Dietary micronutrients/antioxidants and their relationship with bronchial asthma severity

BACKGROUND: Because little is known about micronutrient/antioxidant intake and asthma severity, we investigated dietary intake and plasma/serum levels of micronutrients/antioxidants in a group of asthma patients with various degrees of severity, and compared the results with healthy subjects. METHODS: A case control study was carried out on 118 asthma patients and 121 healthy subjects. The severity of the disease was classified by division of patients into four groups. Normal dietary micronutrient/antioxidant intake was estimated from a food frequency questionnaire. Plasma/serum levels of vitamins C, E, and A, selenium, magnesium, zinc, and platelet glutathione peroxidase (GSH-Px) activity were also determined. RESULTS: No differences in daily micronutrient/antioxidant intake were seen between patients and healthy subjects. The severity of the disease showed no significant relationship with micronutrient/antioxidant intake. There were no differences in plasma/serum levels in any of the micronutrients/antioxidants between healthy subjects and asthmatics. Nor were any differences found between asthma groups in severity in the biochemical measures, except in platelet GSH-Px activity, which was significantly lower in the most severe groups. CONCLUSIONS: In this study, we found no evidence of any association between micronutrient/antioxidant intake or plasma/serum levels of micronutrients/antioxidants and asthma. Reduction of platelet GSH-Px activity in the most severe patients suggests that these patients have a diminished capacity to restore part of the antioxidant defences.     

Mechanisms of nutrient modulation of the immune response

Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.     

Nutrient-gene interaction in ageing and successful ageing. A single nutrient (zinc) and some target genes related to inflammatory/immune response

In this paper, we reviewed data regarding to the pivotal role played by the zinc-gene interaction in affecting some relevant cytokines (IL-6 and TNF-alpha) and heat shock proteins (Hsp70-2) in ageing, successful ageing (nonagenarians) and in some age-related diseases (atherosclerosis and infections). The polymorphisms of the genes codifying these proteins are predictive on one hand in longevity, such as IL-6 -174G/C locus, on the other hand 1267 Hsp70-2A/B or TNF-alpha -308G/A polymorphisms are associated to worsening atherosclerosis or severe infections, respectively, rather than longevity. Taking into account that longevity has a strong genetic component but, at the same time, is affected by life style and environmental factors, the analysis of these polymorphisms in association to some immune parameters (NK cell cytotoxicity) and nutritional factors (zinc) is a useful tool to unravel the role played by these genetic factors in longevity and in the appearance of age-related diseases. Indeed, these polymorphisms are associated with chronic inflammation, low zinc ion bioavailability, depressed innate immune response and high gene expression of metallothioneins, which have a limited zinc release for an optimal innate immune response in ageing. Therefore, the nutrient (zinc)-gene (IL-6, TNF-alpha and Hsp70-2) interaction is pivotal to keep under control the inflammatory/immune response with subsequent longevity, indicating these genes as "robust" for "healthy ageing".     

Inflammatory networks in ageing, age-related diseases and longevity

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progressive activation of macrophages and related cells. This pro-inflammatory status, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases as atherosclerosis. Thus, the analysis of polymorphisms of the genes that are key nodes of the natural immunity response might clarify the patho-physiology of age-related inflammatory diseases as atherosclerosis. On the other hand, centenarians are characterized by marked delay or escape from age-associated diseases that, on average, cause mortality at earlier ages. In addition, centenarian offspring have increased likelihood of surviving to 100 years and show a reduced prevalence of age-associated diseases, as cardiovascular disease (CVD) and less prevalence of cardiovascular risk factors. So, genes involved in CVD may play an opposite role in human longevity. Thus, the model of centenarians can be used to understand the role of these genes in successful and unsuccessful ageing. Accordingly, we report the results of several studies in which the frequencies of pro-inflammatory alleles were significantly higher in patients affected by infarction and lower in centenarians whereas age-related controls displayed intermediate values. These findings point to a strong relationship between the genetics of inflammation, successful ageing and the control of cardiovascular disease at least in men, in which these studies were performed. These data are also briefly discussed in the light of antagonistic pleiotropy theory and in order to pursuit a pharmacogenomics approach.     

