Elderly humans have compromised humoral and cellular immune responses, which lead to reduced protection to infectious agents and to vaccines. Currently, available vaccines suboptimally protect the elderly population. The capacity to class switch the Ig H chain is critical to the effectiveness of humoral immune responses in mice and humans. We have previously shown in mice that the E2A-encoded transcription factor E47, which regulates many B cell functions, is down-regulated in old splenic B cells. This leads to a reduction in the activation-induced cytidine deaminase (AID), which is known to induce class switch recombination and Ig somatic hypermutation. The old activated murine B cells also have less AID and less switched Abs. We have extended our study here to investigate whether aging also affects Ab production and E47 and AID expression in B cells isolated from the peripheral blood of human subjects (18–86 years). Our results obtained with activated CD19+ B cells show that the expression of E47, AID, and Igγ1 circle transcripts progressively decrease with age. We also show an age-related decline in the percentage of switch memory B cells (IgG+/IgA+), an increase in that of naive B cells (IgG−/IgA−/CD27−) for most individuals, and no decrease in that of IgM memory cells in peripheral blood, consistent with our data on the decrease seen in class switch recombination in vitro. Our results provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging and suggest avenues for improvement of vaccine response in elderly humans.

Objective To evaluate the effects of obesity-associated inflammation on influenza vaccine responses. Methods We measured in young and elderly individuals, both lean and with obesity, antibody responses to influenza vaccination. Results We found a decrease in in vivo vaccine responses, circulating switched memory and transitional B cells and an increase in pro-inflammatory late/exhausted memory B cells. In vitro B cell function was measured by activation-induced cytidine deaminase (AID) and E47, markers of optimal antibody responses. Moreover, IL-6 production was increased, whereas IL-10 production was decreased, in cultures of B cells from individuals with obesity. Markers of immune activation (TNF-α, TLR4, micro-RNAs) in unstimulated B cells were also found increased and were negatively correlated with B cell function. In order to reveal potential mechanisms, we stimulated B cells from lean individuals in vitro with leptin, the adipokine increased in obesity. Leptin increased phospho-STAT3, crucial for TNF-α production, and decreased phospho-AMPK, the energy sensing enzyme upstream of phospho-p38 MAPK and E47. Leptin-induced phospho-STAT3 and phospho-AMPK levels were similar to those in B cells from individuals with obesity. Conclusions These results demonstrate that leptin can be responsible for decreased B cell function in obesity.

This study examined patients' perceptions that having cancer led to positive life changes, or benefit-finding (BF), e.g. improved relationships, enhanced appreciation of life, increased resilience and self-reliance. We investigated the relations between BF, sociodemographic (e.g. gender, age, marital status, education, income) and disease-related variables (e.g. severity of disease or cancer stage, time since diagnosis). The sample was comprised of 83 men and women with various types of cancer, and all 4 stages of disease were represented. Participants were most likely to be Caucasian (90%), married (66%) and well-educated (68% partial college/specialized training). Of the demographic variables investigated, younger age was associated with greater BF scores. As hypothesized, BF also differed by stage of disease in a curvilinear fashion. Individuals with stage II disease had significantly higher BF scores than those with Stage IV or Stage I cancer. Time since diagnosis and treatment status (i.e. currently in treatment, completed treatment, no treatment) were not related to BF. Findings suggest that stage of disease is an important factor to consider when investigating positive perceptions of disease in individuals with cancer.

Background Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the causal direction of that relationship has not been established. This study tested whether a Cognitive-Behavioral Stress Management (CBSM) intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a major medical threat. Methods 199 women undergoing primary treatment of Stage 0–III breast cancer were randomized to a 10-week CBSM protocol or an active control condition. 79 provided peripheral blood leukocyte samples for genome-wide transcriptional profiling and bioinformatic analyses at baseline, 6-, and 12-month follow-ups. Results Baseline negative affect was associated with > 50% differential expression of 201 leukocyte transcripts, including up-regulated expression of pro-inflammatory and metastasis-related genes. CBSM altered leukocyte expression of 91 genes by > 50% at follow-up (Group × Time interaction), including down-regulation of pro-inflammatory and metastasis-related genes and up-regulation of Type I interferon response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-κB/Rel and GATA family transcription factors and increased activity of Interferon Response Factors and the Glucocorticoid Receptor (GR) as potential mediators of CBSM-induced transcriptional alterations. Conclusions In early stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related up-regulation of pro-inflammatory gene expression in circulating leukocytes. These findings clarify the molecular signaling pathways by which behavioral interventions can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive processes.