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Relationship between nutrition and infectious The duration and severity of many infectious diseases are related to host immunity and nutritional status. Lack of specific nutrients may lead to dysregulated or ineffective immune response and higher morbidity and mortality. 1 HISTORICAL OVERVIEW The relationship between less obvious malnutrition and infection was largely characterized in the twentieth century. Outbreaks of infections were observed among animals subjected to certain experimental diets An increased susceptibility to infections was especially common in animals that were deficient in vitamin A, and soon vitamin A became known as the antiinfective vitamin 2 HISTORICAL OVERVIEW An increased susceptibility to infection and mortality in infants and young children to the lack of vitamin A, and he advocated the use of milk, cream, and butter for children to reduce their infections In 1932 in London, Joseph Ellison discovered that vitamin A supplementation reduced the mortality of children with measles From 1920 through 1940, vitamin A underwent considerable evaluation in at least 30 therapeutic trials for different infectious diseases By the early 1940s, it was generally accepted that vitamin A was important in maintaining mucosal immunity against infections 3 HISTORICAL OVERVIEW In the late 1980s and 1990s, zinc supplementation was evaluated as therapy for diarrheal disease, pneumonia, malaria, and child growth and development Zinc was recommended as therapy for infections such as diarrhea and dysentery as early as the nineteenth century 4 Relationship between nutrition and infectious Poor nutrition increased susceptibility to infectious diseases, leading to immunological dysfunction and metabolic responses 5 6 Relationship between nutrition and infectious Malnutrition resulted in increased susceptibility to infection, and that infection caused deterioration of nutritional status. The cycle of malnutrition–infection–more nutritional deterioration– more infection was a powerful pathway. Infection caused a loss of critical body stores of protein, energy, minerals and vitamins. 7 Relationship between nutrition and infectious Part of the defect in antibody immunity in malnourished persons was shown to be attributed to the profound effect of these deficits on the maturation of T-cells, resulting in a reduction in fully functional mature T-cells and an excess of poorly functional immature T-cells. 8 Relationship between nutrition and infectious Recurrent infections increase the risk of malnutrition. Poor nutritional status results in lowered immune status and predisposes to infectious disease thus propagating the vicious cycle of infection and malnutrition. 9 Relationship between nutrition and infectious Nutritional deficiencies can alter a host's immune response and increase susceptibility to infection. From a nutritional point of view, the process of nutrient loss and redistribution has the potential for being exploited to the benefit of the infected malnourished host. 10 Relationship between nutrition and infectious Cycle of malnutrition and infection is the main cause of morbidity and mortality in children in underdeveloped countries. 11 Nutrient/Food Compounds that Influence Immune Function 12 Perinatal infection is a major cause of maternal, fetal and neonatal morbidity and mortality. Perinatal infections are more common among the poorest women and in the geographic areas with the least resources as well as with the most malnutrition; these facts have given rise to speculation that the relationship between infection and adverse pregnancy outcomes is at least in part mediated by some nutritional deficiency 13 Nutritional deficits may increase the risk of perinatal infection by diminishing or abolishing protective mechanisms. Various epithelial surfaces such as the squamous epithelium of the skin and the mucosal surfaces of the lung, gastrointestinal tract and genitourinary tract provide the first line of defense against various microorganisms; various nutritional deficiencies have a welldocumented negative effect on skin and mucus membrane integrity. 14 The ability of various cells such as leukocytes and macrophages to phagocytize invading organisms is another type of defense. Cellmediated responses of the T cells and natural killer (NK) cells play a crucial role in controlling invading organisms as do the antibody-producing B cells. Other immune cell products such as cytokines and metalloproteases, as well as complement, are important components of the immune system that act together to protect pregnant women from infection (Table 1). Nutritional deficiencies have been linked to decreases of all cellular and serum immune functions. 15 Protein energy malnutrition Protein-energy-malnutrition (PEM) is one of the major causes of immunodeficiency worldwide. Lymphoid atrophy, for example, is a prominent feature of PEM, with substantial reductions seen in the size of the thymus and the spleen. Because immune cells have a high requirement for energy and amino acids for both cell division and protein synthesis. 16 Protein energy malnutrition Therefore, reduced availability of both energy and amino acids appears to substantially reduce the ability of the host to mount an appropriate immune response to various types of bacteria, viruses and other pathogens. Other immune deficiencies associated with PEM are decreased phagocytic activity by neutrophils and macrophages, decreased numbers of circulating T cells and impaired lymphokine production 17 Protein energy malnutrition PEM is also associated with impairment of many of the host barriers to infection, such as the integrity of the skin and mucus membranes. On the other hand, antibody response is usually maintained. 