The inflammatory response to vaccination is altered in the elderly

To further explore whether immune function and acute phase response are altered during ageing, the response to a mild inflammatory stress (DT-Polio-Typhim vaccination) was studied in elderly and young subjects. Cytokine production (IFN-gamma, TNF-alpha, IL-6, IL-10) by whole blood cultures, circulating cytokines and acute phase proteins were analysed before and 2 days after vaccination. Prior to vaccination, only IFN-gamma production was lower in the elderly than in the young subjects due to a lower mononuclear cell number. In the same time, although in the normal range, several acute phase proteins were greater in elderly than in young subjects, suggesting a low-grade inflammatory state in the elderly. After vaccination, IFN-gamma production remained lower in the elderly than in the young, supporting an altered cell-mediated immunity with advancing age. TNF-alpha production was unaffected by either ageing or vaccination. IL-6 production was stimulated by vaccination in young subjects but not significantly in the elderly. IL-10 production was inhibited by vaccination in the elderly but not in the young. Acute phase proteins were less increased in elderly than in young subjects. Taken together, these results support a general lack of inflammatory response in the elderly exposed to an immune challenge and suggest that immune deficiency may concern both Th1 and Th2 responses. However, the interpretation must respect the limitation of small subjects number.     

Innate immune response in the hemolymph of an ascidian, Halocynthia roretzi, showing soft tunic syndrome, using label-free quantitative proteomics

Soft tunic syndrome of Halocynthia roretzi manifests as soft, weak, and rupturable tunics, causing mass mortality. Utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS), innate immune response was established by comparing hemolymph protein profiles of ascidians with healthy or softened tunics. Of 100 proteins in each individual ascidian, 59 proteins from healthy and 56 proteins from diseased ascidians were functionally classified. Proteins found only in diseased individuals included trypsin inhibitor and Hr-29, and with high exponentially modified protein abundance index (emPAI) values. From 41 proteins identified to be common to both healthy and diseased ascidians, 15 were associated with innate immune response. Ficolin 3, a component of the lectin-complement system, was significantly decreased in diseased ascidians, but a cell surface protein, type II transmembrane serine protease-1 (TTSP), was considerably elevated. These results suggest that trypsin inhibitor, ficolin 3, and TTSP are probably involved in the innate immune response related to this tunic disease. Beside, Hr-29 could be suggested as a biomarker for soft tunic syndrome.     

Galectins and their ligands: amplifiers,silencers or tuners of the inflammatory response?

Recent evidence has implicated galectins and their ligands as master regulators of immune cell homeostasis. Whereas some members of this family, such as galectin-3, behave as amplifiers of the inflammatory cascade, others, such as galectin-1, trigger homeostatic signals to shut off T-cell effector functions. These carbohydrate-binding proteins, identified by shared consensus amino acid sequences and affinity for beta-galactoside-containing sugars, participate in the homeostasis of the inflammatory response, either by regulating cell survival and signaling, influencing cell growth and chemotaxis, interfering with cytokine secretion, mediating cell-cell and cell-matrix interactions or influencing tumor progression and metastasis. The current wealth of new information promises a future scenario in which individual members of the galectin family or their ligands will be used as powerful anti-inflammatory mediators and selective modulators of the immune response.     

DNA damage response, telomere maintenance and ageing in light of the integrative model

The complexity of the ageing process is reflected in the fact that numerous models have been proposed to explain why and how organisms age and yet they address the problem only to a limited extent. A logical solution is to integrate individual models together into a wider theoretical framework now known as the "network" theory of ageing. The "network" approach overcomes reduction nature of individual models and allows for interactions between individual contributing mechanisms. This review focuses on some aspects of the "network" approach, namely interactions between two individual mechanisms that contribute to ageing: DNA damage response and telomere maintenance. The key framework for considering these interactions is the previously proposed integrative model, which predicts that telomere maintenance is an integral part of DNA damage response machinery. The integrative model predicts the dual phenotype, namely dysfunctional DNA damage response and dysfunctional telomere maintenance, when one of these mechanisms is the cause of ageing. In line with this prediction between 87 and 90% of mouse and human models of premature ageing show this dual phenotype. It is concluded that the integrative model is consistent with the "network" theory of ageing.     

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a “poor” diet or protection against disease with a “healthy” diet. In addition, many mucosa-associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host-microbiome and inter-microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.     

