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.

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.

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.

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.

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.

A randomized controlled trial of cognitive-behavioral stress management in breast cancer: survival and recurrence at 11-year follow-up.

Non-metastatic breast cancer patients often experience psychological distress which may influence disease progression and survival. Cognitive-behavioral stress management (CBSM) improves psychological adaptation and lowers distress during breast cancer treatment and long-term follow-ups. We examined whether breast cancer patients randomized to CBSM had improved survival and recurrence 8-15 years post-enrollment. From 1998 to 2005, women (N = 240) 2-10 weeks post-surgery for non-metastatic Stage 0-IIIb breast cancer were randomized to a 10-week, group-based CBSM intervention (n = 120) or a 1-day psychoeducational seminar control (n = 120). In 2013, 8-15 years post-study enrollment (11-year median), recurrence and survival data were collected. Cox Proportional Hazards Models and Weibull Accelerated Failure Time tests were used to assess group differences in all-cause mortality, breast cancer-specific mortality, and disease-free interval, controlling for biomedical confounders. Relative to the control, the CBSM group was found to have a reduced risk of all-cause mortality (HR = 0.21; 95 % CI [0.05, 0.93]; p = .040). Restricting analyses to women with invasive disease revealed significant effects of CBSM on breast cancer-related mortality (p = .006) and disease-free interval (p = .011). CBSM intervention delivered post-surgery may provide long-term clinical benefit for non-metastatic breast cancer patients in addition to previously established psychological benefits. Results should be interpreted with caution; however, the findings contribute to the limited evidence regarding physical benefits of psychosocial intervention post-surgery for non-metastatic breast cancer. Additional research is necessary to confirm these results and investigate potential explanatory mechanisms, including physiological pathways, health behaviors, and treatment adherence changes.

A molecular mechanism for TNF-α-mediated downregulation of B cell responses.

B cell function with age is decreased in class switch recombination (CSR), activation-induced cytidine deaminase (AID), and stability of E47 mRNA. The latter is regulated, at least in part, by tristetraprolin (TTP), which is increased in aged B cells and also negatively regulates TNF-α. In this study, we investigated whether B cells produce TNF-α, whether this changes with age, and how this affects their function upon stimulation. Our hypothesis is that in aging there is a feedback mechanism of autocrine inflammatory cytokines (TNF-α) that lowers the expression of AID and CSR. Our results showed that unstimulated B cells from old BALB/c mice make significantly more TNF-α mRNA and protein than do B cells from young mice, but after stimulation the old make less than the young; thus, they are refractory to stimulation. The increase in TNF-α made by old B cells is primarily due to follicular, but not minor, subsets of B cells. Incubation of B cells with TNF-α before LPS stimulation decreased both young and old B cell responses. Importantly, B cell function was restored by adding anti-TNF-α Ab to cultured B cells. To address a molecular mechanism, we found that incubation of B cells with TNF-α before LPS stimulation induced TTP, a physiological regulator of mRNA stability of the transcription factor E47, which is crucial for CSR. Finally, anti-TNF-α given in vivo increased B cell function in old, but not in young, follicular B cells. These results suggest new molecular mechanisms that contribute to reduced Ab responses in aging.

Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine.

In order to develop predictive markers for a beneficial humoral immune response, we evaluated the in vivo and in vitro response to the pandemic (p)H1N1 vaccine in young and elderly individuals. We measured serum antibody response and associated this with the in vitro B-cell response to the vaccine, measured by activation-induced cytidine deaminase (AID). Both responses decrease with age and are significantly correlated. The percentage of switched memory B cells in blood, both before and after vaccination, is decreased with age. The percentage of switched memory B cells at t0 correlates with the hemagglutination inhibition response and therefore, we suggest that this may be used as a predictive marker for B-cell responsiveness. AID induced by CpG before vaccination also predicts the robustness of the vaccine response. Plasmablasts showed a trend to increase after vaccination in young individuals only. This report establishes molecular biomarkers of response, percentage of switched memory B cells and AID response to CpG, useful for identifying individuals at risk of poor response and also for measuring improvements in vaccines and monitoring optimal humoral responses.

