Increased susceptibility of cord blood B lymphocytes to undergo spontaneous apoptosis

In this study, we compared the rate of spontaneous apoptosis of B cells from umbilical cord blood with adult B cells and assessed the role of Bcl-2, CD5, interleukin (IL)-4 and B cell-activating factor in B cell spontaneous apoptosis. We found that spontaneous apoptosis of cultured B cells, as assessed by utilizing annexin-V binding, was significantly higher in cord blood than in healthy adult individuals (77·5; 95 CI, 73·5–81·5 versus 59·2; 95 CI, 54–64, respectively, P < 0·0001) and further confirmed by 4′ 6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining. Whereas the expression of B cell-activating factor from the tumour necrosis factor family (BAFF) receptor mRNA was similar in B cells from adults and cord blood, we detected lower levels of circulating BAFF in the serum of cord blood (0·68 ± 0·13 ng versus 1·83 ± 0·54 ng, P = 0·01). The latter may explain, in part, our observation of lower levels of mean fluorescence intensity of Bcl-2 in cord B cells compared with adults (1·6 ± 0·9 versus 2·85 ± 1·3, P = 0·033). CD19(+) CD5(+) B cells from cord blood underwent a lower rate of apoptosis in comparison to CD19(+) CD5(−) B cells (25·1 ± 9·3% versus 58·5 ± 12·5%, P < 0·0001). This pattern of sensitivity was comparable in adult blood (15 ± 5·5% versus 22·7 ± 9·3%, P = 0·01). Nevertheless, the rate of apoptosis was higher in CD19(+) CD5(+) from cord blood compared to CD19(+) CD5(+) from adults (25·1 ± 9·3% versus 15 ± 5·5%, P = 0·0013). The addition of rIL-4 (10 u/ml) to cultured cells decreased B cell apoptosis in a similar fashion in both cord and adults blood. This rescue was strengthened when BAFF (100 µg/ml) was further added. Thus, alterations in Bcl-2 or serum BAFF level may explain the increased rate of cord blood B cell apoptosis

Low expression of the interleukin (IL)-4 receptor alpha chain and reduced signalling via the IL-4 receptor complex in human neonatal B cells

Diminished neonatal antibody responses following infection or immunization may stem in part from intrinsic characteristics of neonatal B cells. In this study, we used B-cell subset sorting combined with gene expression assays to investigate major differences in the expression of host genes in neonatal and adult naïve B cells. We discovered significantly reduced expression of the interleukin (IL)-4 receptor alpha chain and reduced IL-4-induced signalling in neonatal B cells. Neonatal naïve B cells were susceptible to more rapid and more profound levels of apoptosis when cultured in vitro. They also exhibited a limited response to IL-4 treatment compared with adult cells. The expression level of the IL-13 receptor alpha 1 chain, a key component of the IL-13 receptor/IL-4 type II receptor, and the response to IL-13 treatment for protection against apoptosis in neonatal B cells were similar to those of the adult B cells. These studies suggest a possible mechanism underlying the limited magnitude and durability of neonatal antibody responses

Ethanol promotes T cell apoptosis through the mitochondrial pathway

Clinical reports suggest that acute ethanol intoxication is often associated with lymphopenia. Previously, ethanol was reported to invoke thymocyte apoptosis. We studied the effect of ethanol on T cell apoptosis. In addition, we evaluated the molecular mechanism of ethanol-induced T cell apoptosis. Human T cells harvested from healthy subjects after an alcohol drinking binge showed enhanced T cell apoptosis (before, 0·4 ± 0·2% versus after, 19·6 ± 2·5% apoptotic lymphocytes/field; P < 0·001). In in vitro studies, ethanol in a concentration of 50 mm and higher enhanced the apoptosis of Jurkat cells. DNA isolated from ethanol-treated Jurkat cells displayed integer multiples of 180 base pairs. Ethanol decreased Jurkat cell expression of Bcl-2, whereas ethanol increased Jurkat cell expression of Bax. Jurkat cells treated with ethanol also showed translocation of cytochrome C into cytosol. Moreover, a caspase-9 inhibitor partially inhibited ethanol-induced Jurkat cell apoptosis. In in vivo studies, after binge drinking, T cell expression of Bcl-2 also decreased. In addition, binge drinking induced the cleavage of caspase-3, suggesting activation of caspase-3 in T cells. These results suggest that ethanol promotes T cell apoptosis through the activation of intrinsic or mitochondrial pathway

Divide and conquer: the importance of cell division in regulating B-cell responses

Proliferation is an essential characteristic of clonal selection and is required for the expansion of antigen reactive clones leading to the development of antibody of different isotypes and memory cells. New data for mouse and human B cells point to an important role for division in regulating isotype class and in optimizing development of protective immunity by the regulated entry of cells to the plasma cell lineage

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

Breast cancer cells often show increased activity of the mitogen-activated protein kinase (MAPK) pathway. We report here that this pathway reduces their sensitivity to death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and present the underlying mechanism. Activation of protein kinase C (PKC) inhibited TRAIL-induced apoptosis in a protein synthesis-independent manner. Deliberate activation of MAPK was also inhibitory. In digitonin-permeabilized cells, PKC activation interfered with the capacity of recombinant truncated (t)Bid to release cytochrome c from mitochondria. MAPK activation did not affect TRAIL or tumor necrosis factor (TNF)alpha-induced Bid cleavage. However, it did inhibit translocation of (t)Bid to mitochondria as determined both by subcellular fractionation analysis and confocal microscopy. Steady state tBid mitochondrial localization was prohibited by activation of the MAPK pathway, also when the Bcl-2 homology domain 3 (BH3) domain of tBid was disrupted. We conclude that the MAPK pathway inhibits TRAIL-induced apoptosis in MCF-7 cells by prohibiting anchoring of tBid to the mitochondrial membrane. This anchoring is independent of its interaction with resident Bcl-2 family members