These features already suggested in the 1970s that immunodeficiency is an integral part of the syndrome [1417]. slightly reduced, but all other immunoglobulin isotypes were in the normal range. The frequency of switched memory A 922500 B cells specific for vaccine antigens was significantly lower in affected children than in their equivalently vaccinated siblings. In vitro switched memory B cells of patients with DS have an increased ability to differentiate into antibody-forming cells in response to TLR9 signals. Tailored vaccination schedules increasing the number of switched memory B cells may improve protection and reduce the risk of death from infection in Bglap DS. Keywords: B cells, Down syndrome, IgM memory, Switched memory, TLR9, Vaccine == Introduction == Down syndrome (DS) is associated with increased susceptibility to bacterial and viral infections [1, 2], and a high frequency of leukemia [3, 4] and autoimmune disorders, such as celiac disease [57], type I diabetes [8, 9], and acquired hypothyroidism [10, 11]. In spite of a dramatic improvement of life expectancy over the last half-century [12], the risk of premature mortality remains high in DS mainly because of respiratory infections and leukemia [13]. These features already suggested in the 1970s that immunodeficiency is an integral part of the syndrome A 922500 [1417]. Indeed, this has been supported by the findings that the thymus, even in newborns, is small and has an abnormal structure A 922500 [18], the absolute number of circulating lymphocytes is decreased and antibody responses to vaccine antigens such as oral polio, acellular pertussis, tetanus, hepatitis B, and influenza A are low [1921]. The absolute number of T lymphocytes has been reported to be low at all ages [22] or decreased during the first 2 years of age approaching normal levels thereafter [23]. A decreased number of A 922500 circulating B cells is a constant finding in DS [24] with variable levels of serum immunoglobulin [25]. Discrepancies between the results of aspects of these studies may derive from the small number of subjects included, differences in the age groups considered, poor matching between DS and controls, inclusion of institutionalized subjects with DS and, in particular, from the use of old and poorly reliable phenotyping techniques that have subsequently greatly improved over recent years driven by the remarkable advances in flow cytometric methods. The most common symptoms reported in children with DS are infections of the respiratory tract suggesting a B-cell defect. Diseases related to T-cell deficiency, such as infection with intracellular microorganism, fungi, and opportunistic pathogens are rare [26]. In order to verify whether a defined B-cell defect may be associated with DS, we studied in detail the B-cell compartment of 19 children with DS and compared them with 19 age-matched controls (CTR). In the peripheral blood, four major populations of B cells can be identified: transitional B cells, representing recent BM emigrants, mature-naive B cells, IgM memory B cells, and switched memory B cells. The cells that we conventionally call IgM memory B cells also express IgD on their surface, but a minor population of IgM-only memory B cells has also been described [27]. The latter is very small in both CTR and DS children (less than 1% of all memory B cells) and its function was not analyzed in this study separately from that of IgM memory B cells. IgM memory, also known as marginal zone B cells, is probably generated through a T-cell-independent mechanism whereas switched memory B cells derive from the T-dependent germinal center reaction [28]. Since each of these subpopulations has a different origin and defined function, we carried out a detailed analysis of these B-cell subpopulations and measured the in vitro proliferation and immunoglobulin production of B cells isolated from peripheral blood isolated from a group of 6- to 12-year-old children with DS compared to age-matched CTR. The results of this study show that switched memory B cells are dramatically reduced in number but have an increased ability to differentiate into antibody-producing cells in vitro. == Results == ==.