Smoking history, and not depression, is related to deficits in detection of happy and sad faces.

INTRODUCTION: Previous research has demonstrated that chronic cigarette smoking and major depressive disorder (MDD) are each associated with cognitive decrements. Further, these conditions co-occur commonly, though mechanisms in the comorbid condition are poorly understood. There may be distinct, additive, or overlapping factors underlying comorbid cigarette smoking and MDD. The present study investigated the impact of smoking and MDD on executive function and emotion processing. METHODS: Participants (N=198) were grouped by diagnostic category (MDD and healthy controls, HC) and smoking status (ever-smokers, ES and never-smokers, NS). Participants completed the Facial Emotion Perception Test (FEPT), a measure of emotional processing, and the parametric Go/No-go task (PGNG), a measure of executive function. RESULTS: FEPT performance was analyzed using ANCOVA with accuracy and reaction time as separate dependent variables. Repeated measures MANCOVA was conducted for PGNG with performance measure and task level as dependent variables. Analyses for each task included diagnostic and smoking group as independent variables, and gender was controlled for. Results for FEPT reveal that lower overall accuracy was found for ES relative to NS, though MDD did not differ from HC. Post-hoc analyses revealed that ES were poorer at identifying happy and sad, but not fearful or angry, faces. For PGNG, poorer performance was observed in MDD relative to HC in response time to Go targets, but there were no differences for ES and NS. Interaction of diagnosis and smoking group was not observed for performance on either task. CONCLUSIONS: The results of this study provide preliminary evidence for distinctive cognitive decrements in smokers and individuals with depression.

Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts.

Although the recruitment of fibroblasts to areas of injury is critical for wound healing, their subsequent apoptosis is necessary in order to prevent excessive scarring. Fibroproliferative diseases, such as pulmonary fibrosis, are often characterized by fibroblast resistance to apoptosis, but the mechanism(s) for this resistance remains elusive. Here, we employed a murine model of pulmonary fibrosis and cells from patients with idiopathic pulmonary fibrosis (IPF) to explore epigenetic mechanisms that may be responsible for the decreased expression of Fas, a cell surface death receptor whose expression has been observed to be decreased in pulmonary fibrosis. Murine pulmonary fibrosis was elicited by intratracheal injection of bleomycin. Fibroblasts cultured from bleomycin-treated mice exhibited decreased Fas expression and resistance to Fas-mediated apoptosis compared with cells from saline-treated control mice. Although there were no differences in DNA methylation, the Fas promoter in fibroblasts from bleomycin-treated mice exhibited decreased histone acetylation and increased histone 3 lysine 9 trimethylation (H3K9Me3). This was associated with increased histone deacetylase (HDAC)-2 and HDAC4 expression. Treatment with HDAC inhibitors increased Fas expression and restored susceptibility to Fas-mediated apoptosis. Fibroblasts from patients with IPF likewise exhibited decreased histone acetylation and increased H3K9Me3 at the Fas promoter and increased their expression of Fas in the presence of an HDAC inhibitor. These findings demonstrate the critical role of histone modifications in the development of fibroblast resistance to apoptosis in both a murine model and in patients with pulmonary fibrosis and suggest novel approaches to therapy for progressive fibroproliferative disorders.

Antipneumococcal effects of C-reactive protein and monoclonal antibodies to pneumococcal cell wall and capsular antigens.

Antibodies to pneumococcal capsular polysaccharides are well known for their ability to protect against pneumococcal infection. Recent studies indicate that antibodies to cell wall antigens, including pneumococcal surface protein A and the phosphocholine (PC) determinant of teichoic acids as well as human C-reactive protein (which also binds to PC), can protect mice against pneumococcal infection. In the present study we compared the protective effects of these agents as measured by mouse protection, the blood bactericidal assay, and clearance of pneumococci from the blood and peritoneal cavity. Our findings extend previous results indicating that human C-reactive protein and antibodies to noncapsular antigens are generally less protective than anticapsular antibodies. The new results obtained indicate the following: (i) mouse protection studies with intraperitoneal and intravenous infections provide very similar results; (ii) monoclonal immunoglobulin G2a (IgG2a) antibodies to PC, like IgG1, IgG2b, and IgG3 antibodies to PC, are highly protective against pneumococcal infection in mice; (iii) human antibody to PC is able to protect against pneumococcal infection in mice; (iv) antibodies to PspA are effective at mediating blood and peritoneal clearance of pneumococci; (v) complement is required for the in vivo protective effects of both IgG and IgM antibodies to PC; (vi) IgG1, IgG2b, and IgG3 anti-PC antibodies all mediate complement-dependent lysis of PC-conjugated erythrocytes; and (vii) antibodies and human C-reactive proteins that are reactive with capsular antigens but not cell wall antigens are able to mediate significant antibacterial activity in the blood bactericidal assay.

B7, a B-cell-restricted antigen that identifies preactivated B cells.

