Browsing School of Medicine by Title "Immune Dysfunction in the Ts65Dn Mouse Model of Down Syndrome: Potential Role(s) of Reactive Oxygen Species (ROS) and Alterations in IL-7Ralpha Expression"
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Immune Dysfunction in the Ts65Dn Mouse Model of Down Syndrome: Potential Role(s) of Reactive Oxygen Species (ROS) and Alterations in IL-7Ralpha ExpressionDown Syndrome (DS), a genetic disease caused by a triplication of chromosome 21, is characterized by increased markers of oxidative stress. In addition to cognitive defects, DS is characterized by hematologic disorders such as myelodysplastic syndrome, premature thymic involution and increased incidence of infections and leukemia. However, the potential causes of these defects have not been fully elucidated. The goal of this study was to examine hematopoietic stem cell, lymphoid progenitor cell, and mature lymphocyte function in DS using the Ts65Dn mouse model, which contains a segmental triplication of mouse chromosome 16 that is partially syntenic to human chromosome 21. Analysis of hematopoietic progenitor populations showed that Ts65Dn mice possessed fewer functional hematopoietic stem cells (HSC) and a significantly decreased percentage of bone marrow lymphoid progenitors. Increased reactive oxygen species (ROS) and markers of oxidative stress were detected in HSC populations and were associated with a loss of quiescence and increased apoptosis. Bone marrow progenitor, immature thymocyte, and mature lymphocyte populations expressed diminished levels of the IL-7Rα chain, which was associated with decreased proliferation and increased apoptosis. Modulating oxidative stress in vitro suggested that oxidative stress induced by diminished glutathione levels selectively leads to decreased IL-7Rα expression, and inhibits the survival of IL-7Rα expressing hematopoietic progenitors, potentially linking increased ROS and immunopathology. Other possible mechanisms identified in Ts65Dn mice that could induce diminished IL-7Rα expression in DS are increased microRNA expression and inhibition of the Notch pathway. The data suggest that hematopoietic stem cell, lymphoid progenitor cell, and mature lymphocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signaling may alter hematologic development in Ts65Dn mice. Therefore, the current study may support modulation of redox balance and IL-7Rα expression as possible therapeutic targets to treat immune dysfunction in DS and may provide a starting point for the manipulation of redox balance to modulate the immune response.