B Cell Immunosenescence.

Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.

Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures.

Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza.

Age-related factors that affect B cell responses to vaccination in mice and humans.

Aging significantly changes the ability to respond to vaccinations and infections. In this review, we summarize published results on age-related changes in response to infection with the influenza virus and on the factors known to increase influenza risk infection leading to organ failure and death. We also summarize how aging affects the response to the influenza vaccine with a special focus on B cells, which have been shown to be less responsive in the elderly. We show the cellular and molecular mechanisms contributing to the dysfunctional immune response of the elderly to the vaccine against influenza. These include a defective interaction of helper T cells (CD4+) with B cells in germinal centers, changes in the microenvironment, and the generation of immune cells with a senescence-associated phenotype. Finally, we discuss the effects of aging on metabolic pathways and we show how metabolic complications associated with aging lead to immune dysfunction.

Effects of neighborhood disadvantage on cortisol and interviewer-rated anxiety symptoms in breast cancer patients initiating treatment.

PURPOSE: Shorter breast cancer (BC) survival outcomes persist by neighborhood disadvantage independent of patient, tumor, and treatment characteristics. This suggests unaccounted mechanisms by which neighborhood disadvantage "gets under the skin" to impact BC survival outcomes. Here, we evaluate the relationship between neighborhood disadvantage and clinical and neuroendocrine markers of stress in BC patients. METHODS: Women with stage 0-III BC were enrolled 2-10 weeks post-surgery and before initiating adjuvant treatment in a study examining stress and stress management processes. Women provided an afternoon-evening (PM) serum cortisol sample and were administered the Hamilton Anxiety Rating Scale (HAM-A). Home addresses were used to determine the Area Deprivation Index (ADI), a validated measure of neighborhood disadvantage. Multiple regression assessed the relationship between ADI and PM serum cortisol and the presence of elevated HAM-A symptoms. RESULTS: Our sample (n = 225) was predominately middle-aged (M = 50.4 years; range 23-70 years), non-Hispanic White (64.3%), with stage I (38.1%), or II (38.6%) disease. The majority (n = 175) lived in advantaged neighborhoods (ADI 1-3). After controlling for age, stage, and surgery type, women from high ADI (4-10) (vs low ADI) neighborhoods had higher PM cortisol levels (ß = 0.19, 95% CI [0.24, 5.00], p = 0.031) and were nearly two times as likely to report the presence of elevated anxiety symptoms (OR = 1.96, 95% CI [1.00, 3.86], p = 0.050). CONCLUSION: Neighborhood disadvantage is significantly associated with higher levels of PM cortisol and elevated anxiety symptoms suggesting stress pathways could potentially contribute to relationships between neighborhood disadvantage and BC survival.

Predictors of initial engagement with an asynchronous cognitive behavioral stress management website among older women with nonmetastatic breast cancer.

PURPOSE: Digital interventions, like websites, offer greater access to psychosocial treatments; however, engagement is often suboptimal. Initial use may be a target to "hook" participants. Few studies examine engagement with cognitive behavioral stress management (CBSM). We tested predictors of engagement in the first week of using a CBSM website among women with breast cancer (BC). METHODS: Older women (≥ 50 years) with nonmetastatic BC enrolled in an on-going trial (8/2016-4/2022, #NCT03955991) and were randomized to receive 10 synchronous, virtual CBSM group sessions immediately (n = 41) or after a 6-month waitlist (n = 34). All received simultaneous access to an asynchronous website, where supplemental videos and resources were released weekly. Engagement was tracked via breadth (features used) and depth (clicks within content). Multilevel modeling tested predictors of engagement (i.e., time, condition, age, daily stress, depression, race, ethnicity, disease stage). RESULTS: Breadth decreased over the first week of CBSM (b = -0.93, p < .01), and women with more advanced stage disease engaged with more breadth (b = 0.52, p < .01) and depth (b = 14.06, p < .01) than women with earlier stage disease. Non-Hispanic (b = -0.59, p = .03) and White (b = -0.97, p < .01) women engaged with more features. Cancer stage and intervention timing interacted. Women with more advanced cancer stage who received CBSM later engaged with the most depth (b = -11.73, p = .04). All other characteristics did not predict engagement. CONCLUSIONS: Disease stage, race, ethnicity, and intervention timing predicted engagement with a CBSM website in older BC patients. IMPLICATIONS FOR CANCER SURVIVORS: Delivering CBSM later in cancer treatment may mitigate competing demands. Fostering greater engagement in racial/ethnic minorities is needed.

