Immune System Markers Research Articles

Acute immobilization stress evokes sexually dimorphic peripheral and hippocampal neuroimmune responses in adult rats

Stress perception and response vary across sexes and may contribute to the sex differences in susceptibility to psychopathology. Stress also engages the immune system and baseline immune system markers are known to be sexually dimorphic. Here, we investigated if the neuroimmune consequences following a single episode of acute immobilization stress (AIS) are sexually dimorphic in male and female Sprague-Dawley rats. We analyzed immune parameters in the periphery, and markers of neuroinflammation in the hippocampus, a key target of stress effects in the brain. We observed sexual dimorphism in the pattern of regulation of peripheral cytokines following stress, with males showing a significant increase in the levels of specific cytokines compared to females. Hippocampal cytokine and neuroinflammation-associated gene expression level analysis did not reveal any sexually dimorphic effects of AIS. However, we noted lower baseline expression levels for specific cytokines and many of the genes analyzed in the hippocampus of control females compared to control males. Finally, we assessed the levels of components of the NLRP3 inflammasome in the hippocampus and observed increased NLRP3 protein levels at baseline in females. We further noted that while males showed an increase in NLRP3 levels following AIS, females failed to show a similar change. Together, our results highlight a sexual dimorphism in neuroimmune consequences following AIS, both in the periphery and within the hippocampus, with males displaying robust proinflammatory changes and similar changes not observed in females. Our study underlines the importance of investigating the effect of sex on neuroimmune consequences following acute stress.

Daily physical activity is negatively associated with thyroid hormone levels, inflammation, and immune system markers among men and women in the NHANES dataset.

The acute effects of exercise on metabolic energy expenditure and inflammation are well studied, but the long-term effects of regular daily physical activity on metabolic and endocrine effects are less clear. Further, prior studies investigating the impact of daily physical activity in large cohorts have generally relied on self-reported activity. Here, we used the U.S. National Health and Nutrition Examination Survey (NHANES) to investigate the relationship between daily physical activity and both thyroid and immune activity. Daily physical activity was assessed through accelerometry or accelerometry-validated survey responses. Thyroid activity was assessed from circulating levels of thyroid stimulating hormone (TSH) and thyroxine (T4). Immune function was assessed from circulating cytokines (C-reactive protein [CRP], immunoglobulin E [IgE], fibrinogen) and blood cell counts. In general linear models including body mass index, age, gender, activity and TSH as factors, active adults had a lower levels of T4 and reduced slope of the TSH:T4 relationship. Similarly, greater physical activity was associated with lower CRP and fibrinogen levels (but not IgE) and lower white blood cell, basophil, monocyte, neutrophil, and eosinophil (but not lymphocyte) counts. Daily physical activity was also associated with lower prevalence of clinically elevated CRP, WBC, and lymphocytes in a dose-response manner. These results underscore the long-term impact of daily physical activity on both systemic metabolic activity (thyroid) and on specific physiological tasks (immune). The regulatory effects of physical activity on other bodily systems are clinically relevant and should be incorporated into public health strategies promoting exercise.

Effects of Inulin-Based Prebiotics Alone or in Combination with Probiotics on Human Gut Microbiota and Markers of Immune System: A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Subjects.

The gut microbiota is implicated in diverse interactions affecting human health. The present study reports a randomized, double-blind, placebo-controlled clinical study conducted by administering a new synbiotic formulation composed of two Lactobacillus strains (L. plantarum and L. acidophilus) and one Bifidobacterium strain (B. animalis subsp. lactis) and two types of fructans (fructo-oligosaccharides with a degree of polymerization of 3–5 and inulin-type fructans with 10 DP). The effects of this synbiotic were evaluated on healthy subjects for 28 days and the maintenance of its efficacy was evaluated at the end of a follow-up period of 28 days. The synbiotic treatment contributes to higher biodiversity of the gut microbiota, increasing the community richness with respect to the group with the prebiotics alone and the placebo group. Its positive effect is also reflected in the variation of microbial community structure favoring the beneficial short-chain fatty acids bacterial producers. The amelioration of the health status of the subjects was also established by the reduction of common infectious disease symptom incidence, the stimulation of the gut immune system showing a noteworthy variation of fecal β-defensin2 and calprotectin levels, and the modulation of the response of the respiratory tract’s immune system by salivary IgA as well as total antioxidant capacity biomarkers.