After activation with antigen or mitogen, a number of cell surface proteins appear that are not expressed on resting B cells. To date, a number of B lineage restricted and associated activation antigens have been reported that appear at distinct intervals after in vitro activation. In this report, we describe a new B lineage restricted activation antigen (B7) that appears within 24 hr of in vitro stimulation. The expression of B7 antigen, which is detected on a minor subpopulation of B cells isolated from peripheral blood and lymphoid tissues, is strongly induced following stimulation with either anti-immunoglobulin or Epstein-Barr virus. In contrast, B7 was not detected on resting or activated T cells or monocytes. The B7 antigen was expressed on a subset of B cell lines and B cell neoplasms, but was not detected on leukemias and lymphomas of T cell or myeloid origin. B7 was distinguished from other B cell restricted and associated activation antigens by its unique pattern of expression on a variety of hemopoietic cell lines. The biochemical characterization of B7, that it is a single chain protein of 60 kDa, further distinguishes it from other B cell activation antigens. The functional importance of the B7 antigen was demonstrated when splenic B cells were fractionated into the B7+ and B7- populations. The peak of proliferation in response to anti-Ig, appeared earlier within the B7+ population. These studies suggest that B7 antigen identifies a subpopulation of B cells that are preactivated or primed in vivo, and have an accelerated response to subsequent activation via cross-linking of surface Ig.

Normal cellular counterparts of B cell chronic lymphocytic leukemia.

In an attempt to compare B cell chronic lymphocytic leukemia (B-CLL) with its normal cellular counterpart, the cell surface phenotype of 100 cases of B-CLL was determined by using a panel of monoclonal antibodies (MoAbs) directed against B cell-restricted and -associated antigens. The majority of B-CLL cells expressed Ia, B4 (CD19), B1 (CD20), B2 (CD21), surface immunoglobulin (sIg), and T1 (CD5) but lacked C3b (CD35) receptors. In contrast, the overwhelming majority of small unstimulated B cells expressed Ia, B4, B1, B2, sIg, and C3b receptors but lacked detectable T1. Small numbers of weakly sIg+ cells could be identified in peripheral blood and tonsil that coexpressed the B1 and T1 antigens. Approximately 16% of fetal splenocytes coexpressed B1, T1, weak sIg, B2, and Ia but lacked C3b receptors and therefore closely resembled most B-CLL cells. With the phenotypic differences between the majority of small unstimulated B cells and B-CLL cells, we examined normal in vitro activated B cells and B-CLL cells for the expression of B cell-restricted and -associated activation antigens. Of 20 cases examined, virtually all expressed B5, and approximately 50% of the cases expressed interleukin-2 receptors (IL-2R) and Blast-1. Normal B cells were activated with either anti-Ig or 12-0-tetradecanoylphorbol-beta-acetate (TPA) and then were examined for coexpression of B1, T1, and the B cell activation antigens B5 and IL-2R. Only cells activated with TPA coexpressed B1 and T1 as well as B5 and IL-2R. B cells activated with either anti-Ig or TPA proliferated in the presence of IL-2, whereas B-CLL cells did not, although they all expressed the identical 60-kilodalton proteins by immunoprecipitation. These studies are consistent with the notion that B-CLL resembles several minor subpopulations of normal B cells including a population of B cells that are activated in vitro directly through the protein kinase C pathway.

Expression of B cell activation antigens on normal and malignant B cells.

In an attempt to relate the functional events of B cell activation with changes in cell surface molecules, we have used a panel of monoclonal antibodies directed against cell surface antigens expressed on activated but not resting B cells, to determine a sequence of activation antigen expression following anti-immunoglobulin stimulation. Within the first 24 hr of culture with anti-Ig, resting splenic B cells were induced to express B5 and interleukin-2 receptor (IL-2R) and subsequently express T9 and BB1 by 48 hr. Maximum antigen expression was seen by day 3 with the majority of cells expressing B5, IL-2R, T9, and BB1, and fewer numbers of cells expressing Blast-1 and Blast-2. By day 6, the expression of these antigens significantly decreased. Dual fluorochrome staining of anti-Ig activated B cells demonstrated heterogeneity of activation antigen expression, suggesting the existence of subpopulations of activated B cells. In an attempt to relate the non-Hodgkin's lymphomas (NHLs) to this sequence of activation, 69 tumor samples from patients with B cell NHLs were then examined for expression of these activation antigens. Histologically defined subgroups of B cell NHLs demonstrated differential expression of activation antigens with B5, BB1, and T9 exhibiting the widest distribution, whereas IL-2R, Blast-1, and Blast-2 demonstrated more limited expression. The finding that no B cell malignancy phenotypically resembles the small resting B lymphocyte coupled with the observation that virtually all B cell NHLs examined expressed activation antigens suggests that these tumors may be the neoplastic counterparts of subpopulations of activated B lymphocytes.

Studies of the in vitro activation and differentiation of human B lymphocytes. II. Optimization of activation by anti-immunoglobulin antibody bound to beads: analysis of the role of autocrine effects on B-cell proliferation and of T-cell help in B-cell differentiation.

We report experiments attempting to optimize the proliferative response of human B cells to rabbit anti-immunoglobulin antibody (RAHIg)-linked beads (anti-Ig beads). By choosing polyacrylamide beads of small size (3 micron) and coupling anti-Ig to them at high concentrations, beads were obtained which were both B-cell specific and more highly mitogenic than other than anti-Ig reagents and B-cell mitogens (SAC, protein A). Using these beads to activate B cells, the augmentation of the anti-Ig-induced proliferative response by added T-cell-derived growth factors was largely eliminated at high cell densities although the effect of these factors was still evident at low cell densities. However, when cultures were performed in round-bottom vessels which crowded the B cells together, the response to anti-Ig beads was independent of T-cell factors even at low B-cell densities, suggesting that normal B cells triggered by anti-Ig beads are able to maintain their own proliferation. In contrast to the proliferative response, even with the most potent anti-Ig bead preparations, no differentiation (Ig production or expression of terminal differentiation markers) was evident unless T-cell help was provided.