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Epidemiological evidence suggests that a high intake of plant foods is associated with lower risk of chronic diseases. However, the mechanism of action and the components involved in this effect have not been identified clearly. In recent years, the scientific community has agreed to focus its attention on a class of secondary metabolites extensively present in a wide range of plant foods: the flavonoids, suggested as having different biological roles. The anti-inflammatory actions of flavonoids in vitro or in cellular models involve the inhibition of the synthesis and activities of different pro-inflammatory mediators such as eicosanoids, cytokines, adhesion molecules and C-reactive protein. Molecular activities of flavonoids include inhibition of transcription factors such as NF-κB and activating protein-1 (AP-1), as well as activation of nuclear factor-erythroid 2-related factor 2 (Nrf2). However, the in vitro evidence might be somehow of limited impact due to the non-physiological concentrations utilized and to the fact that in vivo flavonoids are extensively metabolized to molecules with different chemical structures and activities compared with the ones originally present in the food. Human studies investigating the effect of flavonoids on markers of inflammation are insufficient, and are mainly focused on flavonoid-rich foods but not on pure molecules. Most of the studies lack assessment of flavonoid absorption or fail to associate an effect on inflammation with a change in circulating levels of flavonoids. Human trials with appropriate placebo and pure flavonoid molecules are needed to clarify if flavonoids represent ancillary ingredients or key molecules involved in the anti-inflammatory properties of plant foods.
It is well known that the consumption of dietary polyphenols leads to beneficial effects for human health as in the case of prevention and/or attenuation of cardiovascular, inflammatory, neurodegenerative and neoplastic diseases. This review summarizes the role of polyphenols from red wine in the immune function. In particular, using healthy human peripheral blood mononuclear cells, we have demonstrated the in vitro ability of Negroamaro, an Italian red wine, to induce the release of nitric oxide and both pro-inflammatory and anti-inflammatory cytokines, thus leading to the maintenance of the immmune homeostasis in the host. All these effects were abrogated by deprivation of polyphenols from red wine samples. We have also provided evidence that Negromaro polyphenols are able to activate extracellular regulated kinase and p38 kinase and switch off the NF-κB pathway via an increased expression with time of the IκBα phosphorylated form. These mechanisms may represent key molecular events leading to inhibition of the pro-inflammatory cascade and atherogenesis. In conclusion, according to the current literature and our own data, moderate consumption of red wine seems to be protective for the host in the prevention of several diseases, even including aged-related diseases by virtue of its immunomodulating properties.
Vitamin D and the vitamin D receptor (VDR) have been shown to be important regulators of the immune system. In particular, vitamin D and VDR deficiency exacerbates experimental autoimmune diseases such as inflammatory bowel disease (IBD). IBD develops due to an immune-mediated attack by pathogenic T-cells that overproduce IL-17 and IFN-γ and a few regulatory cells. VDR knockout mice have twice as many T-cells making IL-17 and IFN-γ than wild-type mice. In addition, vitamin D and the VDR are required for normal numbers of regulatory T-cells (iNKT and CD8αα) that have been shown to suppress experimental IBD. In the absence of vitamin D and the VDR, autoimmunity occurs in the gastrointestinal tract due to increased numbers of IL-17 and IFN-γ secreting T-cells and a concomitant reduction in regulatory T-cells.
Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. The nutritional factor, zinc, may remodel these changes with subsequent healthy ageing, because zinc improves the inflammatory/immune response as shown by in vitro and in vivo studies. The intracellular zinc homeostasis is regulated by buffering metallothioneins (MT) and zinc transporters (ZnT and ZIP families) that mediate the intracellular zinc signalling assigning to zinc a role of ‘second messenger’. In ageing, the intracellular zinc homeostasis is altered, because high MT are unable to release zinc and some zinc transporters deputed to zinc influx (ZIP family) are defective leading to low intracellular zinc content for the immune efficiency. Physiological zinc supplementation in the elderly improves these functions. However, the choice of old subjects for zinc supplementation has to be performed in relation to the specific genetic background of MT and IL-6, because the latter is involved both in MTmRNA and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (C–carriers) in the IL-6–174G/C locus display high IL-6, low intracellular zinc content, impaired innate immunity and enhanced MT. Old subjects carrying GC and CC genotypes (C+carriers) display satisfactory intracellular zinc content, adequate innate immunity and are more prone to reach longevity. Zinc supplementation in old C–carriers restores natural killer cell cytotoxicity and zinc status. The genetic variations of the IL-6−174G/C locus when associated with those of the MT1A+647A/C locus are useful tools for the choice of old people for zinc supplementation.