18 MALNUTRITION AND SPECIFIC INFECTIOUS DISEASES The impact of malnutrition on the severity of infection has been investigated most extensively in children with measles, diarrheal disease, respiratory infections, and malaria and in children and adults with tuberculosis and human immunodeficiency virus (HIV) infection. In general, the severity of morbidity and mortality during different infections is worse among persons with malnutrition. 19 Measles Measles is estimated to account for 1 million deaths and a great deal of morbidity among the 30 million cases of measles per year, most of which occur in developing countries where malnutrition is more prevalent. Deaths from measles are largely the result of an increased susceptibility to secondary bacterial and viral infections, and the underlying mechanism includes immune suppression related to malnutrition, especially vitamin A deficiency 20 Measles 21 Measles Malnutrition is an important determinant of the severity of measles More persistent measles infection and viral shedding have been reported in malnourished children A close synergism exists between measles and vitamin A deficiency, because children with measles who are vitamin A deficient have a much higher risk of xerophthalmia, corneal ulceration, keratomalacia, and subsequent blindness 22 Measles Vitamin A supplementation reduces the morbidity and mortality of measles among preschool children Vitamin A supplementation appears to reduce the infectious complications associated with measles immune suppression, such as pneumonia and diarrheal disease, and these effects have been associated with modulation of immune responses by vitamin A Zinc supplementation does not appear to have an effect on morbidity among children with 23 measles that is accompanied by pneumonia Malaria Malaria, a parasitic infection with protozoan organisms of the genus Plasmodium ,causes an estimated 1 to 3 million deaths worldwide each year. Of the four malaria species that infect humans (P. falciparum, P. vivax, P. malariae ,and P. ovale) the most serious morbidity and mortality are caused by P. falciparum ,and nearly 90% of all cases and fatalities occur in sub-Saharan Africa 24 Malaria Severity of malaria may be related to nutritional status. Persons with better nutritional status have less severe malaria and a lower risk of death Nutritional indicators of poor vitamin A status have been associated with malaria 25 Malaria Vitamin A significantly reduced the incidence of malaria attacks by about 20 to 50% for all except those with extremely high levels of parasitemia. Zinc supplementation was associated with a 30% reduction in the incidence of clinical malaria episodes, and 38% reduction in malaria morbidity. 26 Malaria Zinc supplementation did not appear to reduce the morbidity of malaria (reduction of fever or parasitemia) when it was given as adjunct therapy with chloroquine to children, aged 6 months to 5 years, who presented with an attack of acute uncomplicated falciparum malaria 27 Diarrheal Disease Diarrheal diseases cause an estimated 3.5 million deaths/year, mostly among those less than 2 years of age The main causes of diarrheal diseases among children in developing countries are rotavirus, Escherichia coli, and Shigella, Vibrio cholerae, Salmonella, and Entamoeba histolytica. The epidemiology, clinical features, immunology, and pathogenesis of diarrhea may differ according to characteristics of the pathogen, such as production of toxins, tissue invasion, fluid and electrolyte loss, and location of infection 28 Diarrheal Disease In developing countries, community-based studies suggest that children less than 5 years of age have a median incidence of 2.6 diarrheal episodes/year In general, host defenses in the gut include gastric acidity, the presence of normal microflora, gut motility, mucus production, integrity of microvilli, local secretion of antibody, and cell-mediated immunity, and micronutrient malnutrition may impair some of these host defenses. 29 Diarrheal Disease Malnourished infants and children are at higher risk of more severe disease and higher mortality from diarrhea and an increased incidence of diarrhea is found among children with evidence of depressed immunity. Clinical vitamin A deficiency is associated with diarrheal disease in children 30 Diarrheal Disease Vitamin A supplementation or fortification has been shown to reduce the morbidity and mortality of diarrheal diseases among preschool children in clinical trials conducted in developing countries over the last 2 decades The severity of diarrheal disease and mortality was reduced by vitamin A supplementation 31 Diarrheal Disease One of the mechanisms by which vitamin A • may improve clinical outcomes in diarrheal disease is through restoration of gut integrity Urinary losses of vitamin A during diarrhea • may be substantial in some children, and persistent diarrhea may reduce the bioavailability of vitamin A. Vitamin A supplementation (60 mg retinol equivalents) reduces morbidity in children with acute shigellosis. 32 Diarrheal Disease Zinc supplementation can reduce the incidence of diarrhea by about 18% Zinc supplementation also reduces the incidence of pneumonia, because a pooled analysis showed a reduction of mortality of 41% Zinc supplementation reduced the duration of diarrhea. 