Obesity accelerates age defects in B cells, and weight loss improves B cell function.

BACKGROUND: We have previously shown that obesity accelerates age-associated defects in B cell function and antibody production leading to decreased secretion of protective antibodies and increased autoimmunity. We wanted to evaluate if obese adults enrolled in a voluntary weight reduction program had higher protective and lower autoimmune antibody responses similar to those observed in lean adults. METHODS: Experiments were performed using blood isolated from an established cohort of female lean adult and elderly individuals, as well as from the blood of female adults with obesity, before and after a voluntary weight reduction program in which their Body Mass Index (BMI) was reduced 10-34% in 12 months. All participants were vaccinated with the Trivalent Inactivated Influenza vaccine. Serum samples were evaluated for the presence of pro-inflammatory cytokines and adipokines, vaccine-specific antibodies and autoimmune antibodies. We evaluated the composition of the B cell pool by flow cytometry, the expression of RNA for class switch transcription factors and pro-inflammatory markers by qPCR, the in vitro secretion of pro- and anti-inflammatory cytokines and their capacity to induce pro-inflammatory T cells. RESULTS: Obesity, similar to aging, induced increased serum levels of pro-inflammatory cytokines and autoimmune antibodies, while vaccine-specific antibodies were reduced. In agreement with the serum results, the B cell pool of obese adults and elderly individuals was enriched in pro-inflammatory B cell subsets and was characterized by higher expression of markers associated with cell senescence, higher levels of T-bet, the transcription factor for autoimmune antibodies and lower levels of E47, the transcription factor associated with protective responses to the influenza vaccine. B cells from obese adults and elderly individuals were also able to secrete inflammatory cytokines and support the generation of inflammatory T cells. All these pro-inflammatory characteristics of B cells from obese individuals were significantly attenuated, but not completely reversed, by weight loss. CONCLUSIONS: Although the results from our small observational study show that obesity-induced dysfunctional B cell responses, similar to those occurring during aging, are ameliorated in some but not all obese individuals after weight loss, the effects of body weight loss on mechanistic pathways are largely missing and deserve further investigation.

The majority of SARS-CoV-2-specific antibodies in COVID-19 patients with obesity are autoimmune and not neutralizing.

BACKGROUND/OBJECTIVES: Obesity decreases the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. How obesity impacts the quality of the antibodies secreted, however, is not understood. Therefore, the objective of this study is to evaluate the presence of neutralizing versus autoimmune antibodies in COVID-19 patients with obesity. SUBJECTS/METHODS: Thirty serum samples from individuals who tested positive for SARS-CoV-2 infection by RT-PCR were collected from inpatient and outpatient settings. Of these, 15 were lean (BMI < 25) and 15 were obese (BMI ≥ 30). Control serum samples were from 30 uninfected individuals, age-, gender-, and BMI-matched, recruited before the current pandemic. Neutralizing and autoimmune antibodies were measured by ELISA. IgG autoimmune antibodies were specific for malondialdehyde (MDA), a marker of oxidative stress and lipid peroxidation, and for adipocyte-derived protein antigens (AD), markers of virus-induced cell death in the obese adipose tissue. RESULTS: SARS-CoV-2 infection induces neutralizing antibodies in all lean but only in few obese COVID-19 patients. SARS-CoV-2 infection also induces anti-MDA and anti-AD autoimmune antibodies more in lean than in obese patients as compared to uninfected controls. Serum levels of these autoimmune antibodies, however, are always higher in obese versus lean COVID-19 patients. Moreover, because the autoimmune antibodies found in serum samples of COVID-19 patients have been correlated with serum levels of C-reactive protein (CRP), a general marker of inflammation, we also evaluated the association of anti-MDA and anti-AD antibodies with serum CRP and found a positive association between CRP and autoimmune antibodies. CONCLUSIONS: Our results highlight the importance of evaluating the quality of the antibody response in COVID-19 patients with obesity, particularly the presence of autoimmune antibodies, and identify biomarkers of self-tolerance breakdown. This is crucial to protect this vulnerable population at higher risk of responding poorly to infection with SARS-CoV-2 than lean controls.

