In contrast, B-cell progenitors were unchanged in the bone marrow of Ts65Dn mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin-7Rα, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the Notch pathway were identified as possible

mediators of decreased interleukin-7Rα Staurosporine expression in Ts65Dn mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling

may alter lymphocyte development in Ts65Dn mice. Numerous studies have indicated that the adaptive immune system is altered in individuals with Down syndrome (DS), with defects ranging from the level of immature haematopoietic progenitor cells to mature lymphocytes in the periphery.[1] Since the 1970s, it has been observed that individuals with DS seemed to exhibit diseases arising from defects in the immune system, such as the increased frequency of respiratory infections, leukaemia, and autoimmune diseases such as diabetes. Significantly, Urocanase these diseases,

although INCB018424 nmr not as commonly associated with DS as the deficiencies in cognitive function, are major causes of morbidity and mortality.[2, 3] For this reason, the hypothesis has been developed that the immune system is inherently defective in DS. However, the underlying mechanisms for these global defects in adaptive immune function are unclear, and the molecular mechanisms inducing these changes have not been examined in detail. T-cell development occurs in the thymus, which does not contain its own self-renewing population of stem cells and must be continuously seeded by bone-marrow-derived haematopoietic progenitors that travel through the circulation.[4, 5] Previous studies have shown loss of bone marrow haematopoietic progenitor populations in Ts65Dn mice, a mouse model for Down syndrome with triplication of a region of mouse chromosome 16 that is syntenic to human chromosome 21.[6, 7] Significantly, there were defects in the common lymphoid progenitor and lymphoid-primed multipotent progenitor populations, which have been reported to have thymus-seeding potential.[8, 9] Previous studies of mechanisms for immune defects in individuals with DS have proposed deficits in the thymic stroma, which supports thymocyte development,[10-12] and others have found decreased recent thymic emigrants to repopulate peripheral lymphocytes.