Investigating inflammatory responses in a corticosterone‐induced model of depression

AbstractBackgroundMajor depressive disorder (MDD) is a prevalent neuropsychiatric condition, affecting approximately 264 million people worldwide. While various hypotheses have been proposed for MDD, the full extent of the neuropathology underlying depression has not yet been elucidated. Nonetheless, evidence suggests that inflammation is a key pathological feature underlying depression, and that inflammation can predispose individuals to developing depression. In this study, we utilised a corticosterone (CORT)‐induced model of depression in rats, since elevated glucocorticoids are an important feature of MDD. Using this model, we investigated the inflammatory changes that occur both systemically and in various brain regions, focusing on inflammatory cytokines and various markers of innate immune pathways. Additionally, we administered CORT for different durations to assess how the inflammatory status changes depending on the length of elevated CORT levels.MethodsCORT or vehicle (sesame oil) is administered daily via subcutaneous injections to Sprague‐Dawley (SD) rats for 14, 21 or 28 days. Afterwards, various tissues samples including liver, kidney, frontal cortex, hippocampus, striatum, thalamus and hypothalamus are collected and processed for qPCR analysis. Additionally, tissue samples from the brain are collected and processed for immunofluorescence staining of GFAP and Iba1.ResultsFollowing 14 days of CORT administration, there are alterations to some of the inflammatory cytokines and markers of the innate immune system assessed in the liver, with no alterations to inflammatory markers in the brain. However, at 21 days there are increases in many of the inflammatory cytokines and innate immune markers assessed in both the liver and the kidney. Additionally, in the brain there are elevated levels of cytokines TNFa and Il1b in the striatum, IL1b in the thalamus and TNFa in the hypothalamus. At 28 days, many of the markers that were altered at 21 days return to baseline in the liver and kidney, though TNFa and IL1b in the kidney and IL1b in the liver remain elevated. Additionally, TNFa is elevated in the frontal cortex and striatum following CORT administration.ConclusionCORT administration impacts inflammation both in the periphery and in the brain. However, the alterations that occur depend on the duration of CORT administration and the tissue.

The association of serum immunoglobulins with cognition and dementia: The Rotterdam Study

AbstractBackgroundChronic neuro‐inflammation has emerged in recent years as important pathological process underlying dementia, including Alzheimer’s disease. Most studies so far have investigated the innate immune system, but the role of the adaptive immune system remains largely unknown. We investigated the association of serum immunoglobulins (IgA, IgG, IgM) as markers of the adaptive immune system with cognitive function and risk of dementia.MethodThis study was embedded in the Rotterdam Study, an ongoing prospective population based cohort study, and included participants with baseline measurements (between 1997 and 2009) of serum immunoglobulins and informed consent for follow‐up. We performed Cox proportional hazard regression analyses to obtain hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between serum immunoglobulins and risk of dementia until 2016 (longitudinal). We performed linear regression analyses to quantify the cross‐sectional association between serum immunoglobulins and cognition summarized into global cognition as well as separate cognitive test scores. Effect estimates are adjusted for age, sex, lifestyle and cardiovascular factors.ResultWe have included 8,768 participants with a mean age of 64 years and of whom 57% are female. Due to non‐proportional hazards, the follow‐up time was divided into two strata (≤10 and >10 years). We found that IgM was associated with a lower risk of dementia after ten years in women (HR: 0.71; 95% CI: 0.58‐0.86). When restricting analyses to participants with immunoglobulin levels within the reference range and excluding users of immunomodulating medication, we found that IgM was associated with a lower risk of dementia after 10 years in the entire population (HR: 0.78; 95% CI: 0.62‐0.97). We furthermore found that higher IgG levels were associated with lower scores of global cognition, Stroop I, and Stroop II (betas ranging from ‐0.01 to ‐0.02; p‐value <0.002 for all).ConclusionHigher IgM levels are associated with a decreased risk of dementia in women and in all participants with reference range immunoglobulin levels. Higher IgG levels are associated with worse cognitive test outcomes. Our results suggest a protective effect of the adaptive immune system on dementia onset, but possibly a reversed effect on cognitive function.