33 Acute Respiratory Infections Acute respiratory infections are a major cause of morbidity and mortality among infants and children in developing countries, and these infections account for an estimated 4 million deaths per year 34 Acute Respiratory Infections Malnutrition is a major determinant of morbidity and mortality during acute respiratory infections in children The main causes of acute lower respiratory infections in children are respiratory syncytial virus, adenovirus, parainfluenza virus, influenza virus, Streptococcus pneumoniae, and Haemophilus influenzae Acute respiratory infections in children have been associated with poor weight gain and stunting 35 Acute Respiratory Infections Zinc supplementation reduced the incidence of pneumonia among children. Zinc supplementation decreased the incidence of pneumonia by 41%. Among infants and young children, zinc supplementation reduced the morbidity of severe acute lower respiratory infection. Vitamin A supplementation has shown little to no effect on reducing the incidence or severity of acute respiratory infections among preschool children, but it does reduce the morbidity of acute respiratory infections associated with measles infection 36 Hookworm Infection About one fourth of the world's population is • infected with hookworm Hookworm infection is a major cause of iron • deficiency. Two species of hookworm, Ancyclostoma • duodenale and Necator americanus, account for a great deal of human morbidity and mortality. Hookworm is usually spread from person-to- • person through contamination of soil and vegetation with feces that contain hookworm eggs. 37 Hookworm Infection In the soil, the eggs develop into larvae that can penetrate human skin on contact. The hookworms attach to the intestinal mucosa and cause chronic blood loss and depletion of iron stores Hookworm infection is associated with growth retardation among infants and children, iron deficiency and impaired mental development in school children, and fatigue and decreased work capacity among adults 38 Hookworm Infection Poor hygiene is the major risk factor for hookworm infection, and hookworm infection, in turn, increases the risk of iron and other micronutrient deficiencies. Hookworm infection was associated with poor mental development, and treatment for hookworm in infected children improved performance on mental development tests compared with infected children who were not treated. 39 Hookworm Infection Treatment of school children for hookworm infection was associated with improved iron status and better growth Combination of hookworm treatment and iron supplementation was associated with improved cognitive performance and growth 40 Human Immunodeficiency Virus Infection An estimated 39.4 million persons are infected with HIV worldwide HIV infection causes a progressive decline in immunity that can lead to the acquired immunodeficiency syndrome (AIDS). HIV-1 is spread person-to-person by three major routes: sexual contact, motherto-child transmission, and through transmission by blood products such as shared needles and syringes. 41 Human Immunodeficiency Virus Infection Poor nutrition may play an important role in disease progression in HIV-infected persons During HIV infection, nutritional intake may be affected by anorexia, central nervous system disease, dysphagia, and odynophagia (painful swallowing) 42 Human Immunodeficiency Virus Infection Fairly high proportions of HIV-infected individuals do not consume at least the recommended dietary allowance for some B-complex vitamins, vitamin E, and zinc and it has been suggested that the recommended dietary allowances should be higher for persons with HIV infection . 43 Human Immunodeficiency Virus Infection Diarrhea and malabsorption of fats, carbohydrates, and vitamin B12 appear to be common in all stages of HIV infection. Cryptosporidia, microsporidia, cytomegalovirus, and Mycobacterium aviumintracellulare are major causes of diarrhea in patients with AIDS, and many pathogens are resistant to treatment and lead to severe weight loss and death Fat malabsorption may be common during HIV infection and can reduce the absorption of fat-soluble vitamins, such as vitamins A and E. 44 Human Immunodeficiency Virus Infection A fairly high prevalence of micronutrient deficiencies has been reported in many HIVinfected risk groups Vitamin A deficiency is common among HIVinfected pregnant women and children in developing countries. A few studies suggested that serum vitamin C concentrations are lower among HIV-infected adults compared with healthy controls. A high proportion of HIV-infected adults appear to have low levels of vitamin B6, vitamin B12, and folate. 45 Human Immunodeficiency Virus Infection Iron deficiency is common among HIVinfected pregnant women, female injection drug users, and children. Low blood zinc concentrations have been described in HIV-infected adults Low serum or plasma levels of selenium consistent with deficiency have been reported in HIV-infected adults (148). 46 Human Immunodeficiency Virus Infection Antioxidant nutrients such as the carotenoids, tocopherols, vitamin C, and selenium have been implicated in the pathogenesis of HIV infection through their interactions with reactive oxygen intermediates and nuclear factor-Kp B. 47 Human Immunodeficiency Virus Infection Vitamin A plays a central role in the growth and function of T and B cells, antibody responses, and maintenance of mucosal epithelium, including that of the respiratory, gastrointestinal, and genitourinary tracts Zinc plays an important role in the growth, development, and function of neutrophils, macrophages, natural killer cells, and T and B lymphocytes 48 Human Immunodeficiency Virus Infection Low plasma or serum vitamin A levels are associated with accelerated HIV progression increased mortality , and, in children, growth failure High serum vitamin E levels were associated with a lower risk of progression to AIDS( The risk of progression to AIDS may be higher in those with vitamin B 12deficiency Low serum zinc levels are associated with reduced secretory function of the thymus and HIV disease progression 49 Human Immunodeficiency Virus Infection Low serum or plasma selenium concentrations are associated with an increased risk of