Selenium (Se) has been known for many years to have played a role in boosting the immune function, but the manner in which this element acts at the molecular level in host defence and inflammatory diseases is poorly understood. To elucidate the role of Se-containing proteins in the immune function, we knocked out the expression of this protein class in T-cells or macrophages of mice by targeting the removal of the selenocysteine tRNA gene using loxP-Cre technology. Mice with selenoprotein-less T-cells manifested reduced pools of mature and functional T-cells in lymphoid tissues and an impairment in T-cell-dependent antibody responses. Furthermore, selenoprotein deficiency in T-cells led to an inability of these cells to suppress reactive oxygen species production, which in turn affected their ability to proliferate in response to T-cell receptor stimulation. Selenoprotein-less macrophages, on the other hand, manifested mostly normal inflammatory responses, but this deficiency resulted in an altered regulation in extracellular matrix-related gene expression and a diminished migration of macrophages in a protein gel matrix. These observations provided novel insights into the role of selenoproteins in the immune function and tissue homeostasis.
The enrichment of immune cell membranes with n-3 PUFA is associated with modulation of immune function. The degree of incorporation of n-3 PUFA (and therefore the impact of dietary n-3 PUFA on immune function) appears to depend on a number of factors including species and age. The mechanisms involved are still largely unclear, but recent work has focused on two areas; lipid rafts and eicosanoids. In vitro studies suggest that lipid rafts could play a role in the immunomodulatory effects of n-3 PUFA, but there is still little information regarding the extent to which membrane microdomains in human lymphocytes are modulated by dietary supplementation. The enrichment of cell membranes with n-3 PUFA also modulates the production of eicosanoids, the full extent of which has not yet been realized; this represents a key area for future research.
Meta- and mega-analysis of randomised controlled trials indicate reduction in tender joint counts and decreased use of non-steroidal anti-inflammatory drugs with fish-oil supplementation in long-standing rheumatoid arthritis (RA). Since non-steroidal anti-inflammatory drugs confer cardiovascular risk and there is increased cardiovascular mortality in RA, an additional benefit of fish oil in RA may be reduced cardiovascular risk via direct mechanisms and decreased non-steroidal anti-inflammatory drug use. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and provision of substrates for synthesis of lipid suppressors of inflammation (resolvins). Future studies need progress in clinical trial design and need to shift from long-standing disease to examination of recent-onset RA. We are addressing these issues in a current randomised controlled trial of fish oil in recent-onset RA, where the aim is to intervene before joint damage has occurred. Unlike previous studies, the trial occurs on a background of drug regimens determined by an algorithm that is responsive to disease activity and drug intolerance. This allows drug use to be an outcome measure whereas in previous trial designs, clinical need to alter drug use was a ‘problem’. Despite evidence for efficacy and plausible biological mechanisms, the limited clinical use of fish oil indicates there are barriers to its use. These probably include the pharmaceutical dominance of RA therapies and the perception that fish oil has relatively modest effects. However, when collateral benefits of fish oil are included within efficacy, the argument for its adjunctive use in RA is strong.
Obesity leads to several chronic morbidities including type 2 diabetes, dyslipidaemia, atherosclerosis and hypertension, which are major components of the metabolic syndrome. White adipose tissue (WAT) metabolism and WAT-derived factors (fatty acids and adipokines) play an important role in the development of these metabolic disturbances. In fact, dysregulated adipokine secretion from the expanded WAT of obese individuals contributes to the development of systemic low-grade inflammation, insulin resistance and metabolic syndrome. The n-3 PUFA EPA and DHA have been widely reported to have protective effects in a range of chronic inflammatory conditions including obesity. In fact, n-3 PUFA have been shown to ameliorate low-grade inflammation in adipose tissue associated with obesity and up-regulate mitochondrial biogenesis and induce beta-oxidation in WAT in mice. Moreover, the ability of n-3 PUFA to regulate adipokine gene expression and secretion has been observed both in vitro and in vivo in rodents and human subjects. The present article reviews: (1) the physiological role of adiponectin, leptin and pre-B cell colony-enhancer factor/visfatin, three adipokines with immune-modulatory properties involved in the regulation of metabolism and insulin sensitivity and (2) the actions of n-3 PUFA on these adipokines focusing on the underlying mechanisms and the potential relationship with the beneficial effects of these fatty acids on obesity-associated metabolic disorders. It can be concluded that the ability of n-3 PUFA to improve obesity and insulin resistance conditions partially results from the modulation of WAT metabolism and the secretion of bioactive adipokines including leptin, adiponectin and visfatin.