Relationships Between Serum Cortisol, RAGE-Associated s100A8/A9 Levels, and Self-Reported Cancer-Related Distress in Women With Nonmetastatic Breast Cancer.

OBJECTIVE: Elevated inflammation and psychological distress in patients with breast cancer (BCa) have been related to poorer health outcomes. Regulation of the hypothalamic-pituitary-adrenal axis and signaling of the receptor for advanced glycation end products (RAGE) are important in the inflammatory response and have been associated with increased stress and poorer health outcomes in patients with cancer. This study examined relationships among circulating cortisol, a measure of hypothalamic-pituitary-adrenal axis activity and physiological stress; s100A8/A9, a RAGE ligand and emerging cancer-related biological measure; and self-reported cancer-related distress. METHODS: Patients with BCa ( N = 183, stages 0-IIIb) were recruited 2 to 10 weeks after surgery but before receiving adjuvant therapies. Participants provided blood samples, from which serum cortisol and s100A8/A9 levels were determined, and completed a psychosocial questionnaire. Regression analyses, adjusting for age, cancer stage, time since surgery, race, and menopausal status, were conducted examining the relationships between cortisol, s100A8/A9, and cancer-related distress (Impact of Event Scale [IES]-Revised). RESULTS: Cortisol and s100A8/A9 levels were positively related ( ß = 0.218, t (112) = 2.332, p = .021), although the overall model was not significant. Cortisol levels were also positively associated with IES-Intrusions ( ß = 0.192, t (163) = 2.659, p = .009) and IES-Hyperarousal subscale scores ( ß = 0.171, t (163) = 2.304, p = .022). CONCLUSIONS: Patients with higher cortisol levels also reported higher s100A8/A9 levels and more cancer-related distress. The relationship between cortisol and s100A8/A9 supports a link between the stress response and proinflammatory physiological processes known to predict a greater metastatic risk in BCa. Stress processes implicated in cancer biology are complex, and replication and extension of these initial findings are important.

Hyper-metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities.

BACKGROUND: Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. METHODS: Splenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer. RESULTS: Results have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion. CONCLUSIONS: These results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.

B Cells with a Senescent-Associated Secretory Phenotype Accumulate in the Adipose Tissue of Individuals with Obesity.

Senescent cells accumulate in the adipose tissue (AT) of individuals with obesity and secrete multiple factors that constitute the senescence-associated secretory phenotype (SASP). This paper aimed at the identification of B cells with a SASP phenotype in the AT, as compared to the peripheral blood, of individuals with obesity. Our results show increased expression of SASP markers in AT versus blood B cells, a phenotype associated with a hyper-metabolic profile necessary to support the increased immune activation of AT-derived B cells as compared to blood-derived B cells. This hyper-metabolic profile is needed for the secretion of the pro-inflammatory mediators (cytokines, chemokines, micro-RNAs) that fuel local and systemic inflammation.

Leptin induces immunosenescence in human B cells.

Leptin is an adipokine secreted primarily by the adipocytes. Leptin has endocrine and immune functions and increases the secretion of pro-inflammatory cytokines by immune cells. Here we show that incubation of B cells from young lean individuals with leptin increases the frequencies of pro-inflammatory B cells and induces intrinsic B cell inflammation, characterized by mRNA expression of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (IL-8), micro-RNAs (miR-155 and miR-16), TLR4 and p16, a cell cycle regulator associated with immunosenescence. We have previously shown that the expression of these pro-inflammatory markers in unstimulated B cells is negatively associated with the response of the same B cells after in vivo or in vitro stimulation. B cells from young lean individuals, after in vitro incubation with leptin, show reduced class switch and influenza vaccine-specific IgG production. Our results altogether show that leptin makes B cells from youn lean individuals similar to those from young obese and elderly lean individuals, suggesting that leptin may be a mechanisms of immunosenescence in human B cells.

Adipose Tissue: A Tertiary Lymphoid Organ: Does It Change with Age?