progression to AIDS and higher mortality Multivitamin supplementation slowed progression to AIDS when this therapy was given to HIV-infected pregnant women through pregnancy and during lactation, and it also reduced fetal deaths and low birth weight. Vitamin A and β-carotene supplementation reduced preterm delivery among pregnant women 50 Tuberculosis Tuberculosis is an infection caused by Mycobacterium tuberculosis or related organisms such as M. bovis .M. tuberculosis ,a slowly growing acid-faststaining bacillus, is the most common cause of tuberculosis in humans. The spectrum of disease ranges from asymptomatic latent tuberculous infection to disseminated disease. The most common form of tuberculosis is latent infection. Active tuberculosis, the form of disease that disrupts normal host physiology to produce symptoms, is generally classified as pulmonary or extrapulmonary disease . 51 Tuberculosis Pulmonary disease, the most common form of active tuberculosis, accounts for about 80% of cases, and clinical manifestations include chronic cough and sometimes hemoptysis, dyspnea, and chest pain. Other constitutional symptoms include fevers, night sweats, and weight loss. Extrapulmonary disease accounts for about 20% of active tuberculosis cases, and the most common extrapulmomary sites are the lymph nodes (most often the cervical lymph nodes), pleura, kidneys, meninges, and bone or joints . 52 Tuberculosis Malnutrition increases the risk of developing clinical disease. In the absence of effective chemotherapy, tuberculosis is characterized by wasting and high mortality. 53 Tuberculosis Worldwide, tuberculosis is the leading infectious cause of death, accounting for 2 million deaths annually About one third of the world's population, or 1.8 billion persons, are infected with M. tuberculosis ,and this group represents an enormous pool of persons at risk of development of future disease. In sub-Saharan Africa, the Indian subcontinent, and southeast Asia, half or more of adults have latent tuberculosis infection. 54 Tuberculosis Each year, between 7 and 8 million people throughout the world develop active tuberculosis, and most cases occur in subSaharan Africa and Asia. Tuberculosis is responsible for about one fourth of all preventable deaths in developing countries, and many of these deaths are associated with underlying HIV infection. 55 Tuberculosis Malnutrition is well known among adults with tuberculosis In general, adults gained weight during 6 months of treatment with chemotherapy, but weight was lost after treatment had finished. Progressive nutritional recovery generally occurs during tuberculosis chemotherapy; however, serum albumin levels and mean arm muscle circumference have been reported as subnormal after 12 months, a finding suggesting that body protein reserves may not be fully recovered during treatment 56 Tuberculosis Altered amino acid metabolism may contribute to wasting in tuberculosis Body composition studies suggest that body cell mass is relatively depleted in adults with tuberculosis and HIV infection Experimental animal studies showed that protein-calorie malnutrition has a marked effect on resistance to tuberculosis Restoration of a full protein diet could reverse the fatal course of tuberculosis in malnourished mice. 57 Tuberculosis Multiple micronutrient deficiencies are common during tuberculosis Cod liver oil, a rich source of vitamin A, was a main treatment for tuberculosis in the era before antibiotics Animal studies suggest that vitamin A improves immune responses to tuberculosis and enhances survival 58 Effects of single-nutrient deficiencies on immune function 59 Micronutrients: Examples of the effects of trace elements on the immune system 60 Examples of the effect of vitamins on the immune system 61 Vitamin A deficiency Vitamin A deficiency is known to result in keratinization of the respiratory epithelium, leading to a decrease in mucus production and diminished capacity of the respiratory epithelium to clear bacterial pathogens. 62 Vitamin A deficiency Vitamin A likely plays a role in reducing infection through its role in enhancing epithelial cell differentiation and the barrier function of the host as well as through its effect on more traditional immune functions. 63 Vitamin A deficiency Vitamin A regulates keratin synthesis by squamous cells and appears to maintain the integrity of mucosal epithelial surfaces— especially of the gut and lung. In animals, vitamin A deficiency decreases T-cell proliferation and various types of antibody production. The ability of neutrophils to phagocytize various organisms and to generate oxidant molecules appears to be reduced in the absence of appropriate levels of vitamin A 64 Vitamin A deficiency Association between vitamin A deficiency and infection whereas in supplementation trials the prevalence of a variety of infections have been reduced. Vitamin A supplementation improves antibody response to vaccines, maintains gut integrity and reduces the incidence and severity of infections 65 associated with diarrhea and measles Mechanisms of vitamin A on immune function Vitamin A has been shown to control differentiation of epithelial cells by regulating the synthesis of keratin and deficiency results in altered epithelial structure (squamous metaplasia) and a reduced number of mucus-secreting cells 66 Mechanisms of vitamin A on immune function The rapidly dividing epithelia at mucosal surfaces (gut and lung) are especially susceptible to vitamin A deficiency, which results in a loss of gap junctions between epithelial cells, increasing the risk of bacterial translocation Vitamin A deprivation has been shown to reduce the replication rate of basal and mucous cells and the proportions of preciliated and ciliated cells, which would further enhance