Immune response to influenza vaccine in healthy elderly: lack of association with plasma beta-carotene, retinol, alpha-tocopherol, or zinc

Immunity and nutritional status are compromised with age, yet the relationship between them is unclear. Immune responses and plasma micronutrient levels of 61 healthy elderly (mean 81 years) and 27 young (mean 27 years) were assessed before and after immunization with trivalent influenza vaccine (FLU). FLU-induced proliferation and IFN-gamma levels of elderly were lower than young before and after immunization. Proliferation and IFN-gamma levels increased after immunization of young, but not elderly. FLU-induced IL-6 and IL-10 levels did not change after immunization of either group. While antibody titers to all three FLU components increased after vaccination of young and elderly, post-vaccination titers of elderly were lower than young. Although plasma retinol and zinc levels of young and elderly were similar before and after vaccination, elderly had higher plasma beta-carotene and alpha-tocopherol levels at both assessments that increased after vaccination. Importantly, plasma micronutrient levels were comparable for elderly with or without intact (titers >/=40 and fourfold rise post-vaccination) antibody responses after vaccination. These results suggest that differences in these plasma micronutrients (1) are not required to observe decreased FLU responses of healthy elderly compared to young and (2) are not associated with differences in antibody responses among healthy elderly.     

Senescent endothelial cells: Potential modulators of immunosenescence and ageing

Recent studies have demonstrated that the accumulation of senescent endothelial cells may be the primary cause of cardiovascular diseases. Because of their multifunctional properties, endothelial cells actively take part in stimulating the immune system and inflammation. In addition, ageing is characterized by the progressive deterioration of immune cells and a decline in the activation of the immune response. This results in a loss of the primary function of the immune system, which is eliminating damaged/senescent cells and neutralizing potential sources of harmful inflammatory reactions.In this review, we discuss cellular senescence and the senescence-associated secretory phenotype (SASP) of endothelial cells and summarize the link between endothelial cells and immunosenescence. We describe the possibility that age-related changes in Toll-like receptors (TLRs) and microRNAs can affect the phenotypes of senescent endothelial cells and immune cells via a negative feedback loop aimed at restraining the excessive pro-inflammatory response. This review also addresses the following questions: how do senescent endothelial cells influence ageing or age-related changes in the inflammatory burden; what is the connection between ECs and immunosenescence, and what are the crucial hypothetical pathways linking endothelial cells and the immune system during ageing.     

Chemokine production by peripheral blood mononuclear cells in elderly subjects

The function of chemokines in promoting and modulating leukocyte migration is essential for a prompt and efficacious inflammatory response and in host defence against infections. In order to investigate whether this important aspect of immunological response is influenced by ageing, we evaluated the basal levels as well as the ability of peripheral blood mononuclear cells from young and healthy elderly subjects to produce chemokines (IL-8, MCP-1, MIP-Iα, RANTES) in response to stimulation with anti-CD3 monoclonal antibody and lipopolysaccharide (LPS), a gram negative bacterial endotoxin. Our main findings are a spontaneous chemokine production; a 20% decrease of proliferative response to anti-CD3 monoclonal antibody accompanied by an age related increase of MIP-Iα and RANTES production and by a general increase of all chemokine production compared to unstimulated conditions; a proliferative defect of monocytes to LPS challenge associated with an increase of chemokine production compared to basal conditions with a progressive age-related increase of MIP-lα. In conclusion, this study suggests that chemokines could have a compensatory role in balancing the impaired mechanisms involved in ‘specific’ immune response during ageing. The successful activation of this strategy could contribute to the good performance of immune system so maintaining healthy status in elderly.     

Micronutrient supplementation increases CD4 count in HIV-infected individuals on highly active antiretroviral therapy: a prospective, double-blinded, placebo-controlled trial

OBJECTIVE: To examine the immunologic, metabolic, and clinical effects of broad spectrum micronutrient supplementation in HIV-infected patients taking highly active antiretroviral therapy (HAART). DESIGN: A prospective, randomized, double-blinded, placebo-controlled trial. METHODS: Forty HIV-infected patients taking a stavudine and/or didanosine-based HAART regimen were prospectively randomized to receive micronutrients or placebo twice daily for 12 weeks. Data were collected at 4-week intervals including immunologic, metabolic, and clinical measurements. The study examined the effect of micronutrient supplementation on immunologic parameters as the primary end point. The secondary end points were metabolic and clinical effects and distal symmetrical polyneuropathy. RESULTS: The mean absolute CD4 count increased by an average of 65 cells in the micronutrient group versus a 6-cell decline in the placebo group at 12 weeks (P = 0.029). The absolute CD4 count increased by an average of 24% in the micronutrient group versus a 0% change in the placebo group (P = 0.01). The mean HIV-1 RNA decreased in the micronutrient supplementation group, although not significantly. Neuropathy scores improved in the micronutrient group by 42% compared with a 33% improvement in the placebo arm. This difference did not reach statistical significance. Fasting serum glucose, insulin, and lipids were not adversely affected in the patients taking the micronutrients. CONCLUSIONS: Micronutrient supplementation can significantly improve CD4 cell count reconstitution in HIV-infected patients taking HAART. The micronutrient supplement tested was well tolerated and may hold promise as an adjuvant therapy in the treatment of HIV. Further investigation is warranted.     