In this manuscript, we summarize published results showing that obesity and aging are inflammatory conditions associated with serious health problems, increased risk for disease and death. We show that fat mass increases with age and represents a major contributor to insulin resistance and the metabolic syndrome. We summarize the effects of age on the adipose tissue (AT), related to the abundance, distribution, cellular composition, endocrine signaling and function of the tissue. The AT is an immunological tissue, with several hallmarks of innate and adaptive immune responses. We show that in both mice and humans, the AT is heavily infiltrated by immune cells that have receptors for pro-inflammatory cytokines and chemokines secreted by the adipocytes and also by the immune cells that have infiltrated the AT. We also show that the AT provides an environment for the secretion of IgG antibodies with anti-self (autoimmune) reactivity. As we have previously shown, this is due to the release of self antigens following cell death due to hypoxia, as well as to the expression of activation-induced cytidine deaminase, the enzyme of class switch recombination, and the transcription factor T-bet by the resident B cells, which also express the membrane marker CD11c, both involved in the production of autoimmune IgG antibodies. We show data in support of the AT as a tertiary lymphoid organ (TLO), showing the examples of TLOs that develop within the AT, such as fat-associated lymphoid clusters and milky spots, as well as artery TLOs that develop in the adventitia areas of the aorta.

Aging induces B cell defects and decreased antibody responses to influenza infection and vaccination.

BACKGROUND: Aging is characterized by a progressive decline in the capacity of the immune system to fight influenza virus infection and to respond to vaccination. Among the several factors involved, in addition to increased frailty and high-risk conditions, the age-associated decrease in cellular and humoral immune responses plays a relevant role. This is in large part due to inflammaging, the chronic low-grade inflammatory status of the elderly, associated with intrinsic inflammation of the immune cells and decreased immune function. RESULTS: Aging is usually associated with reduced influenza virus-specific and influenza vaccine-specific antibody responses but some elderly individuals with higher pre-exposure antibody titers, due to a previous infection or vaccination, have less probability to get infected. Examples of this exception are the elderly individuals infected during the 2009 pandemic season who made antibodies with broader epitope recognition and higher avidity than those made by younger individuals. Several studies have allowed the identification of B cell intrinsic defects accounting for sub-optimal antibody responses of elderly individuals. These defects include 1) reduced class switch recombination, responsible for the generation of a secondary response of class switched antibodies, 2) reduced de novo somatic hypermutation of the antibody variable region, 3) reduced binding and neutralization capacity, as well as binding specificity, of the secreted antibodies, 4) increased epigenetic modifications that are associated with lower antibody responses, 5) increased frequencies of inflammatory B cell subsets, and 6) shorter telomeres. CONCLUSIONS: Although influenza vaccination represents the most effective way to prevent influenza infection, vaccines with greater immunogenicity are needed to improve the response of elderly individuals. Recent advances in technology have made possible a broad approach to better understand the age-associated changes in immune cells, needed to design tailored vaccines and effective therapeutic strategies that will be able to improve the immune response of vulnerable individuals.

The effects of a randomized trial of brief forms of stress management on RAGE-associated S100A8/A9 in patients with breast cancer undergoing primary treatment.

BACKGROUND: Women with breast cancer (BCa) experience heightened distress, which is related to greater inflammation and poorer outcomes. The s100 protein family facilitates the inflammatory response by regulating myeloid cell function through the binding of Toll-like receptor 4 and the receptor for advanced glycation end products (RAGE). The heterodimer s100A8/A9 RAGE ligand is associated with hastened tumor development and metastasis. Previously, a 10-week stress-management intervention using cognitive behavioral therapy (CBT) and relaxation training (RT) was associated with less leukocyte inflammatory gene expression in patients with BCa; however, its impact on s100A8/A9 was not examined. Because a 10-week intervention may be impractical during primary treatment for BCa, the authors developed briefer forms of CBT and RT and demonstrated their efficacy in reducing distress over 12 months of primary treatment. Here, the effects of these briefer interventions were tested effects on s100A8/A9 levels over the initial 12 months of BCa treatment. METHODS: Postsurgical patients with BCa (stage 0-IIIB) were randomized to a 5-week, group-based condition: CBT, RT, or health education control (HE). At baseline and at 12 months, women provided sera from which s100A8/A9 levels were determined using any enzyme-linked immunosorbent assay. RESULTS: Participants (mean age ± standard deviation, 54.81 ± 9.63 years) who were assigned to either CBT (n = 41) or RT (n = 38) had significant s100A8/A9 decreases over 12 months compared with those who were assigned to HE (n = 44; F[1,114]  = 4.500; P = .036) controlling for age, stage, time since surgery, and receipt of chemotherapy or radiation. Greater increases in stress-management skills from preintervention to postintervention predicted greater reductions in s100A8/A9 levels over 12 months (ß = -0.379; t[101]  = -4.056; P < .001). CONCLUSIONS: Brief, postsurgical, group-based stress management reduces RAGE-associated s100A8/A9 ligand levels during primary treatment for BCa.