the susceptibility to infection 67 Mechanisms of vitamin A on immune function Because vitamin A is needed for glycoprotein synthesis, a deficiency of it would likely impair the synthesis of the many glycoproteins involved in the immune response (e.g., integrins, fibronectin, and globulins) 68 Mechanisms of vitamin A on immune function Direct mechanisms The role of vitamin A in lymphocyte proliferation likely occurs through activation of the retinoic acid receptor (RAR)-, because provision of RA has been shown to increase mRNA levels of RAR- in T lymphocytes. Substantial evidence supports a role for vitamin A in negatively regulating IFNsecretion, thus influencing the development of Th-2- versus Th-1-type responses 69 mechanisms of vitamin A on immune function Vitamin A deficiency in mice strongly favors the production of IFN- (a Th-1-type cytokine), but adding RA in vitro to T lymphocytes from vitamin A-deficient mice inhibits IFNproduction. RA was shown to alter IFN- synthesis at the level of transcription, implicating direct effects of this vitamin on cytokine genes. The promotion of Th-1-type responses, via excessive IFN- production and limited Th-2 cell growth and differentiation, would contribute to the impaired humoral immune response capacity observed in animals and humans deficient in vitamin A 70 Mechanisms for the Essentiality of Vitamin A to the Immune System 71 Vitamin C deficiency Vitamin C deficiency is scurvy, a disease marked by an increased incidence of infections and decreased immune response Vitamin C functions as an antioxidant and appears to reduce oxidation mediated damage to DNA in lymphocytes and may enhance production of interleukin-1 and tumor necrosis factor-a. Vitamin C also reduces T-cell death and increases NK activity. It is highly concentrated in neutrophils and appears to be used during infection to prevent oxidative damage. 72 Vitamin C deficiency Vitamin C supplementation may reduce the incidence of the common cold and other viral infections. Vitamin C supplementation may also increase lymphoproliferation and phagocytosis by neutrophils and macrophages. Vitamin C can reduce damage to lymphocytes by reactive oxygen 73 intermediates Vitamin C Ascorbic acid is an essential component of every living cell. Vitamin C is highly concentrated in leukocytes and is used rapidly during infection (e.g., to prevent oxidative damage). Reduced concentrations of this vitamin in leukocytesis associated with reduced immune function 74 Proposed mechanisms The actions of vitamin C as a reducing agent and oxygen-radical quencher are well-established. Reduction of free radicals will prevent DNA damage to immune cells, thereby maintaining their functional and structural integrity. 75 Proposed mechanisms Immune system (which relies heavily on membrane receptors and signals) is particularly sensitive to oxidative stress Ascorbic acid can reduce directly or indirectly through the regeneration of vitamin E damage to lymphocytes by reactive oxygen intermediates (ROI). 76 Proposed mechanisms Ascorbate levels exert this effect by down-regulating ROI-dependent expression of proinflammatory IL genes via inhibition of transcription of NF-B 77 Proposed mechanisms Vitamin C might “boost” T-cell capacity via several mechanisms. In vitro, three T-cell death pathways (growth factor withdrawal- , spontaneous- , and steroid-induced death) were inhibited when T cells were incubated with ascorbic acid 78 Proposed Mechanisms for Effects of Vitamin C on Immune Function 79 Vitamin E Vitamin E is a potent antioxidant and its deficiency results n increased free radical membrane damage. Supplementation with vitamin E increases lymphocyte proliferation and interleukin-2 responses and improves antibody response to vaccines. 80 Vitamin E Providing vitamin E to healthy individuals was shown to increase the CD4/CD8 ratio, enhance T-cell proliferation, and lower measures of oxidative stress However, supplementation of vitamin E to “healthy” individuals did not attenuate oxidative DNA damage in peripheral blood lymphocytes 81 Vitamin E Animal studies support the immune benefits of supplemental vitamin E, which increased CD4 CD8 thymocytes and IL-2 production in rodents, and improved responses to infection in swine. The optimal intake of vitamin E required to provide immune benefits has not been established and likely depends on vitamin E status and the presence or absence of other conditions 82 Influence of Se on immune function Se plays a role in balancing the redox state of the cell and removing reactive oxygen species, which likely contributes to its antiinflammatory effects Se deficiency has been shown to decrease the production of free radicals and killing by neutrophils , IL-2R affinity and expression on T cells, T-cell proliferation and differentiation, and lymphocyte cytotoxicity 83 Influence of Se on immune function Se deficiency in vitro enhances neutrophil adherence to endothelial cells, an important preliminary event in inflammation. These alterations in immune function likely contribute to the increased cancer susceptibility associated with Se deficiency and implicate Se deficiency in the pathogenesis and exacerbation of some chronic inflammatory and viral diseases 84 Influence of Se on immune function Supplementation with Se increases lymphocyte proliferation, expression of the high-affinity IL-2R , cytolytic T lymphocyte (CTL) tumor destruction, and NK- cell function in humans and increases lymphocyte proliferation, IL2R expression, and macrophage and CTL tumor cytotoxicity in mice 85 Influence of Se on immune function Benefit of providing Se during HIV-1 infection, where it has been demonstrated to reduce oxidative stress, modulate cytokine synthesis (increase IL-2; decrease TNF and IL-8), improve T-cell proliferation