Effect of Tai Chi Chuan practice on immune system and pro-metastasis markers in early post-treatment breast cancer survivors

Purpose: To investigate the effect of Tai Chi Chuan (TCC) to improve immune system and decrease pro-metastasis markers in early post-treatment breast cancer survivors. Methods: 130 post-treatment breast cancer survivors were recruited and randomized 1:1 into TCC group and wait-list (control) group. The TCC group practiced for a 60-minutes session once per week, for a total of 52 weeks. 115 forms of Yang-style TCC were taught by a Tai Chi master. Blood samples were taken from each subject and complete blood count was performed. The expressions of NKG2D protein, P-selectin, and vascular endothelial growth factor (VEGF) in plasma were measured. Lymphocyte activity was measured by cell proliferation reagent and ATP assay. Images of lymphocyte colony formation were taken with an inverted microscope. Results: At 52 weeks, TCC group demonstrated a significantly higher WBC (p=0.001) , a significantly higher NKG2D value (p=0.001) and a significantly lower VEGF value (p=0.005) when compared to the wait-list group. However, there was a small, non-significant change for P-selectin values between the breast cancer survivor groups. After 72h incubation, TCC group had a significant increase in lymphocyte proliferation (p=0.001) and greater area of lymphocyte clusters or colonies (p=0.001). Conclusion: The practice of TCC could stimulate tumor immunosurveillance via NKG2D and activate the immune response. VEGF, a marker playing an important role in breast cancer and its metastases, was also reduced in those who practiced TCC. As an alternative for conventional exercise, post-treatment breast cancer survivors may select TCC in their rehabilitation program.

Effect of Tai Chi Chuan practice on immune system and pro-metastasis markers in early post-treatment breast cancer survivors

Effect of Tai Chi Chuan practice on immune system and pro-metastasis markers in early post-treatment breast cancer survivors

Association between serum markers of the humoral immune system and inflammation in the Swedish AMORIS study

BackgroundAlthough the onset of inflammatory cascades may profoundly influence the nature of antibody responses, the interplay between inflammatory and humoral (antibody) immune markers remains unclear. Thus, we explored the reciprocity between the humoral immune system and inflammation and assessed how external socio-demographic factors may influence these interactions. From the AMORIS cohort, 5513 individuals were identified with baseline measurements of serum humoral immune [immunoglobulin G, A & M (IgG, IgA, IgM)] and inflammation (C-reactive protein (CRP), albumin, haptoglobin, white blood cells (WBC), iron and total iron-binding capacity) markers measured on the same day. Correlation analysis, principal component analysis and hierarchical clustering were used to evaluate biomarkers correlation, variation and associations. Multivariate analysis of variance was used to assess associations between biomarkers and educational level, socio-economic status, sex and age.ResultsFrequently used serum markers for inflammation, CRP, haptoglobin and white blood cells, correlated together. Hierarchical clustering and principal component analysis confirmed the interaction between these main biological responses, showing an acute response component (CRP, Haptoglobin, WBC, IgM) and adaptive response component (Albumin, Iron, TIBC, IgA, IgG). A socioeconomic gradient associated with worse health outcomes was observed, specifically low educational level, older age and male sex were associated with serum levels that indicated infection and inflammation.ConclusionsThese findings indicate that serum markers of the humoral immune system and inflammation closely interact in response to infection or inflammation. Clustering analysis presented two main immune response components: an acute and an adaptive response, comprising markers of both biological pathways. Future studies should shift from single internal marker assessment to multiple humoral and inflammation serum markers combined, when assessing risk of clinical outcomes such as cancer.

Habitual cold-water swimming and upper respiratory tract infection.