Session 4: Dietary strategies to prevent and mitigate inflammatory diseases
Several epidemiological and clinical studies have evaluated the effects of a Mediterranean diet (Med-Diet) on total cardiovascular mortality, and all concluded that adherence to the traditional Med-Diet is associated with reduced cardiovascular risk. However, the molecular mechanisms involved are not fully understood. Since atherosclerosis is nowadays considered a low-grade inflammatory disease, recent studies have explored the anti-inflammatory effects of a Med-Diet intervention on serum and cellular biomarkers related to atherosclerosis. In a pilot study of the PREvencion con DIeta MEDiterranea (PREDIMED) trial, we analysed the short-term effects of two Med-Diet interventions, one supplemented with virgin olive oil and another with nuts, on vascular risk factors in 772 subjects at high risk for CVD, and in a second study we evaluated the effects of these interventions on cellular and serum inflammatory biomarkers in 106 high-risk subjects. Compared to a low-fat diet, the Med-Diet produced favourable changes in all risk factors. Thus, participants in both Med-Diet groups reduced blood pressure, improved lipid profile and diminished insulin resistance compared to those allocated a low-fat diet. In addition, the Med-Diet supplemented with virgin olive oil or nuts showed an anti-inflammatory effect reducing serum C-reactive protein, IL-6 and endothelial and monocytary adhesion molecules and chemokines, whereas these parameters increased after the low-fat diet intervention. In conclusion, Med-Diets down-regulate cellular and circulating inflammatory biomarkers related to atherogenesis in subjects at high cardiovascular risk. These results support the recommendation of the Med-Diet as a useful tool against CVD.
Social acceptance of drinking involves social and cultural roles and has important implications for public health. Since extensive evidence indicates that alcohol possesses immunomodulatory properties, scientists have recently debated the influence of alcohol consumption on the immune response, particularly in countries where drinking in a social setting is a part of cultural identity. Experimental and clinical data support the conclusion that alcohol is a potent immunomodulator. While high alcohol consumption suppresses a wide range of immune responses, leading to an increased incidence of a number of infectious diseases, moderate alcohol consumption may have a beneficial impact on the immune system, compared to alcohol abuse or abstinence, most likely due to the multiple components of polyphenol-rich alcoholic contributing to the protective effect seen for moderate alcohol consumption on CVD and the immune system. Despite this, the scientific literature appears to be concerned about the diseases associated with excessive drinking in some societies and cultures. Thus, the present review recognizes the importance to consider social and cultural aspects of drinking when examining the whole dimension of alcohol consumption (amount, beverage type, frequency and variability), in order to estimate global risk of consequences on host defence to better understand alcohol-related harm or benefit.
Celiac disease is an inflammatory disorder of the small intestine, triggered by the ingestion of gluten proteins contained in wheat, barley or rye, in genetically susceptible individuals. This disorder is considered to be mainly mediated by cellular immunity and restricted to the human leucocyte antigen-DQ presentation of gluten-derived toxic peptides to T-cells. Moreover, the involvement of innate immunity has been recently demonstrated to be necessary also for the development of intestinal tissue damage. Genetic susceptibility accounts for an uncertain proportion of the disease risk and gluten introduction works as the precipitating factor. However, currently, the research interest is also focused on environmental factors and gene–environment interactions, especially during the first months of life, which might help explain the onset of the disease. Infectious and dietary factors that could modulate the immune response orientating it either towards tolerance or intolerance/autoimmunity are the focus of primary attention. A significant number of studies have looked into the protective effect of breast-feeding against the disease. It is generally accepted that breast-feeding during the introduction of dietary gluten and increasing the duration of breast-feeding are associated with reduced risk of developing celiac disease. However, it is still not fully established whether breast-feeding truly protects with permanent tolerance acquisition or only reduces the symptoms and delays the diagnosis. Moreover, the timing and dose of gluten introduction also seem to be relevant and long-term prospective cohort studies are being carried out in order to elucidate its role in celiac disease development.
