Immune Modulatory Activities of Arginyl-Fructose (AF) and AF-Enriched Natural Products in In-Vitro and In-Vivo Animal Models.

The immune system plays an important role in maintaining body homeostasis. Recent studies on the immune-enhancing effects of ginseng saponins have revealed more diverse mechanisms of action. Maillard reaction that occurs during the manufacturing processes of red ginseng produces a large amount of Amadori rearrangement compounds (ARCs), such as arginyl-fructose (AF). The antioxidant and anti-hyperglycemic effects of AF have been reported. However, the possible immune enhancing effects of non-saponin ginseng compounds, such as AF, have not been investigated. In this study the effects of AF and AF-enriched natural product (Ginofos, GF) on proliferation of normal mouse splenocytes were evaluated in vitro and male BALB/c mice models. The proliferation of splenocytes treated with mitogens (concanavalin A, lipopolysaccharide) were further increased by addition of AF (p < 0.01) or GF (p < 0.01), in a dose dependent manner. After the 10 days of oral administration of compounds, changes in weights of spleen and thymus, serum immunoglobulin, and expression of cytokines were measured as biomarkers of immune-enhancing potential in male BALB/c mice model. The AF or GF treated groups had higher weights of the thymus (0.94 ± 0.25 and 0.86 ± 0.18, p < 0.05, respectively) than that of cyclophosphamide treated group (0.59 ± 0.18). This result indicates that AF or AF-enriched extract (GF) increased humoral immunity against CY-induced immunosuppression. In addition, immunoglobulin contents and expression of cytokines including IgM (p < 0.01), IgG (p < 0.05), IL-2 (p < 0.01), IL-4 (p < 0.01), IL-6 (p < 0.01), and IFN-γ (p < 0.05) were also significantly increased by supplementation of AF or GF. These results indicate that AF has immune enhancing effects by activation of adaptive immunity via increase of expression of immunoglobulins and cytokines such as IgM, IgG, IL-2, IL-4, IL-6 and thereby proliferating the weight of thymus. Our findings provide a pharmacological rationale for AF-enriched natural products such as ginseng and red ginseng that can possibly have immune-enhancement potential and should be further evaluated.

Peripheral Immunosenescence and Central Neuroinflammation: A Dangerous Liaison - A Dietary Approach.

BACKGROUND & OBJECTIVES: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS). AIMS: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases. DISCUSSION: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer's disease, Parkinson's disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics. CONCLUSION: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.

Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Systems Biology Views of Vaccine Innate and Adaptive Immunity.

During the last decade, several high-throughput technologies have been applied to gather deeper understanding on the biological events elicited by vaccination. The main goal of systems biology is to integrate different sources of data and extract biologically meaningful information. This holistic approach has provided new insights on the impact that the innate immune status has on vaccine responsiveness. Other factors like chronic infections, age, microbiome, and metabolism can influence the outcome of vaccination, and systems biology offers unique opportunities to expand our understanding of their role on the immune response. However, a few challenges that still need to be overcome will be discussed.

Auditory closed-loop stimulation of EEG slow oscillations strengthens sleep and signs of its immune-supportive function.

Sleep is essential for health. Slow wave sleep (SWS), the deepest sleep stage hallmarked by electroencephalographic slow oscillations (SOs), appears of particular relevance here. SWS is associated with a unique endocrine milieu comprising minimum cortisol and high aldosterone, growth hormone (GH), and prolactin levels, thereby presumably fostering efficient adaptive immune responses. Yet, whether SWS causes these changes is unclear. Here we enhance SOs in men by auditory closed-loop stimulation, i.e., by delivering tones in synchrony with endogenous SOs. Stimulation intensifies the hormonal milieu characterizing SWS (mainly by further reducing cortisol and increasing aldosterone levels) and reduces T and B cell counts, likely reflecting a redistribution of these cells to lymphoid tissues. GH remains unchanged. In conclusion, closed-loop stimulation of SOs is an easy-to-use tool for probing SWS functions, and might also bear the potential to ameliorate conditions like depression and aging, where disturbed sleep coalesces with specific hormonal and immunological dysregulations.

Acute Effects on the Counts of Innate and Adaptive Immune Response Cells After 1 Month of Taoist Qigong Practice.

