Sex differences in the impact of childhood socioeconomic status on immune function.

Early life stress increases one's risk for health problems later in life, and many studies find that these effects are sex-differentiated. Here, we examined relationships between multiple sources of early life stress and adult immune function in humans across several functional assays. Adult participants provided retrospective information about their childhood (a) socioeconomic status, (b) household unpredictability, and (c) exposure to adverse experiences. Participants' peripheral blood mononuclear cells (PBMCs) were then isolated for use in functional assays of immune performance: (a) tumor cell lysis by natural killer cells, (b) phagocytosis of Escherichia coli bioparticles, and (c) mitogen-induced leukocyte proliferation and cytokine release. In men, lower childhood socioeconomic status predicted decrements in immunological performance across functional assays, along with greater spontaneous cytokine release from PBMCs. These changes co-occurred with elevations in plasma testosterone levels. Similar effects were not observed for other sources of stress, nor were they found in women (with the exception of spontaneous cytokine release). These findings provide evidence that low childhood socioeconomic status has a lasting negative impact on multiple aspects of immune function, particularly in men.

Day length predicts investment in human immune function: Shorter days yield greater investment.

Winter is characterized by stressful conditions which compromise health and render animals more vulnerable to infection and illness than during other times of the year. Organisms are hypothesized to adapt to these seasonal stressors by increasing investment in immune function in response to diminished photoperiod duration. Here, we examined this hypothesis in a sample of healthy human participants. Using several functional immune assays in vitro, as well as by utilizing measures of in vivo proinflammatory cytokine levels, we predicted that shorter day length would be associated with greater investment in immunological function. Results revealed that shorter days predicted significant upregulation of several facets of immune function, including natural killer cell cytotoxicity, peripheral blood mononuclear cell proliferation (in response to, and in the absence of stimulation), and plasma levels of interleukin-6, as well as lower rates of Staphylococcus aureus growth in serum ex vivo. Further, consistent with the hypothesis that these trade-offs would be offset by decreased investment in mating effort, shorter day length also predicted lower levels of total testosterone in men. These results suggest that ambient photoperiod may be a powerful regulator of human immunological activity, providing some of the first evidence of seasonal changes in multiple facets of human immune function.

Inflammation Predicts Decision-Making Characterized by Impulsivity, Present Focus, and an Inability to Delay Gratification.

Here, we propose a novel theoretical model linking present-focused decision-making to the activities of the immune system. We tested our model by examining the relationship between inflammatory activity - in vivo and in vitro - and decision-making characterized by impulsivity, present focus, and an inability to delay gratification. Results support our model, revealing that inflammation predicts these outcomes even after controlling for factors that may contribute to a spurious linkage between them. Moreover, subsequent analyses revealed that our model was a better fit for the data than alternative models using present-focused decision-making and its health-harming behavioural sequelae (e.g., smoking, risky sexual behaviour) to predict inflammation, lending support for the proposed directionality of this relationship. Together, these results suggest that inflammation may contribute to decision-making patterns that can result in undesirable personal and societal outcomes.

Behavioral immune system activity predicts downregulation of chronic basal inflammation.

Here, we present a mechanistically grounded theory detailing a novel function of the behavioral immune system (BIS), the psychological system that prompts pathogen avoidance behaviors. We propose that BIS activity allows the body to downregulate basal inflammation, preventing resultant oxidative damage to DNA and promoting longevity. Study 1 investigated the relationship between a trait measure of pathogen avoidance motivation and in vitro and in vivo proinflammatory cytokine production. Study 2 examined the relationship between this same predictor and DNA damage often associated with prolonged inflammation. Results revealed that greater trait pathogen avoidance motivation predicts a) lower levels of spontaneous (but not stimulated) proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs), b) lower plasma levels of the proinflammatory cytokine interleukin-6 (IL-6), and c) lower levels of oxidative DNA damage. Thus, the BIS may promote health by protecting the body from the deleterious effects of inflammation and oxidative stress.

Probiotic Streptococcus thermophilus FP4 and Bifidobacterium breve BR03 Supplementation Attenuates Performance and Range-of-Motion Decrements Following Muscle Damaging Exercise.