and differentiation, and reduce cytokineinduced HIV-1 replication 86 Influence of Se on immune function Se deficiency in the host enhances the mutation rate of coxsackievirus and influenza A virus This suggests that the oxidative stress status of the host can alter the genome and pathogenicity of an infectious virus 87 Mechanisms of vitamin E and Se on immune function Vitamin E is an oxidant scavenger that acts to protect cell membranes from damage by reactive oxygen species Immune cells are particularly susceptible to oxidative damage because of their highly unsaturated membranes and their ability to produce large amounts of free radicals (i.e., during inflammation) 88 Mechanisms of vitamin E and Se on immune function The ability of vitamin E to scavenge • lipid soluble-free radicals is dependent to some extent on the status of two other antioxidant compounds, vitamin C and glutathione, which are involved in reducing oxidized vitamin E back to a reusable (i.e., able to be oxidized) 89 Mechanisms of vitamin E and Se on immune function Vitamin E may improve T-cell function by decreasing macrophage PGE2 production by modulating the AA cascade initiated by lipoxygenase and/or cyclooxygenase Vitamin E influences lymphocyte maturation, possibly by stabilizing membranes and allowing enhanced binding of antigenpresenting cells (APC) to immature T cells via increased expression of intercellular adhesion molecule-1 90 Mechanisms of vitamin E and Se on immune function Se is essential for the function of several selenoproteins, because of the selenocysteine residues present at their active sites. Glutathione peroxidase (GPX) is a selenoprotein that acts as an oxidant scavenger and protects against oxidative damage. 91 Mechanisms of vitamin E and Se on immune function Thioredoxin reductase is another selenoprotein that affects the redox regulation of a variety of key enzymes, transcription factors, and receptors, including ribonucleotide reductase, the glucocorticoid receptor, AP-1, and NF-B. In addition to reducing thioredoxin, this enzyme breaks down hydroperoxide and lipid peroxides in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) more efficiently than GPX, thus making it an effective protector against ROS. 92 Mechanisms of vitamin E and Se on immune function The stimulation of T-cell proliferation, CTL and macrophage cytotoxicity, and NK activity by Se may be a result of the ability of Se to enhance the expression of the and/or subunits of the IL-2R on these activated immune cells. This results in a greater number of functional IL-2R/cell and in enhanced proliferation and clonal expansion of cytotoxic precursor cells. Se deficiency causes in increased neutrophil adhesion and increased expression of E-selectin and ICAM-1 , suggesting that Se can downregulate neutrophil activation. 93 Proposed Mechanisms for the Effects of Vitamin E and Selenium on Immune Function 94 Fatty acids Fish oil contains large quantities of the n–3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid. These fatty acids have been shown to modulate T-cell function. Increasing intake of dietary fish oil suppresses interleukin-2 secretion and T-cell proliferation, thus accounting for the antiinflammatory effects. 95 Fatty acids Feeding n-3 PUFA has been shown to decrease tumor growth, incidence, and/or metastasis in a large number of animal studies and to prolong survival of cancer patients in a human clinical trial. Feeding n-3 PUFA to tumor-bearing animals enhances natural killer (NK) cell activity, CD8 T-cell activation, and interferon- (IFN-) and tumor necrosis factor (TNF-) cytokine production after mitogen stimulation 96 Fatty acids Feeding EPA and DHA has been shown to modulate specific functions of innate and acquired immunity. Feeding high levels (10% of total fat) of n-3 PUFA (compared with diets high in n-6 PUFA) to healthy animals or human subjects results in suppression of the ability of lymphocytes to respond to mitogen stimulation, NK cell activity, and delayed-type hypersensitivity (DTH) reactions. 97 Mechanisms by which n-3 PUFA may modulate immune function Immunomodulatory effects of dietary n-3 PUFA, including effects on eicosanoid formation, signal transduction, gene expression, and lipid peroxidation 98 Mechanisms Responsible for the Role of Long Chain n-3 PUFA (EPA and DHA) on Immune Function 99 Iron deficiency Iron deficiency appears to have a stronger effect on cell-mediated immunity than on antibody production Both neutrophil and NK cell activity are decreased with iron deficiency. Macrophages sequester iron as part of their normal function and this sequestration may limit various microorganisms’ replication and toxicity because these functions are often iron dependent 100 Iron and immune function Iron regulates the function of T lymphocytes, and in most studies (in vivo and in vitro), a deficiency results in impaired cell-ediated immunity Iron deficiency may also delay the development of cell-mediated immunity 101 Iron and immune function Immune cells appear to differ from one another in their synthesis and use of iron binding proteins and in the amount of iron they take up and store; this suggests that there would be differential effects of iron status on various immune functions 102 Iron and immune function Lymphocytes meet an increased iron requirement during proliferation or other conditions by increasing the synthesis and expression of surface transferrin receptors Humoral immunity may be less affected by iron deficiency than cellular immunity, because antibody production in response to immunization with most antigens is preserved in animals and humans with poor iron status (reviewed in refs 103 Iron and immune function Neutrophil function (decreased myeloperoxidase activity and bactericidal activity) and NK activity are impaired with iron deficiency Macrophage phagocytosis is generally unaffected by iron deficiency, but bactericidal activity of these cells is attenuated 104 Iron and immune function When activated (i.e., during inflammation, possibly signaled by IL-1 and IFN-γ, macrophages increase their uptake of iron and bind it in the cells (via increased transferrin receptors and ferritin synthesis). 