It has long been claimed that non-wetsuit cold water swimming (CWS) benefits health (1), and anecdotally cold-water swimmers claimed to suffer fewer and milder infections, though this was not directly measured. A boost to immunity is biologically plausible: stress hormones are released during cold-water immersion (2), and short-term stress may ready the immune system for injury or infection (3). However, very few studies have investigated immune system markers and/or actual illness in habitual cold-water swimmers.

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

BackgroundPeople living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine‐N‐oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV.Methods and ResultsThe study population consisted of participants enrolled in the multisite cross‐sectional study called CHART‐HIV (Characterizing Heart Function on Anti‐Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut‐related circulating metabolites; diastolic dysfunction was determined by study‐specific criteria. Multivariable linear regression models were performed to examine the relationship of gut‐related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV‐related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART‐HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis (R=0.35; P<0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis.ConclusionsIn this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV‐associated cardiovascular disease warrants further investigation.RegistrationURL: https://clinicaltrials.gov; Unique identifier: NCT02860156.

Comprehensive pan-genome analysis of Lactiplantibacillus plantarum complete genomes.

AimsThe aim of this work was to refine the taxonomy and the functional characterization of publicly available Lactiplantibacillus plantarum complete genomes through a pan‐genome analysis. Particular attention was paid in depicting the probiotic potential of each strain.Methods and resultsComplete genome sequence of 127 L. plantarum strains, without detected anomalies, was downloaded from NCBI. Roary analysis of L. plantarum pan‐genome identified 1436 core, 414 soft core, 1858 shell and 13,203 cloud genes, highlighting the ‘open’ nature of L. plantarum pan‐genome. Identification and characterization of plasmid content, mobile genetic elements, adaptative immune system and probiotic marker genes (PMGs) revealed unique features across all the L. plantarum strains included in the present study. Considering our updated list of PMGs, we determined that approximatively 70% of the PMGs belongs to the core/soft‐core genome.ConclusionsThe comparative genomic analysis conducted in this study provide new insights into the genomic content and variability of L. plantarum.Significance and Impact of the StudyThis study provides a comprehensive pan‐genome analysis of L. plantarum, including the largest number (N = 127) of complete L. plantarum genomes retrieved from publicly available repositories. Our effort aimed to determine a solid reference panel for the future characterization of newly sequenced L. plantarum strains useful as probiotic supplements.

No evidence for association between human body odor quality and immune system functioning

Previous studies have shown that women perceive male faces with a more reactive immune system as more attractive, but whether body odor might likewise provide cues to immune function has not been investigated yet. These two studies tested a possible relationship between body odor quality and immunoreactivity (Study 1) and immune system function (Study 2).In Study 1, we collected body odor samples from 21 men just before and two weeks after vaccination against hepatitis A/B and meningococcus. We determined the levels of specific antibodies (selected as markers of immune system’s reactivity), testosterone, and cortisol. Subsequently, 88 female raters assessed the odor samples for their attractiveness, intensity, and healthiness. In Study 2, we collected body odor and blood samples from 35 men and women. We assessed key parameters of their innate and adaptive immunity, such as complement activity or total lymphocyte T and B counts and asked 95 raters to assess the odor samples for their attractiveness, intensity, and healthiness.In Study 1, we found no significant association between antibody levels induced by vaccination and perceived body odor attractiveness, intensity, and healthiness. We also found no significant relationship between antibody levels and steroid hormones (testosterone and cortisol). In Study 2, we likewise found no association between basal key parameters (innate and adaptive) of the immune system and body odor quality. Our results indicate that body odor may not serve as a cue to the reactivity of the immune system.

Prognostic Impact of Immunoglobulin Kappa C (IGKC) in Early Breast Cancer.