Effects of age on H1N1-specific serum IgG1 and IgG3 levels evaluated during the 2011-2012 influenza vaccine season.

BACKGROUND: We have previously reported an age-related impairment in the serum antibody response to pandemic (p)2009 H1N1, measured by hemagglutination inhibition assay and ELISA. The present study extends these observations and evaluates IgG subclass distribution in healthy individuals of different ages vaccinated during the 2011-2012 season. RESULTS: The 2011-2012 vaccination season was characterized by a vaccine containing the pandemic (p)2009 H1N1 strain for the third consecutive year. All of our subjects were previously immunized, and therefore seroprotected at t0. Nevertheless, aging impaired the serum antibody response to H1N1, as antibody titers increased after vaccination in young and less in elderly individuals. The peak of the response was at day 7 (t7), in contrast with what is usually seen at day 21-28, suggesting a memory response characterized by the induction of an IgG subclass with a shorter half-life. We hypothesized that the IgG3 response, with its much shorter half-life, might be more represented. Antibodies were predominantly of the IgG1 subclass in both age groups, although a robust IgG3 response was also induced and accounted for a significant proportion of the overall response. IgG2 and IgG4 antibodies were at indiscernible levels. We showed a much higher percentage of IgG3 (40-50%) than previously in the literature (less than 10%). To explain if this was associated with a particular cytokine profile, we measured H1N1-induced T cell cytokines in vitro and found that IgG3 levels were positively correlated with TNF-α and IL-6. Moreover, activation-induced cytidine deaminase (AID) mRNA expression, a predictive biomarker of optimal in vivo vaccine response, was found to significantly correlate with IgG3 and also with IgG1 similar to what we have shown previously for total IgG. CONCLUSIONS: In the 2011-2012 season, the pandemic (p)2009 H1N1 strain was present in the vaccine for the third consecutive year and therefore each individual was seroprotected at t0. The peak of the response was at t7, suggesting a memory response characterized by a robust induction of IgG3, which was associated with TNF-α and IL-6 production. Both IgG1 and IgG3 responses were decreased by age. AID was confirmed to be a predictive biomarker of optimal vaccine responses.

B cells from old mice induce the generation of inflammatory T cells through metabolic pathways.

We have measured the capacity of B cells from young and old mice to induce the differentiation of naïve CD4 + T cells from young mice into pro-inflammatory subsets. We found that only B cells from old mice are inflammatory and induce in vitro secretion of the pro-inflammatory cytokines IL-17A and IFN-γ by T cells. In co-culture experiments, B cells from old mice showed a strong helper function on T cells from young mice, making them pro-inflammatory, and this effect is regulated by metabolic pathways, mainly anaerobic glycolysis, leading to increased RNA expression of the enzyme lactate dehydrogenase (LDHA) and increased secretion of lactate. These results have indicated that lactate is a crucial player of the B cell-induced polarization of T cells. When we measured the effects of lactate on isolated CD4 + T cells from young mice, we found that lactate increases RNA expression of LDHA, secretion of pro-inflammatory cytokines and NF-kB activation. Moreover, lactate effects in culture can be abrogated in the presence of the specific inhibitor of LDHA, FX11. These results altogether may have relevant clinical implications and suggest novel targets for therapeutic interventions in patients with inflammatory conditions and diseases.

Phenotypic and functional features of B cells from two different human subcutaneous adipose depots.

In this study, we have compared frequencies, phenotype, function and metabolic requirements of B cells isolated from the breast and abdominal subcutaneous adipose tissue (AT) of women with obesity who underwent weight reduction surgeries. Results show that B cells from the abdominal AT are more inflammatory than those from the breast, characterized by higher frequencies of inflammatory B cell subsets and higher expression of RNA for inflammatory markers associated with senescence. Secretion of autoimmune antibodies is also higher in the abdominal AT as compared to the breast, and is associated with higher frequencies of autoimmune B cells with the membrane phenotype CD21lowCD95+ B cells expressing the transcription factor T-bet. Moreover, glucose uptake is higher in B cells from the abdominal AT as compared to the breast, thereby suggesting a better capacity to perform glycolysis, needed to support intrinsic B cell inflammation and autoimmune antibody secretion.