Social well-being is associated with less pro-inflammatory and pro-metastatic leukocyte gene expression in women after surgery for breast cancer.

PURPOSE: Satisfaction with social resources, or "social well-being," relates to better adaptation and longer survival after breast cancer diagnosis. Biobehavioral mechanisms linking social well-being (SWB) to mental and physical health may involve inflammatory signaling. We tested whether reports of greater SWB were associated with lower levels of pro-inflammatory and pro-metastatic leukocyte gene expression after surgery for non-metastatic breast cancer. METHODS: Women (N = 50) diagnosed with non-metastatic (0-III) breast cancer were enrolled 2-8 weeks after surgery. SWB was assessed with the social/family well-being subscale of the FACT-B. Leukocyte gene expression for specific pro-inflammatory (cytokines, chemokines, and COX-2) and pro-metastatic genes (e.g., MMP9) was derived from microarray analysis. RESULTS: Multiple regression analyses controlling for age, stage of disease, days since surgery, education, and body mass index (BMI) found higher levels of SWB related to less leukocyte pro-inflammatory and pro-metastatic gene expression (p < 0.05). Emotional well-being, physical well-being, and functional well-being did not relate to leukocyte gene expression (p > 0.05). Greater SWB remained significantly associated with less leukocyte pro-inflammatory and pro-metastatic gene expression after controlling for depressive symptoms. CONCLUSIONS: Results have implications for understanding mechanisms linking social resources to health-relevant biological processes in breast cancer patients undergoing primary treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT01422551.

Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age.

With old age (∼2y old), mice show substantial differences in B cell composition within the lymphoid tissues. In particular, a novel subset of IgM+ CD21/35lo/- CD23- mature B cells, the age-associated B cells or ABC, increases numerically and proportionately. This occurs at the expense of other B cell subsets, including B2 follicular B cells in spleen and recirculating primary B cells in bone marrow. Our studies suggest that ABC have a distinctive antibody repertoire, as evidenced by relatively high reactivity to the self-antigens phosphorylcholine (PC) and malondialdehyde (MDA). While PC and MDA are found on apoptotic cells and oxidized lipoproteins, antibodies to these antigens are also cross-reactive with epitopes on bacterial species. In old mice, ABC express TNFα and are pro-inflammatory. ABC can inhibit growth and/or survival in pro-B cells as well as common lymphoid progenitors (CLP). In particular, ABC cause apoptosis in pro-B cells with relatively high levels of the surrogate light chain (SLC) and, consequently, promote an "SLC low" pathway of B cell differentiation in old mice. SLC together with µ heavy chain comprises the pre-B cell receptor (preBCR) critical for pre-B cell expansion and selection of the µ heavy chain Vh repertoire. The low level of SLC likely impairs normal preBCR driven proliferation and alters µ heavy chain Vh selection thereby affecting the antibody specificities of new B cells. In this manner, ABC may contribute to both qualitative and quantitative disruptions of normal B lymphopoiesis in old age.

Aging effects on T-bet expression in human B cell subsets.

In order to compare human and mouse B cell subset markers, we evaluated T-bet expression in human B cell subsets from individuals of different ages. We found T-bet expressed in unstimulated memory more than naïve B cells, and more in young individuals. TLR7 stimulation up-regulated T-bet in all B cell subsets from young and elderly individuals, and more in the elderly. By fold-increase the best effect was seen in subsets of the elderly and especially in those that undergo class switch (naïve and IgM). We also evaluated CD11c expression, as T-bet+CD11c+ B cells are expanded in healthy elderly individuals and also in patients with autoimmunity. Similar to T-bet, CD11c expression was higher in memory than in naïve B cells, but no differences were observed between young and elderly individuals. After TLR7 stimulation, CD11c increases in all B cell subsets (especially in naïve and IgM) from the elderly.

B Cell-Specific Biomarkers for Optimal Antibody Responses to Influenza Vaccination and Molecular Pathways That Reduce B Cell Function with Aging.

