scholarly journals Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Sara B. Fernandes ◽  
Neha D. Patil ◽  
Sophie Meriaux ◽  
Maud Theresine ◽  
Claude. P. Muller ◽  
...  
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Early Life ◽  
Maternal Separation ◽  
Immune Cell ◽  
Economic Status ◽  
Immune Cell Population ◽  
Early Life Adversity ◽  
Social Economic Status ◽  
Human Situation

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells’ profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psycho-Social Stress

2021 ◽  
Author(s):  
Sara B. Fernandes ◽  
Neha D. Patil ◽  
Sophie B. Meriaux ◽  
Maud Theresine ◽  
Fleur A.D. Leenen ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Nk Cells ◽  
Early Life ◽  
Social Stress ◽  
Maternal Separation ◽  
Economic Status ◽  
Childhood Adversity ◽  
Early Life Adversity ◽  
Human Situation

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD), the closest animal model available to the human situation, is known to similarly induce long lasting behavioural effects, to cause changes in the HPA axis and to have an impact in the immune system. Even though the immune responses to potential pathogens after early stress have been somehow documented, the mechanisms by which they occur are still not fully understood. Here, we have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells’ profile and response to target cell lines are significantly changed after childhood adversity. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. Altogether, these results lead us to conclude that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

scholarly journals Maternal separation in rodents: a journey from gut to brain and nutritional perspectives

2019 ◽  
Vol 79 (1) ◽  
pp. 113-132 ◽  
Author(s):  
Marion Rincel ◽  
Muriel Darnaudéry
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Human Subjects ◽  
Early Life Stress ◽  
Long Term Effects ◽  
Early Life Adversity ◽  
Critical Window ◽  
Beneficial Impact ◽  
The Impact

The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut–brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut–brain axis. Further research is required to understand the complex mechanisms underlying gut–brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.

scholarly journals Evolution during primary HIV infection does not require adaptive immune selection

2020 ◽  
Author(s):  
David A Swan ◽  
Morgane Rolland ◽  
Joshua Herbeck ◽  
Joshua T Schiffer ◽  
Daniel B Reeves
Keyword(s):  
Viral Load ◽  
Immune System ◽  
Hiv Infection ◽  
Evolutionary Dynamics ◽  
Immune Cell ◽  
Adaptive Immune System ◽  
Viral Fitness ◽  
Immune Cell Population ◽  
Adaptive Immune

AbstractModern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we developed multiple within-host phylodynamic (wi-phy) models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The most parsimonious and accurate model required no positive selection, suggesting that the host adaptive immune system reduces viral load, but does not drive observed viral evolution. Rather, random genetic drift primarily dictates fitness changes. These results hold during early infection, and even during chronic infection when selection has been observed, viral fitness distributions are not largely different from in vitro distributions that emerge without adaptive immunity. These results highlight how phylogenetic inference must consider complex viral and immune-cell population dynamics to gain accurate mechanistic insights.One sentence summaryThrough the lens of a unified population and phylodynamic model, current data show the first wave of HIV mutations are not driven by selection by the adaptive immune system.

Abstract 008: Early Life Stress Induces Renal Pro-inflammatory Immune Responses

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Carmen De Miguel ◽  
Dao H Ho ◽  
Analia S Loria ◽  
Ijeoma Obi ◽  
Jennifer S Pollock
Keyword(s):  
Immune Response ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Immune Cell ◽  
Early Life Stress ◽  
Adult Rats ◽  
Activation Markers ◽  
Ifn Gamma ◽  
Inflammatory Status