BACKGROUND: Qigong is an ancient form of health maintenance, dating back thousands of years, which is part of Traditional Chinese Medicine. Numerous physical as well as mental benefits have been classically ascribed to this traditional mind-body method which integrates slow body movements, breathing, and meditation. Albeit we have already reported an immunomodulatory action of qigong in other investigations, measures were then assessed 1 day after the qigong program ended. PURPOSE: The aim of the present study was to assess the acute effects of Taoist qigong practice on immune cell counts in healthy subjects 1 h after training. METHOD: Forty-three healthy subjects participated in the study of whom 25 were randomly allocated to the experimental group and 18 to the control group. The experimental subjects underwent daily qigong training for 1 month. Blood samples for the quantification of immune parameters (number and percentage of monocytes, neutrophils, eosinophils, total lymphocytes, B lymphocytes, and natural killer (NK) cells) were taken the day before the experiment commenced and 1 h after the last session of the training program ended. As statistical analysis, analysis of covariance (ANCOVA) was performed. RESULTS: Statistically significant differences were found between the experimental and control groups, with the experimental group showing higher values in the number (p = 0.006) and the percentage (p = 0.04) of B lymphocytes, as well as lower values in the percentage of NK cells (p = 0.05), as compared to control. CONCLUSION: This study demonstrates that Taoist qigong is able to exert acute immunomodulatory effects on components of both innate as well as adaptive immune response.

BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Impact of mineral and vitamin status on beef cattle immune function and health.

The importance of optimal mineral and vitamin nutrition on improving immune function and health has been recognized in the preceding decades. In the southeast, beef cattle are raised predominantly on forages that may be limiting in nutrients for optimal health, especially trace minerals such as Cu, Zn, and Se. Clinical deficiencies of these nutrients produce classic symptoms that are common to several nutrient deficiencies (e.g., slow growth and unthrifty appearance); however, subclinical deficiencies are more widespread and more difficult to detect, yet may result in broader economic losses. Dietary mineral concentrations often considered adequate for maximum growth, reproductive performance, or optimal immune function have been found to be insufficient at times of physiological stress (weaning, transport, comingling, etc.), when feed intake is reduced. The impacts of these deficiencies on beef cattle health are not apparent until calves have been subjected to these stressors. Health problems that are exacerbated by mineral or vitamin deficiencies include bovine respiratory disease, footrot, retained placenta, metritis, and mastitis. Many micronutrients have antioxidant properties through being components of enzymes and proteins that benefit animal health. In dairy cattle, high levels of supplemental Zn are generally associated with reduced somatic cell counts and improved foot health, possibly reflecting the importance of Zn in maintaining effective epithelial barriers. Neutrophils isolated from ruminants deficient in Cu or Se have reduced ability to kill ingested bacteria in vitro. Supplemental vitamin E, in its role as an intracellular antioxidant has been shown to decrease morbidity in stressed calves. There is more understanding of the important biological role that these nutrients play in the functioning of the complex and multifaceted immune system. However, there is still much to be learned about determining the micronutrient status of herds (and hence when supplementation will be beneficial), requirements for different genetic and environmental conditions, understanding the bioavailability of these nutrients from feedstuffs and forages, quantifying the bioavailability of different supplemental sources of these nutrients, and identifying the impact of dietary antagonists on these nutrients.

Effect of low dosage of chito-oligosaccharide supplementation on intestinal morphology, immune response, antioxidant capacity, and barrier function in weaned piglets.

This study was conducted to determine the effect of dietary supplementation of a low dose of chito-oligosaccharide (COS) on intestinal morphology, immune response, antioxidant capacity, and barrier function in weaned piglets. A total of 120 weaned pigs (21 d of age; 7.86 ± 0.22 kg average BW) were randomly assigned (6 pens/diet; 10 pigs/pen) to 2 dietary treatments consisting of a basal diet (negative control) or the basal diet supplemented with COS (30 mg/kg) for a 14-d period. Six randomly selected piglets from each treatment were killed for blood and tissue sampling. No significant differences were observed in ADG, ADFI, and G:F between treatment and the control group. Piglets fed the COS-supplemented diet had greater ( < 0.05) stomach pH than those fed the control diet on d 14 postweaning. Dietary supplementation with COS reduced villus height ( < 0.05) and villus height:crypt depth ( < 0.05) in the ileum. Dietary COS supplementation tended to reduce villus height in the duodenum ( = 0.065) and jejunum ( = 0.058). There was no effect on crypt depth in the intestinal segments of treatment group. Piglets fed the COS-supplemented diet increased ( < 0.05) the number of intraepithelial lymphocytes in duodenum or jejunum and goblet cells of ileum. However, COS decreased ( < 0.05) the number of intraepithelial lymphocytes in ileum of weaned piglets. The concentrations of IL-10 (duodenum, jejunum, and ileum) and secretory immunoglobulin (SIgA; duodenum and ileum) were higher in piglets fed the COS-supplemented diet compared with control ( < 0.05). Dietary COS supplementation reduced ( < 0.05) the concentration of total antioxidant capacity and superoxide dismutase of the jejunum or ileum. The mRNA expression of occludin in the ileum and ZO-1 in jejunum and ileum had a significant change in piglets fed the COS-supplemented diet compared with the control group ( < 0.05). In conclusion, these results indicated that dietary COS supplementation at 30 mg/kg had no effects on promoting growth performance and tended to reduce villus height in the duodenum or jejunum of weaned piglets. The results further showed that supplemental COS at this level may cause an immune and oxidative stress response in small intestine and have compromised the intestinal barrier integrity in weaned piglets. The research will provide guidance on the low dosage of COS supplementation on weaning pigs.

