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Targeted disruption of death receptor (DR)6 results in enhanced CD4(+) T cell expansion and T helper cell type 2 differentiation after stimulation. Similar to T cells, DR6 is expressed on resting B cells but is down-regulated upon activation. We examined DR6(-/-) B cell responses both in vitro and in vivo. In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. This hyperproliferative response was due, at least in part, to both increased cell division and reduced cell apoptosis when compared with wild-type B cells. Consistent with these observations, increased nuclear levels and activity of nuclear factor kappaB transcription factor, c-Rel, and elevated Bcl-x(l) expression were observed in DR6(-/-) B cells upon stimulation. In addition, DR6(-/-) B cells exhibited higher surface levels of CD86 upon activation and were more effective as antigen-presenting cells in an allogeneic T cell proliferation response. DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells.

Immature B cells display increased sensitivity to tolerance induction compared with their mature counterparts. The molecular mechanisms underlying these differences are poorly defined. In this study, we demonstrate unique maturation stage-dependent differences in B cell Ag receptor (BCR) signaling, including BCR-mediated calcium mobilization responses. Immature B cells display greater increases in intracellular calcium concentrations following Ag stimulation. This has consequences for the induction of biologically relevant responses: immature B cells require lower Ag concentrations for activation than mature B cells, as measured by induction of receptor editing and CD86 expression, respectively. BCR-induced tyrosine phosphorylation of CD79a, Lyn, B cell linker protein, and phospholipase Cgamma2 is enhanced in immature B cells and they exhibit greater capacitative calcium entry in response to Ag. Moreover, B cell linker protein, Bruton's tyrosine kinase, and phospholipase Cgamma2, which are crucial for the induction of calcium mobilization responses, are present at approximately 3-fold higher levels in immature B cells, potentially contributing to increased mobilization of calcium. Consistent with this possibility, we found that the previously reported lack of inositol-1,4,5-triphosphate production in immature B cells may be explained by enhanced inositol-1,4,5-triphosphate breakdown. These data demonstrate that multiple mechanisms guarantee increased Ag-induced mobilization of calcium in immature B cells and presumably ensure elimination of autoreactive B cells from the repertoire.

Available evidence indicates that B cell tolerance is attained by receptor editing, anergy, or clonal deletion. Here, we describe a p-azophenylarsonate (Ars)-specific immunoglobulin transgenic mouse in which B cells become anergic as a consequence of cross-reaction with autoantigen in the bone marrow. Developing bone marrow B cells show no evidence of receptor editing but transiently upregulate activation markers and appear to undergo accelerated development. Mature B cells are present in normal numbers but are refractory to BCR-mediated induction of calcium mobilization, tyrosine phosphorylation, and antibody responses. Activation marker expression and acquisition of the anergic phenotype is prevented in bone marrow cultures by monovalent hapten. In this model, it appears that induction of anergy in B cells can be prevented by monovalent hapten competing with autoantigen for the binding site.

Objective: Although stressor uncontrollability has been shown to suppress immune responses in animals and for human subjects, the results have been inconsistent. We reanalyzed results of our previous study regarding stress-related immune deviation in man, to establish whether perceived uncontrollability of an acute stressor acts as a co-determinant in the observed changes in immunological parameters., Method: Three types of cognitive reactions to an acute interpersonal stressor were assessed: "motivation," "uncontrollability," and "guiltiness." Stress-induced changes in the number of several types of immune cells in peripheral blood and proliferative responses of lymphocytes to antigens and mitogens were assessed., Results: In comparison with control subjects and with subjects perceiving high control over the experimental stress situation, the subject perceiving low control showed a stressor-induced decrease in the number of T helper cells. Reversely, subjects perceiving high control showed an increase in the number of B cells as opposed to the other two groups. The effects of perceived uncontrollability could not be accounted for by mood changes, but they were related to previously experienced life stress., Conclusions: Perceived uncontrollability of an acute stressor can have immuno-modulating effects over and above those of the stressor per se.

This study investigated the effects of self-reported life stress and locus of control on reactivity of several immune parameters to a mild and short-lasting interpersonal stressor. Subjects were 86 male teachers aged 24 to 55 years. Immune reactivity was defined as changes in numbers of monocytes. T-lymphocytes and subsets, HLA-DR+ cells, and NK cells as well as changes in (in vitro) proliferative responses of peripheral blood lymphocytes to the antigens PHA and PWM. Multiple regression analysis was used to study the interaction effects of life stress and locus of control by experimental condition on immune reactivity. Life stress, but not locus of control, influences reactivity of the immunological parameters to the stressor. In particular, high numbers of daily hassles were associated with stressor-induced decreases in numbers of T cells and NK cells in peripheral blood. On the other hand, numbers of HLA-DR+ cells in high life stress scorers decreased only slightly during the stressor, whereas they increased in the control condition. The findings suggest that accumulated life stress is related to reactivity of immunological parameters to subsequent experimental stress. Possible physiological explanations and implications of these effects are discussed.

Fifty male subjects (aged 24 to 55 years) were subjected to a mild and potentially uncontrollable interpersonal stress situation. They were asked to solve a difficult puzzle. Subsequently they were requested to explain their solution to "another subject," actually a confederate to the researchers. The confederate frustrated the subjects' explanation efforts. Care was taken that neither solving nor explaining of the puzzle was successful. The experimental situation induced mild psychological strain as documented by mood changes in the experimental group when compared with a control group of 36 male subjects. Peripheral blood was drawn by an indwelling catheter just before, directly after, 15 minutes after, and 30 minutes after the stress situation. Numbers of leukocytes, lymphocytes, monocytes, T-cell subsets, natural killer (NK) cells, and B-cells were determined. As functional assays we used in vitro proliferative responses of T- and B-cells to mitogenic stimulation (PHA and PWM) and to an antigen cocktail. The potential influences of health- and biobehavioral variables were taken into account in the analyses, as well as incidental differences in initial mood or immunological baseline. The results replicated and expanded on previous research. In contrast to controls, experimental subjects showed a significant increase in numbers of NK cells after the stress-period, returning to baseline values after 15 minutes of rest. A similar effect was shown on T-suppressor/cytotoxic cells and, inversely, on T-helper/suppressor ratio, but these effects could be attributed to changes in the numbers of CD8+CD57+ cells. No effects were observed on proliferation. From the results we conclude that the effects of a short lasting mild psychological stressor are mainly restricted to cells of the NK cell population.