Brief Post-Surgical Stress Management Reduces Pro-Inflammatory Cytokines in Overweight and Obese Breast Cancer Patients Undergoing Primary Treatment.

BACKGROUND: Overweight and obese (OW/OB) body mass index (BMI) is associated with greater inflammation and poorer outcomes in breast cancer (BC). Stress management interventions using cognitive behavioral therapy (CBT) and relaxation training (RT) have reduced inflammation in BC patients but have not been tested specifically in OW/OB patients undergoing primary treatment. We developed brief CBT and RT-based group interventions and tested their effects (vs time-matched Health Education [HE] control) on serum inflammatory cytokines (IL-6, IL-1ß and TNF-α) in OW/OB vs normal weight (NW) BC patients during primary treatment. We hypothesized OW/OB women would show higher levels of inflammatory cytokines, and that stress management would decrease these cytokines more in OW/OB women than in NW women. METHODS: Stage 0 - III BC patients were enrolled post-surgery and before initiating adjuvant therapy, were randomized to either 5 weeks of CBT, RT, or HE, and provided questionnaires and blood samples at baseline and 6-months. Serum cytokine levels were measured by ELISA. Repeated measures analysis of variance tested the interaction of condition by BMI by time in predicting cytokine levels over 6 months, controlling for age, stage, ethnicity, and income. RESULTS: The sample (N = 153) majority was OW/OB (55.6%). We found differences in baseline IL-6 and IL-1ß across BMI categories, with greater IL-6 (p < 0.005) and IL-1ß (p < 0.04) in OW and OB vs NW women, but no difference between OW and OB women. There were no differences in baseline TNF-α among BMI groups. BMI category moderated the effect of brief stress management interventions on IL-6 changes over 6-months (p = 0.028): CBT/RT vs HE decreased IL-6 in OW/OB (p = 0.045) but not in NW patients (p = 0.664). There were no effects on IL-1ß or TNF-α. Results could not be explained by differences in receipt of adjuvant therapy, prescription medications, or changes in physical activity. CONCLUSIONS: OW/OB women with newly diagnosed BC had significantly greater serum IL-6 and IL-1ß than NW women post-surgery. Brief stress management delivered with primary treatment among OW/OB patients may reduce the increases in inflammatory markers known to accompany adjuvant treatments and could thus promote better outcomes. CLINICAL TRIAL REGISTRATION: NCT02103387.

Metformin Enhances B Cell Function and Antibody Responses of Elderly Individuals With Type-2 Diabetes Mellitus.

Our previous work has shown that young and elderly patients with Type-2 Diabetes Mellitus (T2DM) treated with Metformin have optimal B cell function and serum antibodies specific for the seasonal influenza vaccine. In this paper, we have evaluated B cell function and the metabolic requirements of B cell antibody responses in elderly T2DM patients (ET2DM) taking or not Metformin, and compared to those of healthy elderly (EH) and healthy young (YH) individuals. Results show that Metformin significantly increases in vivo B cell function, measured by influenza vaccine-specific serum antibodies, in ET2DM patients to the levels observed in EH and more importantly in YH individuals. Metformin also decreases the frequencies of pro-inflammatory B cell subsets, as well as intrinsic inflammation and metabolic requirements of peripheral B cells from ET2DM. This hyper-metabolic phenotype of B cells from ET2DM is needed to support intrinsic inflammation, measured by the expression of transcripts for markers of the senescence-associated secretory phenotype (SASP), and the secretion of autoimmune antibodies. Importantly, B cell function in ET2DM patients taking Metformin is not only increased as compared to that in ET2DM patients not taking Metformin, but is comparable to B cell function measured in YH individuals. These results altogether strongly support the anti-aging effects of Metformin on humoral immunity.