We previously reported that maternal separation (MatSep), an animal model of early life stress, sensitizes rats to pro-hypertensive stimuli in adulthood. We hypothesized that MatSep induces a renal pro-inflammatory immune response. Immune cell populations and expression of cytokines were assessed by magnetic bead isolation, FACS analysis, ELISA and RT-PCR in adult male MatSep and normally-reared littermate control rats. Circulating and renal mononuclear or T cell numbers were similar between control and MatSep rats (n=4-11/group, p>0.05). Both groups presented similar percentages of circulating macrophages and T H , T C , and T reg cells (n=4, p>0.05). However, the percentage of circulating B cells was significantly decreased in MatSep rats (23.7±1.2% vs. 20.1±0.7%; n=4, p<0.05). Pro-inflammatory cytokine IL-1Beta was significantly elevated in kidneys from MatSep rats (4.4±0.5 vs. 7.9±1.0 pg/mg prot; n=7-8/group; p<0.05). However, IFN-gamma, IL-6, and IL-4 were not different between control and MatSep rats. To further assess the immune system in MatSep and control rats, we acutely challenged adult rats with lipopolysaccharide (LPS; 2 mg/kg; i.v., 14 h). LPS significantly elevated renal expression of pro-inflammatory chemokine receptors (CCR3, CCR4, CXCR4), cytokines (IFN-gamma, CCL3, CCL4, IL-16), and activation markers (CD40, CD40lg) in MatSep rats (4 to 6 fold increase; n=5/group, p<0.05), suggesting that MatSep induces an exaggerated pro-inflammatory renal immune response to LPS. In conclusion, early life stress induces a renal pro-inflammatory status in adulthood that leads to sensitization to further immune challenges. Funded by P01 HL 69999 to JSP, NIH T32 DK007545 to CDM, F32 HL 116145 to DHH and K99/R00 HL 111354 to ASL.

scholarly journals Repeated Three-Hour Maternal Separation Induces Depression-Like Behavior and Affects the Expression of Hippocampal Plasticity-Related Proteins in C57BL/6N Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yaoyao Bian ◽  
Lili Yang ◽  
Zhongli Wang ◽  
Qing Wang ◽  
Li Zeng ◽  
...  
Keyword(s):  
Early Life ◽  
Maternal Separation ◽  
Forced Swimming Test ◽  
Life Experiences ◽  
Tail Suspension Test ◽  
Early Life Stages ◽  
Early Life Adversity ◽  
Swimming Test ◽  
Related Proteins ◽  
The Brain

Adverse early life experiences can negatively affect behaviors later in life. Maternal separation (MS) has been extensively investigated in animal models in the adult phase of MS. The study aimed to explore the mechanism by which MS negatively affects C57BL/6N mice, especially the effects caused by MS in the early phase. Early life adversity especially can alter plasticity functions. To determine whether adverse early life experiences induce changes in plasticity in the brain hippocampus, we established an MS paradigm. In this research, the mice were treated with mild (15 min, MS15) or prolonged (180 min, MS180) maternal separation from postnatal day 2 to postnatal day 21. The mice underwent a forced swimming test, a tail suspension test, and an open field test, respectively. Afterward, the mice were sacrificed on postnatal day 31 to determine the effects of MS on early life stages. Results implied that MS induces depression-like behavior and the effects may be mediated partly by interfering with the hippocampal GSK-3β-CREB signaling pathway and by reducing the levels of some plasticity-related proteins.

scholarly journals Early life adversity alters normal sex-dependent developmental dynamics of DNA methylation

2016 ◽  
Vol 28 (4pt2) ◽  
pp. 1259-1272 ◽  
Author(s):  
Renaud Massart ◽  
Zsofia Nemoda ◽  
Matthew J. Suderman ◽  
Sheila Sutti ◽  
Angela M. Ruggiero ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Early Life ◽  
Maternal Separation ◽  
Methylation Profile ◽  
Early Life Adversity ◽  
Developmental Evolution ◽  
Dna Methylation Profile ◽  
Males And Females ◽  
The Difference ◽  
The Impact