Inflammation, immunity, and hypertensive end-organ damage.

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

25-hydroxyvitamin D3 status is associated with developing adaptive and innate immune responses in the first 6 months of life.

BACKGROUND: Vitamin D (25[OH]D3) status in early life has been linked to the risk of allergic disease in multiple observational studies. While immunomodulating properties are well recognized, there are few longitudinal studies of 25(OH)D3 status, immune function and allergic disease in infants. OBJECTIVE: To investigate 25(OH)D3 levels at birth [cord blood (CB)] and at 6 months of age in relation to immune function at 6 months of age, and clinical outcomes up to 30 months of age in infants with a maternal history of atopy. METHODS: In a subset of infants (n = 225) enrolled in a RCT (ACTRN12606000281594), 25(OH)D3 levels were assessed in relation to peripheral blood mononuclear cell cytokine responses to house dust mite (HDM), ovalbumin (OVA) and ß-lactoglobulin allergens, or Toll-like receptor (TLR) ligands (lipopolysaccharide, lipoteichoic acid, polyinosinic : polycytidylic acid and CpG oligonucleotide) at 6 months of age, in addition to clinical outcomes (eczema, wheeze and allergen sensitisation) up to 30 months of age. RESULTS: Infants with higher 25(OH)D3 at birth (≥ 75 nmol/L, compared with < 50 nmol/L) had lower IL-5 and IL-13 responses to HDM by 6 months (P < 0.001 and P = 0.003, respectively). This was also reflected in strong inverse correlations between CB 25(OH)D3 levels and HDM IL-13 (ρ = -0.57; P = 0.0002) and IL-5 (ρ = -0.59, P = 0.0001) responses, with a similar trend for IL-5 (ρ = -0.29; P = 0.009) responses to OVA. For innate stimulations, higher 25(OH)D3 levels at 6 months were associated with greater responses to TLR ligands. Additionally, higher CB 25(OH)D3 was associated with reduced risk eczema at 6 months (P = 0.011) and 12 months (P = 0.034). CONCLUSION: This suggests that improving 25(OH)D3 status in pregnancy or early infancy may reduce the development of allergic disease in high-risk infants by inhibiting cytokine profiles associated with allergy. Results of clinical trials are awaited to determine the efficacy of vitamin D supplementation in allergy prevention.

The gut microbiome and the brain.

The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.

Innate and adaptive immune responses of snatch-farrowed porcine-colostrum-deprived pigs to Mycoplasma hyopneumoniae vaccination.

BACKGROUND: The snatch-farrowed porcine-colostrum-deprived (SF-pCD) pig model, in which neonates are raised on commercially available bovine colostrum, is an alternative model for porcine infectious disease research. It is not known if SF-pCD pigs possess growth performance and immunity comparable to conventional, farm-raised pigs. The current experiment compared growth performance and immune responses of SF-pCD pigs to their farm-raised siblings following Mycoplasma hyopneumoniae (Mhyo) vaccination. Twelve SF-pCD and 13 farm-raised siblings were vaccinated on day 7 (D7) and D26 of age. Body weights were measured once or twice weekly and average daily gain (ADG) was calculated. Peripheral blood mononuclear cells (PBMC) were isolated on D40. Cytokine secretion from PBMC stimulated with Mhyo antigen or phorbol myristate acetate plus ionomycin (PMA/Iono) was assessed using a multiplexed fluorescent microsphere immunoassay (FMIA). Additionally, interferon gamma (IFNγ) secretion from stimulated PBMC was assessed using ELISPOT. Mhyo IgG titers were measured by an ELISA in D40 sera. RESULTS: Growth performance did not differ between groups before weaning, but SF-pCD pigs had higher ADG after weaning. In response to Mhyo stimulation, numbers of IFNγ secreting PBMC and levels of interleukin 8 (IL8) and IL10 in PBMC supernatants were significantly higher in SF-pCD pigs, as were Mhyo antibody levels in sera, and levels of IL1ß, IL8 and IL12 in supernatants of PMA/Iono stimulated PBMC. CONCLUSIONS: Under the conditions of this experiment, SF-pCD pigs demonstrated superior growth performance and enhanced humoral and cell-mediated immunity following vaccination. Whether or not this reflects greater resistance or tolerance to infection is unknown but the ability to react positively to the vaccination provides evidence that SF-pCD pigs are a suitable alternative model for swine disease research.