Probiotics have immunomodulatory effects. However, little is known about the potential benefit of probiotics on the inflammation subsequent to strenuous exercise. In a double-blind, randomized, placebo controlled, crossover design separated by a 21-day washout, 15 healthy resistance-trained men ingested an encapsulated probiotic Streptococcus (S.) thermophilus FP4 and Bifidobacterium (B.) breve BR03 at 5 bn live cells (AFU) concentration each, or a placebo, daily for 3 weeks prior to muscle-damaging exercise (ClinicalTrials.gov NCT02520583). Isometric strength, muscle soreness, range of motion and girth, and blood interleukin-6 (IL-6) and creatine kinase (CK) concentrations were measured from pre- to 72 h post-exercise. Statistical analysis was via mixed models and magnitude-based inference to the standardized difference. Probiotic supplementation resulted in an overall decrease in circulating IL-6, which was sustained to 48 h post-exercise. In addition, probiotic supplementation likely enhanced isometric average peak torque production at 24 to 72 h into the recovery period following exercise (probiotic-placebo point effect ±90% CI: 24 h, 11% ± 7%; 48 h, 12% ± 18%; 72 h, 8% ± 8%). Probiotics also likely moderately increased resting arm angle at 24 h (2.4% ± 2.0%) and 48 h (1.9% ± 1.9%) following exercise, but effects on soreness and flexed arm angle and CK were unclear. These data suggest that dietary supplementation with probiotic strains S. thermophilus FP4 and B. breve BR03 attenuates performance decrements and muscle tension in the days following muscle-damaging exercise.

Peripheral administration of poly I:C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse.

Alzheimer's disease (AD) is a progressive disorder characterized by neuronal and behavioral deterioration. Two hallmark pathologies of AD are amyloid-beta (Aß) plaques and neurofibrillary tangles, and the presence of such pathology can limit cell-to-cell communication, leading to cognitive deficits, and neuronal cell death. Although Aß plaques were originally thought to cause the cognitive deficits, more simple forms of Aß, such as monomers, dimers, tetramers and oligomers, have also been shown to be neurotoxic. Moreover, chronic inflammation has also been implicated in the onset and progression of these AD-related pathologies. The current study was designed to further our understanding of peripheral inflammation-induced AD-like pathology, by administering polyinosinic:polycytidylic acid (poly I:C), a viral mimetic. Mice were administered intraperitoneal injections of poly I:C or saline once daily for 7 consecutive days. Hippocampal tissue from animals receiving poly I:C contained significantly higher levels of the Aß1₋42 peptide. Even after ensuring that potential sickness behavior could not confound cognitive testing, we found that animals administered poly I:C displayed significant cognitive deficits in the hippocampus-dependent contextual fear conditioning paradigm. These results confirm our hypothesis that peripheral inflammation can lead to increased levels of hippocampal-Aß and associated cognitive deficits.

Imatinib methanesulfonate reduces hippocampal amyloid-ß and restores cognitive function following repeated endotoxin exposure.

Alzheimer's disease (AD) is characterized, in part, by atrophy of the adult brain and increased presence of extracellular amyloid-beta (Aß) plaques. Previous studies in our lab have shown that peripheral inflammation can lead to increased central Aß and deficits in learning and memory. In order to determine whether Aß accumulation in the brain is responsible for the learning deficits, we attempted to decrease peripheral production of Aß in order to reduce central Aß accumulation. It has previously been shown that Aß is produced in large quantities in the liver, and is transferred across the blood-brain barrier (BBB). Recent research has shown that peripheral treatment with imatinib methanesulfonate salt (IM), known to interfere with the interaction between gamma (γ)-secretase and the γ-secretase activating protein (GSAP), decreases the cleavage of peripheral amyloid precursor protein into Aß. Because IM poorly penetrates the BBB, we hypothesized that co-administration of IM with LPS would decrease peripheral production of Aß in the presence of LPS-induced inflammation, leading to a decrease in Aß accumulation in the hippocampus. We show that peripheral IM treatment eliminates hippocampal Aß elevation that follows LPS-induced peripheral inflammation. Importantly, IM also eliminates the cognitive impairment seen following seven consecutive days of LPS administration, implicating Aß peptides as a likely cause of these cognitive deficits.

Peripheral administration of D-cycloserine rescues memory consolidation following bacterial endotoxin exposure.

In the current study, the partial NMDA receptor agonist D-cycloserine (DCS) rescued memory consolidation following systemic bacterial endotoxin exposure. DCS failed, however, to restore hippocampal BDNF mRNA levels that were diminished following a systemic administration of LPS, and did not alter NR1 or NR2C NMDA receptor subunit expression. These results extend prior research into the role of DCS in neural-immune interactions, and indicate that the detrimental effects of peripheral LPS administration on consolidation of contextual fear memory may be ameliorated with DCS treatment, though the mechanisms underlying these effects are currently unclear.