الفهرس 
AbstractOnly 14 pages are availabe for public view
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Abstract
HIV infection continues to be a major global health issue and is characterized by a profound dysregulation of various immune cells, including B cells. Recently, increased frequencies of regulatory, granzyme B-expressing B cells have been identified in HIV-infected patients compared to healthy subjects, but their function remains unclear. Due to limitations in studies with HIV-infected individuals, animal studies are needed. To date, the experimental infection of rhesus macaques (Macaca mulatta) with simian immunodefiency virus (SIV) is the best animal model for HIV/AIDS research. The aim of this work was to analyse frequencies, phenotype and the possible function of granzyme B-expressing B cells in healthy and SIV-infected rhesus macaques. Then B cells were purified using magnetic cell separation and different stimulation protocols were applied to induce granzyme B expression in vitro. Finally Co-culture experiments of these in vitro induced granzyme B-expressing B cells with T cells performed. Furthermore, we aimed at analyzing these cells in so-called long-term survivors (LTS), which lack disease progression in the absence of antiretroviral therapy, but can suddenly lose this status and progress to AIDS. By using multicolor flow cytometry the phenotype and frequencies of granzyme B-expressing B cells have been assessed and correlated with other immunologic parameters. Similar to HIV patients, significantly higher frequencies of these cells have been found in the blood of chronically SIV-infected rhesus monkeys compared with uninfected healthy ones. These frequencies correlated with plasma viral load and inversely with absolute CD4 T-cell counts. When investigating GrB+ B cells in different compartments, levels were highest in blood, spleen and bone marrow, but considerably lower in lymph nodes and tonsils. Analysis of expression of various surface markers on this particular B-cell subset in SIV-infected macaques revealed differences between the phenotype in macaques and in humans. GrB+ B cells in SIV-infected rhesus macaques exhibit an elevated expression of CD5, CD10, CD25 and CD27, while expression of CD19, CD185 and HLA-DR is reduced. In contrast to human GrB+ B cells, a significantly increased expression of CD43 and CD86 has not been observed. B-cell receptor stimulation in combination with IL-21 of purified B cells from healthy animals led to the induction of GrB expression. Furthermore, initial functional analyses indicated a regulatory role on T-cell proliferation. Overall, this data pave the way for longitudinal analyses including studies on the functionality of GrB+ B cells in the nonhuman primate model for AIDS.