In vitro approaches to pharmacological screening in the field of atopic dermatitis.

In vitro models are valuable for evaluating potential active ingredients and other molecules used in medications for atopic dermatitis (AD). However, finding appropriate in vitro models can be problematic. Our strategy was to set up different in vitro models that would mimic the pathomechanisms of AD. We describe five such models - the AD keratinocyte model, the AD reconstructed human epidermis model, the adaptive immunity model, the innate immunity model and the pruritus model - which we have used to evaluate a new ingredient for emollients derived from a biological extract. The models chosen provide useful data for the pharmacological characterization of active ingredients in adjunctive treatments for AD.

Vitamin D and immune function.

Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.

Vitamin D and cardiovascular disease: is the evidence solid?

Vitamin D deficiency, prevalent in 30-50% of adults in developed countries, is largely due to inadequate cutaneous production that results from decreased exposure to sunlight, and to a lesser degree from low dietary intake of vitamin D. Serum levels of 25-hydroxyvitamin D (25-OH D) <20 ng/mL indicate vitamin D deficiency and levels >30 ng/mL are considered optimal. While the endocrine functions of vitamin D related to bone metabolism and mineral ion homoeostasis have been extensively studied, robust epidemiological evidence also suggests a close association between vitamin D deficiency and cardiovascular morbidity and mortality. Experimental studies have demonstrated novel actions of vitamin D metabolites on cardiomyocytes, and endothelial and vascular smooth muscle cells. Low 25-OH D levels are associated with left ventricular hypertrophy, vascular dysfunction, and renin-angiotensin system activation. Despite a large body of experimental, cross-sectional, and prospective evidence implicating vitamin D deficiency in the pathogenesis of cardiovascular disease, a causal relationship remains to be established. Moreover, the cardiovascular benefits of normalizing 25-OH D levels in those without renal disease or hyperparathyroidism have not been established, and questions of an epiphenomenon where vitamin D status merely reflects a classic risk burden have been raised. Randomized trials of vitamin D replacement employing cardiovascular endpoints will provide much needed evidence for determining its role in cardiovascular protection.

Circadian control of the immune system.

Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.

Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer.

Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.

Vitamin D and influenza.

Vitamin D has become increasingly recognized in the literature for its extra-skeletal roles, including an effect on inflammation and the immune response to infection. Our goal was to describe the role of vitamin D in the immune response and implications for the risk of influenza infection in humans. In this review, we first consider literature that provides molecular and genetic support to the idea that vitamin D is related to the adaptive and innate immune responses to influenza infection in vitro and in animal models. We then discuss observational studies and randomized controlled trials of vitamin D supplementation in humans. Finally, we consider some of the knowledge gaps surrounding vitamin D and immune response that must be filled.

Vitamin D metabolism and signaling in the immune system.

Vitamin D has emerged as a pleiotropic regulator of human physiology, and recent work has revealed that it has several roles in control of human immune system function. Vitamin D was originally characterized for its role in calcium homeostasis, and the active form, 1,25-dihydroxyvitamin D (1,25D), can be produced in the kidney by 1α-hydroxylation of circulating 25-hydroxyvitamin D catalyzed by the enzyme CYP27B1. Renal CYP27B1 expression is regulated by calcium regulatory inputs, and 1,25D produced in the kidney was thought to function largely as an endocrine hormone. However, it is now clear that CYP27B1 is expressed in numerous tissues, and that 1,25D acts at several sites in the body in an intracrine or paracrine manner. In particular, both CYP27B1 and the vitamin D receptor (VDR) are expressed in several cell types in the immune system, where CYP27B1 production is controlled by a number of immune-specific inputs. Recent research has opened several windows on the molecular mechanisms by which 1,25D signaling regulates both innate and adaptive immune responses in humans. Moreover, intervention trials are beginning to provide evidence that vitamin D supplementation can bolster clinical responses to infection. This review will discuss recent developments in our understanding of how immune signaling controls local vitamin D metabolism and how, in turn, the 1,25D-bound VDR modulates immune system function. A particular emphasis will be placed on the interplay between vitamin D signaling and signaling through different classes of pattern recognition receptors in the production of antimicrobial peptides during innate immune responses to microbial infection.