Chemokine production by peripheral blood mononuclear cells in elderly subjects

The function of chemokines in promoting and modulating leukocyte migration is essential for a prompt and efficacious inflammatory response and in host defence against infections. In order to investigate whether this important aspect of immunological response is influenced by ageing, we evaluated the basal levels as well as the ability of peripheral blood mononuclear cells from young and healthy elderly subjects to produce chemokines (IL-8, MCP-1, MIP-Ialpha, RANTES) in response to stimulation with anti-CD3 monoclonal antibody and lipopolysaccharide (LPS), a gram negative bacterial endotoxin. Our main findings are a spontaneous chemokine production; a 20% decrease of proliferative response to anti-CD3 monoclonal antibody accompanied by an age related increase of MIP-Ialpha and RANTES production and by a general increase of all chemokine production compared to unstimulated conditions; a proliferative defect of monocytes to LPS challenge associated with an increase of chemokine production compared to basal conditions with a progressive age-related increase of MIP-lalpha. In conclusion, this study suggests that chemokines could have a compensatory role in balancing the impaired mechanisms involved in 'specific' immune response during ageing. The successful activation of this strategy could contribute to the good performance of immune system so maintaining healthy status in elderly.     

The potential for Toll-like receptors to collaborate with other innate immune receptors

Cells of the innate immune system express a large repertoire of germ-line encoded cell-surface glycoprotein receptors including Toll-like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non-TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.     

Obesity and dysregulated innate immune responses: impact of micronutrient deficiencies

Obesity is associated with the development of various complications, including diabetes, atherosclerosis, and an increased risk for infections, driven by dysfunctional innate immune responses. Recent insights have revealed that the availability of nutrients is a key determinant of innate immune cell function. Although the presence of obesity is associated with overnutrition of macronutrients, several micronutrient deficiencies, including Vitamin D and zinc, are often present. Micronutrients have been attributed important immunomodulatory roles. In this review, we summarize current knowledge of the immunomodulatory effects of Vitamin D and zinc. We also suggest future lines of research to further improve our understanding of these micronutrients; this may serve as a stepping-stone to explore micronutrient supplementation to improve innate immune cell function during obesity.     

Gene variants as determinants of longevity: focus on the inflammatory factors

Human longevity is an extremely complex trait with various genetic, epigenetic and environmental factors acting upon the longevity phenotype. It is now becoming evident that whilst the genetic differences contribute only modestly to life expectancy before the age of 60 years, their impact on survival becomes more prominent at the extreme ages. Several longevity gene candidates have emerged during the past decade; the majority of them are related either to inflammatory functions, stress response or to lipid and glucose metabolism. The variants of inflammatory and immune response genes are of special interest since advancing ages is accompanied by a decline in several immune functions—a phenomenon called immunosenescence. Paradoxically, ageing is also characterised by chronic low-grade inflammation termed “inflammaging”, which manifests as a two- to fourfold increase in the production of proinflammatory cytokines and acute phase proteins. These contrasting phenomena provide a functional rationale of how the genetic differences in inflammatory mediators may modify the life span of the elderly. Besides describing the pre-existing inflammatory and immune-related longevity gene variants, in this review, we also explain some of the theoretical and practical challenges that genetic longevity studies often encounter.     

Toll-like receptors, endogenous ligands, and systemic autoimmune disease

Summary: The critical role of Toll‐like receptors (TLRs) as mediators of pathogen recognition by the innate immune system is now firmly established. Such recognition results in the initiation of an inflammatory immune response and subsequent instruction of the adaptive immune system, both of which are designed to rid the host of the invading pathogen. More controversial is the potential role of TLRs in the recognition of endogenous ligands and what effect this might have on the consequent development of autoimmune or other chronic sterile inflammatory disorders. An increasing number of studies implicate TLRs as being involved in the immune response to self‐molecules that have in some way been altered from their native state or accumulate in non‐physiologic sites or amounts, although questions have been raised about possible contaminants in certain of these studies. In this review, we discuss the evidence for endogenous ligand–TLR interactions with particular emphasis on mammalian chromatin, systemic lupus erythematosus, and atherosclerosis. Overall, the data support the general concept of a role for TLRs in the recognition of endogenous ligands. However, the precise details of the interactions and the extent to which they may contribute to the pathogenesis of human disease remain to be clarified.