AbstractStudies in rodents, nonhuman primates, and humans suggest that epigenetic processes mediate between early life experiences and adult phenotype. However, the normal evolution of epigenetic programs during child development, the effect of sex, and the impact of early life adversity on these trajectories are not well understood. This study mapped the genome-wide DNA methylation changes in CD3+ T lymphocytes from rhesus monkeys from postnatal day 14 through 2 years of age in both males and females and determined the impact of maternal deprivation on the DNA methylation profile. We show here that DNA methylation profiles evolve from birth to adolescence and are sex dependent. DNA methylation changes accompany imposed weaning, attenuating the difference between males and females. Maternal separation at birth alters the normal evolution of DNA methylation profiles and targets genes that are also affected by a later stage maternal separation, that is, weaning. Our results suggest that early life events dynamically interfere with the normal developmental evolution of the DNA methylation profile and that these changes are highly effected by sex.

scholarly journals Trajectories of Mother-Infant Communication: An Experiential Measure of the Impacts of Early Life Adversity

2021 ◽  
Vol 15 ◽  
Author(s):  
Lauren Granata ◽  
Alissa Valentine ◽  
Jason L. Hirsch ◽  
Jennifer Honeycutt ◽  
Heather Brenhouse
Keyword(s):  
Maternal Care ◽  
Early Life ◽  
Maternal Separation ◽  
Developmental Trajectories ◽  
Later Life ◽  
Developmental Trajectory ◽  
Acoustic Properties ◽  
Emission Rates ◽  
Acoustic Parameters ◽  
Early Life Adversity

Caretaking stability in the early life environment supports neurobehavioral development, while instability and neglect constitute adverse environments that can alter maturational processes. Research in humans suggests that different types of early life adversity (ELA) can have differential effects on caretaker relationships and later cognitive and social development; however, identifying mechanistic underpinnings will require animal models with translational validity. Two common rodent models, maternal separation (MS) and limited bedding (LB), influence the mother-infant relationship during a critical window of development. We hypothesized that these paradigms may affect the development of communication strategies on the part of the pup. Ultrasonic vocalizations (USVs) are a care-eliciting mechanism and ethologically relevant response to stressors in the rat pup. USV emission rates and acoustic parameters change throughout early development, presenting the opportunity to define developmental milestones in USVs that would reflect neurobehavioral aberrations if disrupted. This study investigated the effects of MS or LB on the dam-pup relationship by quantifying pup USVs, maternal behavior, and the relationship between the two. First, we used a generalized additive model approach to establish typical developmental trajectories of USV acoustic properties and determine windows of change in MS or LB rearing. Additionally, we quantified maternal behaviors and the predictability of maternal care sequences using an entropy rate calculation. MS and LB each shifted the developmental trajectories of USV acoustic parameters and call types in a sex-specific manner. MS more often impacted male USVs, while LB impacted female USVs. MS dams spent more time passive nursing, and LB dams spent more time on the nest. The predictability of maternal care was associated with the rate of USV emissions exclusively in females. Taken together, findings demonstrate sex- and model-specific effects of rearing environments on a novel developmental trajectory involving the mother-infant relationship, facilitating the translation of animal ELA paradigms to assess later-life consequences.

scholarly journals Effects of early life adversity on meningeal mast cells and proinflammatory gene expression in male and female Mus musculus

2021 ◽  
Author(s):  
Natalia Duque-Wilckens ◽  
Erika Sarno ◽  
Robby E. Teis ◽  
Frauke Stoelting ◽  
Sonia Khalid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Early Life ◽  
Inflammatory Markers ◽  
Disease Susceptibility ◽  
Early Life Adversity ◽  
Male And Female ◽  
The Brain

ABSTRACTExposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.

Glucocorticoid receptor signaling in leukocytes after early life adversity

2019 ◽  
Vol 32 (3) ◽  
pp. 853-863 ◽  
Author(s):  
Martha M. C. Elwenspoek ◽  
Xenia Hengesch ◽  
Fleur A. D. Leenen ◽  
Krystel Sias ◽  
Sara Beatriz Fernandes ◽  
...  
Keyword(s):  
Immune System ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Early Life ◽  
Promoter Region ◽  
Target Genes ◽  
Early Life Adversity ◽  
Time Points ◽  
Biological Parents ◽  
Separation From Parents

AbstractEarly life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

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