105 Iron and immune function Sequestration of iron in macrophages has been proposed to be beneficial during the early, acute stages of infection with pathogens, because it would limit availability to microorganisms (particularly intracellular microorganisms); however, it would also limit availability to other immune cells, and this would impair host resistance 106 Iron and immune function Increased risk of infection during iron deficiency. Deleterious effects of iron deficiency on most measures of functional immunity 107 Iron supplementation and immune function Relationship between iron repletion/supplementation and increased morbidity from acute and chronic infections. Microbiology studies show a close relationship between the availability of iron and bacterial virulence; one might conclude therefore that providing iron would benefit the infectious organisms 108 Iron supplementation and immune function Administration of parenteral iron has been shown in human and animal studies to be harmful when administered during infection. 109 Mechanisms Responsible for the Effects of Iron Deficiency on Immune Function 110 Iron toxicity Iron overload (hemochromatosis) include decreased antibody-mediated and mitogen stimulated phagocytosis by monocytes and macrophages, reduced neutrophil migration, alterations in T-lymphocyte subsets, modification of lymphocyte distribution in different compartments of the immune system, suppression of the complement system, and increased rate of infections. 111 Iron toxicity Hydroxyl radicals, produced by the Fenton reaction or by the Fe-catalyzed Haber-Weiss reaction, are responsible for many of the damaging effects of iron. Within minutes, however, the immune system, iron and its binding proteins have immunoregulatory properties, and shifting these immunoregulatory balances by providing too much iron may result in deleterious physiological effects. In fact, the carcinogenic effects of excess iron have been attributed to the suppressive effect of excess iron on the host’s immune system in addition to the formation of hydroxyl radicals and promotion of cancer 112 cell multiplication Zinc deficiency Intake enough of zinc, reduced levels of infections ,inflammation and less oxidative stress. In humans, severe zinc deficiency is associated with frequent infections, depressed immune function and various types of infectious dermatitis . 113 Zinc deficiency Zinc deficiency was associated with lymphopenia and thymic atrophy Zinc supplementation has reduced various types of human infections in a variety of settings Zinc-deficient animals are susceptible to a wide variety of infections, and repletion often reverses this susceptibility 114 Zinc deficiency Zinc deficiency damages epithelial cells as well as the cells lining the gastrointestinal tract and pulmonary system. It is therefore likely that squamous and columnar epithelial cell damage associated with zinc deficiency allows various types of microorganisms to enter the body and become established in otherwise protected sites 115 Zinc deficiency Zinc deficiency reduces the ability to develop acquired immunity through repression of cytokine and antibody production. Zinc deficiency also inhibits normal macrophage functions including cytokine production, phagocytosis and intracellular killing 116 Zinc Ability of Zn to improve immune function during various diseases Zn supplementation resulted in a reduced duration and severity of cold symptoms In patients with sickle-cell disease, Zn supplementation increased IL-2 production, decreased incidence of bacteriologically positive infections, decreased the number of hospitalizations, and decreased the number of vasoocclusive pain crises 117 Zinc In young children, Zn supplementation reduced diarrhea duration, pneumonia , growthstunting, acute lower respiratory infections and morbidity, respiratory morbidity, incidence of dysentery, and altered intestinal permeability 118 Zinc Children receiving Zn supplementation had a significantly higher proportion of CD4 CD3 cells (CD3, CD4, and CD4/CD8 ratio) in peripheral blood and improved T-cellmediated immunity (CMI) Animal studies have confirmed that Zn deficiency is associated with a significant reduction in T-helper cell function, impaired DTH responses, compromised B-cell development, low IgG production, decreased NK lytic activity, and increased mortality to various infectious organisms 119 Zinc Maternal Zn deprivation results in offspring • with reduced thymus and spleen size, splenocyte numbers, mitogen responses, and antibody production. However, the poor Ab-mediated response • capacity and defective DTH could be restored by Zn supplementation. It is interesting that the effects of Zn • deficiency may be immune cell-type specific, because one study suggests that myeloid cell numbers and function are not compromised by such a deficiency 120 Proposed mechanisms for the immune essentiality of zinc The proposed mechanisms by • which Zn influences immune functions include generation of oxygen radicals, lymphocyte maturation, cytokine production, and the regulation of apoptosis and gene expression as described in 121 Mechanisms Responsible for the Essentiality of Zn to Immune Function 122 Proposed mechanisms for the immune essentiality of zinc During Zn deficiency, the presence of higher proportions of granulocytes (as much as 50%) and monocytes (almost twofold) suggest