Simple SummaryWe examined the relevance of immunoglobulin kappa C (IGKC), an important part of the humoral immune system, in early breast cancer. To our knowledge, our results confirm for the first time previous retrospective findings of a cancer recurrence protective role of IGKC in a large cohort of early breast cancer patients who were treated in the prospective, randomized FinHer clinical trial. We show that an increased amount of IGKC in the tumor is linked to longer distant metastasis-free survival, especially in patients whose breast cancer does not express hormone receptors or human epidermal growth factor receptor-2. This type of breast cancer often has poor prognosis. Since an improved outcome is associated with the presence of tumor-infiltrating IGKC expressing immune cells, this may be a further argument for the use of immunotherapies in these patients.We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan–Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis also including age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870–0.995, p = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724–0.983, p = 0.029), but not in luminal (HR 0.957, 95% CI 0.867–1.056, p = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826–1.055, p = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.

Vitamin D Status as a Potential Modifiable Risk Factor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

In March 2020, the infection COVID-19 spread as a pandemic emergence. Among multiple biological and environmental factors, hypovitaminosis D is a credible candidate. The aim of this study is to shed light on the pathogenic role of vitamin D deficiency in the susceptibility to SARS-CoV-2 and in the aggressive immune and inflammatory response by the host. We retrospectively analyzed the biochemical panel of immune system markers and the tandem mass spectrometry coupled to liquid chromatography (LC-MS-MS) measured vitamin D, in the serum samples of patients with SARS-CoV-2 studied in all aspects of clinical relevant parameters. RESULTS between 18th March and 20th April 2020 we enrolled 29 consecutive patients with COVID-19. They were 17 (58.6%) males and 12 (41.4) females, and the median age was 79 (69–88) years. Mean 25OHD was 17.3±2.1 ng/ml, with a median of 15.7 1 ng/ml (i.r. 6.7–25). Twenty-five patients (86.2%) had 25OHD levels <30 ng/ml, 18 patients (62.0%) had 25OHD levels <20 ng/ml and 10 patients (34.5%) had severe vitamin D deficiency (<10 ng/ml). In the group of patients with severe disease (ARDS, cardiovascular complications, CID) 69.2% (n=9/13) of patients presented hypovitaminosis D (<20 ng/ml). All patients who dead for COVID-19 during hospitalization (n=6) had 25OHD≤30 ng/ml and 5/6 had 25OHD≤20 ng/ml. IL-6 and CRP were measured in all patients and were considered surrogate markers of cytokines storm. The majority of patients had levels of IL-6 (n=22, 75.8%) and CRP (n=25, 86.2%) above the upper limit of the reference range of our laboratory (IL6 6.59 and CRP 1 mg/dl) and the median was IL 6=16.1 (i.r. 7.3–36.3) and CRP=6.67 (2.64–11.52). Patients with 25OHD <20 ng/ml had higher levels of IL-6 (p=0.004; 19.9 vs 10.4) and CRP (p=0.009, 9.85 vs 1.40) and did not differ for the other clinical and biochemical variables. If we considered as 25OHD cut-off the mean value in our population (17.3 ng/ml), patients with lower levels of 25OHD had higher age (p=0.033) and higher levels of IL6 (p=0.016), CRP (p=0.04), troponin (p=0.04) and D-dimer (p=0.017), compared to the others. An inverse correlation was found between 25OHD levels and IL-6, CRP, and troponin. In a univariate regression analysis hypovitaminosis D (<20 ng/ml) was a predictive factor for IL6 (expressed as LnIL6) levels (β=0.57, P=0.003) and for PCR levels (β=0.42, P=0.034). We also performed a multivariate regression analysis with hypovitaminosis D (<20 ng/ml), sex, BMI, age (<70 years) and ARDS as independent variables. Notably, hypovitaminosis D (β=0.49, P<0.02), BMI (β=0.4, P=0.04) and ARDS (β=0.44, P=0.02) were confirmed to be significant variables for IL6 (expressed as LnIL6) level prediction. In the same multivariate model hypovitaminosis D (β=0.49, P=0.034) was confirmed as independent predictor of CRP levels. In conclusion, hypovitaminosis D is related to the negative prognostic inflammatory status in patients with SARS-Cov2.