This review highlights recent findings on the effects of aging on influenza vaccine responses, with major emphasis on T and B cells, which are significantly impaired by aging. We discuss changes in T cell production and thymic output; T cell subsets; and TCR repertoire, function, and response to latent persistent infection. We also discuss changes in B cell subsets, repertoire, and function, and how function is impaired by increased intrinsic B cell inflammation and reduced signal transduction. This review presents age-related effects on antigen-presenting cells, summarizes recent studies, including our own, aimed at the identification of biomarkers of protective vaccine responses, and provides examples of recent technical advances and insights into human vaccine responses that are helping to define the features associated with successful vaccination and that may enable a more predictive vaccinology in the future.

MicroRNAs miR-155 and miR-16 Decrease AID and E47 in B Cells from Elderly Individuals.

Our research in the past few years has identified B cell-specific biomarkers able to predict optimal Ab responses in both young and elderly individuals. These biomarkers are activation-induced cytidine deaminase (AID), the enzyme of class switch recombination and somatic hypermutation; the transcription factor E47, crucial for AID expression; and the ability to generate optimal memory B cells. Moreover, we have found that the increased proinflammatory status of the elderly, both in sera and intrinsic to B cells, negatively impacts B cell function. We have now investigated whether particular inflammatory microRNAs (miRs) contribute to decreased E47 and AID in aged B cells. Our data indicate that E47 and AID mRNA stability is lower in stimulated B cells from elderly individuals. We measured the expression of two miRs crucial for class switch recombination, miR-155 and miR-16, in human unstimulated B cells from young and elderly individuals with the rationale that increases in these before stimulation would decrease E47/AID upon cell activation. We found these miRs and B cell-intrinsic inflammation upregulated in aged unstimulated B cells and negatively associated with AID in the same B cells after stimulation with CpG. We propose that the downregulation of AID in aged human B cells may occur through binding of miR-155 to the 3'-untranslated regions of AID mRNA and/or binding of miR-16 to the 3'-untranslated regions of E47 mRNA, as well as at the transcriptional level of less E47 for AID. Our results indicate novel molecular pathways leading to reduced B cell function with aging.

Postsurgical Depressive Symptoms and Proinflammatory Cytokine Elevations in Women Undergoing Primary Treatment for Breast Cancer.

OBJECTIVE: Depression and inflammation may independently promote breast cancer (BCa) disease progression and poorer clinical outcomes. Depression has been associated with increased levels of inflammatory markers in medically healthy individuals and patients with cancer. However, inconsistencies in study time frames complicate interpretation of results within specific cancer types. This study examined relationships between depressive symptoms and inflammation in women with early-stage BCa before beginning adjuvant treatment. METHODS: Women with Stage 0-III BCa were recruited approximately 4 to 8 weeks after surgery. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression, and blood samples were collected to quantify circulating levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor α (TNF-α) by enzyme-linked immunosorbent assay. Analyses of covariance were used to test for group differences (elevated versus low depressive symptoms) in levels of cytokines. Multiple regression analyses were used to examine relationships between continuous severity of depressive symptoms and levels of cytokines adjusting for relevant biobehavioral covariates. RESULTS: Thirty-six (40%) of 89 patients showed elevated levels of depressive symptoms and, in adjusted models, had marginally higher levels of IL-1ß (mean [M] = 14.49 [95% confidence interval {CI} = 6.11-32.65] versus M = 4.68 [95% CI = 1.96-9.86] and IL-6 [M = 88.74 {95% CI = 33.28-233.96} versus M = 61.52 {95% CI = 27.44-136.40}]) significantly higher levels of TNF-α (M = 17.07 [95% CI = 8.27-34.32] versus M = 6.94 [95% CI = 3.58-12.80]) than did women with low depressive symptoms. Across the spectrum of depressive symptoms, greater magnitude of depressive symptoms was related to greater levels of IL-1ß (ß = 0.06, p = .006, R = 0.25) and TNF-α (ß = 0.06, p = .003, R = 0.27). CONCLUSIONS: Postsurgery and preadjuvant treatment for early-stage BCa, depressive symptoms covary with elevated levels of multiple proinflammatory cytokines. Findings have implications for psychosocial and biological interventions concurrently focusing on depression and inflammation. TRIAL REGISTRATION: NCT01422551.