The aim of this preliminary study was to determine specific proteins, related to inflammation process and nutritional status as well as to total antioxidant capacity, in children suffering from cystic fibrosis (CF). The study was performed on 17 nonhospitalized children (12 boys and 5 girls) with CF aged 3 months to 10 years, who were assisted at the Nutrition Service from Pedro de Elizalde Hospital. Transferrin, transthyretin, ceruloplasmin (Cp), haptoglobin, C-reactive protein (CRP) and fibrinogen were measured by single radial immunodiffusion techniques. Total antioxidant capacity (TAC) was determined by a decolorization assay. Statistical analyses were performed by the Student's t test. Transferrin and transthyretin values were lower in CF patients in comparison with data obtained from healthy children (reference group, RG). The decreased transferrin concentration and the tendency towards low plasma transthyretin values suggested an abnormal nutritional status. However, higher Cp and haptoglobin levels were shown in patients than in RG. The fact that 23 and 50% of patients exceeded the desirable values for fibrinogen (<285·0 mg/dl) and CRP (<0·2 mg/dl), respectively, should be highlighted. The TAC (mM; Trolox equivalents) was shown to be lower in the CF group than in RG. The diminished TAC concomitant with an increased plasma Cp concentration would exacerbate the inflammatory status and could explain the depression of the immune system. These preliminary results could explain the need to include biochemical and functional parameters in the early nutritional status evaluation in CF patients in order to use appropriate nutritional and pharmacological therapies and consequently to improve their survival and quality of life.
Session 5: Early programming of the immune system and the role of nutrition
The conceptual framework for reproductive immunology was put in place over 50 years ago when the survival of the fetal semi-allograft within an immunocompetent mother was first considered. During this time, a number of paradigms have emerged and the mechanisms receiving current attention are those related to immune tolerance, such as regulatory T-cells and indoleamine 2,3,-dioxygenase, and innate immunity, such as natural killer cells, trophoblast debris and inflammation. A key consideration is the temporal and spatial variation in any of these pathways (e.g. implantation v. parturition). As fetally derived trophoblasts are the semi-allogeneic cells with which the maternal immune system comes into contact, understanding the immune response to these cells is critical. There is much interest in the immunological pathways that support a healthy pregnancy and how they might be perturbed in adverse pregnancy outcomes. Additionally, there is increasing awareness that antenatal determinants of the immune function of pregnant women and their offspring have consequences for health and disease in childhood and beyond. Changes in maternal diet over recent decades coincide with the increasing prevalence of allergic and other immune-mediated diseases, and the modification of maternal diet has emerged as a strategy for disease prevention. Approaches undergoing trial at numerous sites around the world include dietary supplementation with fish oil and/or probiotics. Understanding the underlying mechanisms of any positive effect on disease outcomes should reveal further novel strategies for disease prevention.
Events and exposures in pregnancy can have critical effects on fetal development with lasting implications for subsequent health and disease susceptibility. There is growing interest in how modern environmental changes influence fetal immune development and contribute to the recent epidemic of allergy and other immune disorders. Rising rates of allergic disease in early infancy, together with pre-symptomatic differences in immune function at birth, suggest that antenatal events play a predisposing role in the development of disease. A number of environmental exposures in pregnancy can modify neonatal immune function including diet, microbial exposure and maternal smoking, and there is emerging evidence from animal models that these factors may have epigenetic effects on immune gene expression and disease susceptibility. Furthermore, functional genetic polymorphisms also alter individual vulnerability to the effects of these environmental exposures, highlighting the complexity of gene–environmental interactions in this period. All these observations underscore the need for ongoing research to understand the pathogenesis and rising incidence of disease in the hope of better strategies to reverse this.
There may be a causal relationship between n-6 PUFA intake and allergic disease and there are biologically plausible mechanisms, involving eicosanoid mediators of the n-6 PUFA arachidonic acid, that could explain this. There is some evidence that high linoleic acid intake is linked with increased risk of atopic sensitisation and allergic manifestations. Fish and fish oils are sources of long-chain n-3 PUFA and these fatty acids act to oppose the actions of n-6 PUFA. It is considered that n-3 PUFA will protect against atopic sensitisation and against the clinical manifestations of atopy. All five epidemiological studies investigating the effect of maternal fish intake during pregnancy on atopic or allergic outcomes in infants/children of those pregnancies concluded protective associations. Epidemiological studies investigating the effects of fish intake during infancy and childhood on atopic outcomes in those infants or children are inconsistent, although the majority of the studies (9/14) showed a protective effect of fish. Fish oil provision to pregnant women is associated with immunologic changes in cord blood. Provision of fish oil during pregnancy may reduce sensitisation to common food allergens and reduce the prevalence and severity of atopic dermatitis in the first year of life. This effect may persist until adolescence with a reduction in prevalence and/or severity of eczema, hayfever and asthma. Fish oil supplementation in infancy may decrease the risk of developing some manifestations of allergic disease, but whether this benefit persists as other factors come into play remains to be determined.