The relationship between calcific severe aortic stenosis and systemic immune‐inflammation index

Calcific aortic stenosis (AS) is a common valvular disease especially in elderly population. Inflammation plays significant role in the pathophysiological mechanism. Systemic immune-inflammation index (SII) is a novel marker of immune system and inflammation that includes neutrophil, lymphocyte, and platelet cell counts. The aim of this study was to investigate the predictive value of SII in calcific severe AS. Severe calcific AS patients were categorized into two groups: High flow-high gradient (HFHG) AS (n=289) and low flow-low gradient AS (n=79). Control group included 273 patients with similar clinical and demographic characteristics but without AS. SII was calculated as absolute platelet count×absolute neutrophil count/absolute lymphocyte count. SII levels were 525±188, 835±402, and 784±348 in control, HFHG AS, and LFLG AS groups, respectively (P<.001). Correlation analyses revealed significant and positive correlation between SII and mean aortic transvalvular pressure gradient (r=.342, P<.001), and negative and significant correlation between SII and AVA (r=-.461, P<.001). Multivariate analysis performed in separate models demonstrated sex, CAD, LDL, and SII levels (Odds ratio [OR]: 1.004, 95 CI%:1.003-1.004) as independent predictors of severe AS in Model 1. According to Model 2, sex, CAD, LDL, and high SII (>661) (OR:5.78, 95 CI%:3.93-4.89) remained as independent predictors of severe AS. SII levels can be useful to predict severe calcific AS patients and significantly correlate with AVA and mean aortic transvalvular pressure gradient.

Spatial Learning Is Impaired in Male Pubertal Rats Following Neonatal Daily but Not Randomly Spaced Maternal Deprivation.

Severe early life stress has long been associated with neuropsychological disorders in adulthood, including depression, schizophrenia, post-traumatic stress disorder, and memory dysfunction. To some extent, all of these conditions involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced negative feedback inhibition of cortisol release in adulthood. However, the time course for mental health and hormonal outcomes across life stages and the attributes of early life stress that direct the behavioral and biological alterations is not fully understood. We designed our studies to compare outcomes of the two most common maternal deprivation schedules on cognitive ability prior to adulthood. We exposed rat pups to daily or randomly spaced maternal separation bouts within the first 3 weeks of life and examined cognitive performance, neurotrophic signaling, and stress and immune system markers during puberty. We found that the daily separation schedule impaired spatial learning while the randomly spaced schedule did not alter maze performance relative to normally reared control animals. Animals that underwent daily separation showed a tendency for reduced body weight compared to the randomly spaced condition, but there were no differences in adrenal weight. Thymus weight normalized by body weight was increased following daily separation compared to random separation and control conditions. Plasma corticosterone levels measured after behavior testing did not differ amongst experimental groups and there was no impact of TrKB receptor inhibition. Combined, the results show that different early life stress schedules produce different behavioral and biological outcomes when measured at puberty. Combined with prior findings from more mature animals, the results presented here suggest that daily neonatal stress produces varied alterations in spatial cognition at different life stages with a transient learning deficit at puberty preceding a more persistent and a progressive memory impairment through adulthood and into aging.

An integrated approach to understand biological stress system dysregulation across depressive and anxiety disorders

BackgroundAffective disorders involve dysregulation of major biological stress systems (hypothalamic-pituitary-adrenal (HPA)-axis, immune system, autonomic nervous system (ANS)). Suchdysregulationshave rarely beensimultaneously examined across different stress systems. MethodsIn the Netherlands Study of Depression and Anxiety (n=2789), we investigated whether current or remitted depressive and/or anxiety disorders (based on the CIDI semi-structured interview), including specific symptom profiles, were associated with separate markers and cumulative indexes of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), immune system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period). ResultsDepressive andanxiety disorderswere significantlyassociated with changes in three biological stress systemsincluding HPA-axis hyperactivity, increased inflammatory activity, and a higher ANS tone, particularly for integrative and cumulative indexes of these stress systems (pFDR <.05) vs. controls. The strongest associations were seen with current disorders andcumulative indexes of the HPA-axis (β=.124, pFDR=.001), the immune system (β =.057, pFDR=.032), and total cumulative index across stress systems (β=.102, pFDR=.004). Atypical, energy-related depression severity was linked to immune system markers (pFDR<0.001), melancholic depression severity to HPA-axis markers (pFDR=.032), and anxiety arousal severity to both HPA-axis and immune system markers (pFDR<0.05). Findings were partially explained by poorer lifestyle, more chronic diseases,or (especially for ANS-function) antidepressant use. LimitationsCross-sectional analyses limit examination of temporal associations. ConclusionPatients withdepressive and anxiety disorders showed consistent dysregulation across biological stress systems, particularly for current episodes.To understand stress system functionality in affective disorders, an integrated approach capturing cumulative stress indices within and across biological stress systems is important.

