immune hypersensitivity 22 and CHDs 24 . The fact that gene signatures of IFN hyperactivity are present in human embryonic tissues with T21 57 and embryonic tissues from mouse models of DS 48,58 indicates that the harmful effects of IFN hyperactivity could start in utero , supporting the notion that DS could be understood, in part, as an inborn error of immunity with similarities to monogenic interferonopathies 59 .…”