Commensal bacteria are important in intestinal homeostasis and appear to play a role in early tolerance to foreign antigens. The requirement for homeostatic balance between tolerance and immunity poses a unique regulatory challenge to mucosal immune systems. Dysregulation of this balance can contribute to the pathogenesis of numerous inflammatory conditions such as inflammatory bowel diseases. The primary response to these bacteria is triggered by pattern recognition receptors (PRR), which bind pathogen-associated molecular patterns (PAMP). PRR comprise Toll-like receptors (TLR), nucleotide-binding oligomerization domains, adhesion molecules and lectins. Probiotics are living commensal micro-organisms of the intestinal tract with clinically documented health effects in human subjects. They are known to affect the gastrointestinal tract and the associated immune system and to have numerous effects on intestinal function and immune responses, including immunotolerance. This last effect appears to be mediated via regulatory T-cell activation by intestinal dendritic cells and the low activation of T-helper 1 and 2 (Th1 and Th2) cell inflammatory responses. However, the precise mechanisms of probiotic activity remain poorly understood. The aim of the present work was to review the function of TLR in the development of immunotolerance and examine the specific role of probiotics in the regulation of tolerance to antigens.
Session 6: Role of physical activity on immune function
During the last few decades, scientific evidence has confirmed a wide range of health benefits related to regular physical activity. How physical activity affects the immune function and infection risk is, however, still under debate. Commonly, intensive exercise suppresses the activity and levels of several immune cells, while other immune functions may be stimulated by moderate physical activity. With this knowledge, the understanding of the relationship between different levels of physical activity on the immune function has been raised as a potential tool to protect health not only in athletes but also in the general population; the mechanisms that translate a physically active lifestyle into good health continue to be investigated. Reviewing the literature, although several outcomes (i.e. the mechanisms by which different levels and duration of physical activity programmes affect numerous cell types and responses) remain unclear, given that the additional benefits encompass healthy habits including exercise, the use of physical activity programmes may result in improved health of elderly populations. Moderate physical activity or moderate–regulated training may enhance the immune function mainly in less fit subjects or sedentary population and the pre-event fitness status also seems to be an important individual factor regarding this relationship. Although adequate nutrition and regular physical activity habits may synergistically improve health, clinical trials in athletes using nutritional supplements to counteract the immune suppression have been inconclusive so far.
Further research is necessary to find out to what extent physical activity training can exert an effect on the immune function.
Prospective studies have shown that chronic low-grade inflammation may contribute to the pathogenesis of the most common chronic diseases and in particular CVD. Obesity has repeatedly been associated with moderately raised levels of inflammation, and this observation has led to the view that obesity is characterised by a state of chronic low-grade inflammation. There is now great interest in elucidating how physical activity and exercise modulate inflammation. This review summarises the current research addressing the influence of physical activity and exercise in mitigating the risks of obesity and diseases such as type-II diabetes and CVD, through its action on the low-grade inflammatory state. Most research on this topic hypothesised that the association between physical activity and inflammatory markers is independent of fatness, but very few studies have proven this. Given that physical activity and obesity are often inversely related, it is not clear as to whether the anti-inflammatory health benefits of a physically active lifestyle are due to exercise per se or result from favourable changes in the body composition.
Session 7: Prebiotics and probiotics usefulness against pathologies
Mucosal dendritic cells are at the heart of decision-making processes that dictate immune reactivity to intestinal microbes. They ensure tolerance to commensal bacteria and a vigorous immune response to pathogens. It has recently been demonstrated that the former involves a limited migration of bacterially loaded dendritic cells from the Peyer's patches to the mesenteric lymph nodes. During lactation, cells from gut-associated lymphoid tissue travel to the breast via the lymphatics and peripheral blood. Here, we show that human peripheral blood mononuclear cells and breast milk cells contain bacteria and their genetic material during lactation. Furthermore, we show an increased bacterial translocation from the mouse gut during pregnancy and lactation and the presence of bacterially loaded dendritic cells in lactating breast tissue. Our observations show bacterial translocation as a unique physiological event, which is increased during pregnancy and lactation. They suggest endogenous transport of intestinally derived bacterial components within dendritic cells destined for the lactating mammary gland. They also suggest neonatal immune imprinting by milk cells containing commensal-associated molecular patterns.