that the myelopoietic environment of the marrow is more protected from, or even up-regulated during, Zn deficiency . Although the numbers may not be compromised, the function of these cells may be. Zn-dependent enzymes or reactions are involved in the generation of oxygen radicals, and suboptimal levels of Zn have been demonstrated to lower the killing ability of 123 internalized parasites by macrophage Proposed mechanisms for the immune essentiality of zinc Furthermore, the capacity of • macrophages to engulf and kill parasites can be restored after treatment with Zn. Whether impaired killing ability of macrophages is a result of decreased production of H2O2 or of another Zn-related function or process remains to be established 124 Proposed mechanisms for the immune essentiality of zinc The decreased cell-mediated immune functions and the increased frequency of infection in Zn-deficient subjects may be linked to the effects of Zn on cytokine production (decreased IL-2 production), a decrease in CD4/CD8 cell ratio, and a decrease in the production of antigen mature CD4CD45R0 cells, suggesting an effect on T-helper cell maturation 125 Proposed mechanisms for the immune essentiality of zinc Zn influences the activity of multiple enzymes at the basic level of replication and transcription. For example, Zn is needed for the activity of thymidine kinase during the S-phase of cell growth and for the activation of the Zn finger protein NF-B that is involved in IL-2 and IL-2R expression. In Zn-deficient cells, the activation, translocation, and binding of NF-B to DNA are inhibited. NK activity and cytotoxic T-cell precursors (CD8CD73) are decreased with Zn restriction, which may be linked to decreased IL-2 production. Zn deficiency is also associated with an increase in plasma corticosterone, which can contribute to T-cell immunosuppression 126 Proposed mechanisms for the immune essentiality of zinc Some of the changes in T-cell maturation and • function observed during Zn deficiency are likely related to decreases in Zn-dependent thymulin activity. Zn deficiency in experimental animals results in atrophy of thymic and lymphoid tissue, with losses of precursor T and B cells in the bone marrow. This is demonstrated by the dose-related decline in the number of pre-B cells (B220), immature B cells (B220IgMIgD), and mature B cells (IgMIgD) 127 Proposed mechanisms for the immune essentiality of zinc In vitro, low concentrations of Zn have been • shown to induce apoptosis in mouse CD4 CD8 thymocytes, whereas high zinc concentrations have been shown to block apoptosis. In vitro, high concentrations of Zn blocked • apoptosis by preventing activation of the endonuclease, which is involved in DNA fragmentation and inhibited steroid binding (possibly by binding to the vicinal cysteines in the receptor-ligandbinding site) to the glucocorticoid receptor during glucocorticoid induced apoptotic death 128 Other Micronutrients Selenium appears to have several roles in protection from infection. First, often in conjunction with vitamin E, selenium appears to act as an oxidant scavenger and protects against oxidative damage. Selenium also appears to stimulate T-cell proliferation and macrophage cytotoxicity 129 NUCLEOTIDES Dietary nucleotides are obtained from nucleoprotein-rich foods, such as organ meats, fish, and poultry, and are especially high in human breast milk. In general, de novo synthesis of nucleotides may be sufficient for normal growth and development in healthy persons, who typically consume 5% (1–2 g/day in adults) of their daily requirement for these compounds. Nucleotides may become conditionally essential during growth and immunological challenges when demand may exceed de novo synthetic capacity 130 NUCLEOTIDES Animals fed nucleotide-free diets suffer impaired cellular and humoral immune function, including decreased NK cell and macrophage activity, lower DTH responses and cytokine production, decreased antibody production, and increased susceptibility to infections. The addition of nucleotides to nucleotide-free diets has been shown to reverse or restore many of the changes observed with nucleotide deficiency, such as increasing Th1-type cytokines, increasing antibody production, and increasing spleen cell proliferation 131 NUCLEOTIDES In addition, human infants fed breast milk or formula supplemented with nucleotides had higher NK cell activity and IL-2 production compared with infants fed formula without nucleotides. The beneficial effects of additional dietary nucleotides on immune function are supported by animal studies. Clinical benefits (i.e., shorter hospital stays and reduced incidence of infection among critically ill patients) have also been demonstrated with the use of enteral formulas containing nucleotides. 132 NUCLEOTIDES Unfortunately, many studies examining nucleotide supplementation have fed mixtures that contain other “immunonutrients” (e.g., fish oil and amino acids), making it impossible to identify specific nucleotide effects on immune and clinical parameters. 133 NUCLEOTIDES The precise mechanism by which exogenous nucleotides modulate immune function is not known, but it is logical that they would contribute to the pool of nucleotides available to immune cells. Nucleotides are building blocks for DNA and RNA synthesis and are involved in diverse cellular processes, serving as sources of chemical energy [e.g., 5-triphosphate (ATP)] and intracellular signals (e.g., adenosine cyclic 3,5-adenosine monophosphate and cyclic 35guanosine monophosphate). Further research is needed to identify the specific functions and mechanisms and to define the importance of these nutrients, particularly in feeding situations such as enteral supplements and infant formula where the intake of nucleotides would be low 134