Immune System Effects of Insulin-Like Peptide 5 in a Mouse Model.

IntroductionInsulin-like peptide 5 (INSL5) is a peptide hormone with proposed actions in glucose homeostasis and appetite regulation via its cognate receptor, relaxin family peptide receptor 4 (RXFP4). Here, we look for evidence for their involvement in the immune system using a mouse model.Methods In silico analyses: we queried public databases for evidence of expression of INSL5-RXFP4 in immune system tissues/cells (NCBI’s SRA and GeoProfiles) and disorders (EMBO-EBI) and performed phylogenetic footprinting to look for evidence that they are regulated by immune-associated transcription factors (TFs). Experimental analyses: We characterized the expression and correlation of INSL5/RXFP4 and other immune system markers in central and peripheral immune organs from C57/bl6 mice in seven cohorts. We tested whether fluctuations in circulating INSL5 induce an immune response, by injecting mice with 30 μg/kg of INSL5 peptide in the peritoneum, and examining levels of immune markers and metabolic peptides in plasma. Lastly, we quantified the expression of Rxfp4 in T-cells, dendritic cells and cell lines derived from human and mouse and tested the hypothesis that co-incubation of ANA-1 cells in INSL5 and LPS alters cytokine expression.ResultsWe find Insl5 expression only in thymus (in addition to colon) where its expression was highly correlated with Il-7, a marker of thymocyte development. This result is consistent with our in silico findings that Insl5 is highly expressed in thymic DP, DN thymocytes and cortical TEC’s, and with evidence that it is regulated by thymocyte-associated TF’s. We find Rxfp4 expression in all immune organs, and moderately high levels in DCs, particularly splenic DCs, and evidence that it is regulated by immune-associated TF’s, such as STAT’s and GATA. Systemic effects: We observed significantly elevated concentrations of blood GLP-1, GIP, GCG and PYY following intraperitoneal injection of INSL5, and significantly altered expression of cytokines IL-5, IL-7, M-CSF, IL-15, IL-27 and MIP-2. Immune cell effects: Incubation of ANA-1 cells with INSL5 impeded cell growth and led to a transient elevation of IL-15 and sustained reduction in IL-1β, IL-6 and TNFα.ConclusionWe propose that INSL5-RXFP4 play a novel role in both central and peripheral immune cell signaling.

Short-term Effect of Gyeongsangnam-do Wellness Tourism on Inflammatory and Immune System Markers, Emotion, Fatigue, Stress, Quality of Life, and Quality of Sleep

Short-term Effect of Gyeongsangnam-do Wellness Tourism on Inflammatory and Immune System Markers, Emotion, Fatigue, Stress, Quality of Life, and Quality of Sleep

Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease.

IntroductionInflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non‐steroidal anti‐inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short‐term treatment of transgenic AD mice with the pro‐inflammatory cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM‐CSF/sargramostim to safely ameliorate AD symptoms/pathology.MethodsA randomized, double‐blind, placebo‐controlled trial was conducted in mild‐to‐moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow‐up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments.ResultsSargramostim treatment expectedly changed innate immune system markers, with no drug‐related serious adverse events or amyloid‐related imaging abnormalities. At end of treatment (EOT), the Mini‐Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aβ40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH‐L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo.DiscussionThe innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long‐term safety and efficacy of GM‐CSF/sargramostim in AD is warranted.