Hostname: page-component-78c5997874-m6dg7 Total loading time: 0 Render date: 2024-11-12T20:20:22.728Z Has data issue: false hasContentIssue false

Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses

Published online by Cambridge University Press:  01 October 2007

Silvia Maggini*
Affiliation:
Bayer Consumer Care Ltd, Peter Merian-Strasse 84, P.O. Box, 4002Basel
Eva S. Wintergerst
Affiliation:
Bayer Diabetes Care Ltd, Peter Merian-Strasse 84, P.O. Box, 4002Basel
Stephen Beveridge
Affiliation:
Bayer Consumer Care Ltd, Peter Merian-Strasse 84, P.O. Box, 4002Basel
Dietrich H. Hornig
Affiliation:
Reinach, Switzerland
*
*Corresponding author: Dr Silvia Maggini, fax +41 58 272 7502, email silvia.maggini.sm@bayer.ch
Rights & Permissions [Opens in a new window]

Abstract

Adequate intakes of micronutrients are required for the immune system to function efficiently. Micronutrient deficiency suppresses immunity by affecting innate, T cell mediated and adaptive antibody responses, leading to dysregulation of the balanced host response. This situation increases susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (active and passive), in individuals with chronic alcohol abuse, in certain diseases, during pregnancy and lactation, and in the elderly. This paper summarises the roles of selected vitamins and trace elements in immune function. Micronutrients contribute to the body's natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A, C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected micronutrients can support the body's natural defence system by enhancing all three levels of immunity.

Type
Full Papers
Copyright
Copyright © The Authors 2007

Excellent reviews on the immune system are availableReference Parkin and Cohen1Reference Wintergerst, Maggini and Hornig4. The immune system is an intricate network of specialized tissues, organs, cells, and chemicals protecting the host from infectious agents and other noxious insults. The immune response to invaders can be divided into two interactive systems: innate and adaptive immunity. Innate immunity is present at birth and provides the first barrier against “invaders” consisting of e.g. skin, mucus secretions, and the acidity of the stomach. Adaptive immunity is the second barrier to infection and is acquired later in life, such as after an immunization or successfully fighting off an infection. It retains a memory of all the invaders it has faced and this accelerates antibody production. Although defence mechanisms of innate and adaptive immunity are very complex, they can be described as being organized in three main clusters: physical barriers (e.g. skin, mucosa, mucus secretions), immune cells and antibodies. Inter-individual variations in many immune functions exist within the normal healthy population and are due to genetics, age, gender, smoking habits, habitual levels of exercise, alcohol consumption, diet, stage in the female menstrual cycle, stress, etcReference Calder and Kew5. Nutrient status is an important factor contributing to immunocompetence and the profound interactions among nutrition, infection, and health have been recognisedReference Scrimshaw, Taylor and Gordon6, Reference Calder and Jackson7. In the recent decade, substantial research has focused on the role of nutrition and especially on the contribution of the role of micronutrients to an optimum functioning of the immune system. The objective of this overview is to demonstrate that selected micronutrients work in synergy and support the different components of the immune system such as physical barriers, cellular response and antibody production. An inadequate or deficient micronutrient status negatively influences the body's defences and thus impairs the body's overall ability to combat infections (Table 1).

Table 1 Summary of the sites of action of micronutrients on the immune system

Vitamins and immune function

Vitamin A

Vitamin A, acting via all-trans retinoic acid, 9-cis retinoic acid, or other metabolites and nuclear retinoic acid receptors, plays an important role in the regulation of innate and cell-mediated immunity and humoral antibody responseReference Stephensen8, Reference Villamor and Fawzi9. In vitamin A deficiency the integrity of mucosal epithelium is altered. As a consequence, an increased susceptibility to various pathogens in the eye, and in the respiratory and gastrointestinal tracts is observed. Vitamin A deficient children have an increased risk of developing respiratory diseaseReference Sommer, Katz and Tarwotjo10, and increased severity of diarrhoeal diseaseReference Barreto, Santos, Assis, Araujo, Farenzena, Santos and Fiaccone11. The benefits of vitamin A supplementation in reducing the morbidity and mortality from acute measles in infants and children, diarrhoeal diseases in pre-school children in developing countries, acute respiratory infections, malaria, tuberculosis, and infections in pregnant and lactating women have been reviewedReference Beaton, Martorell, Aronson, Edmonston, McCabe, Ross and Harvey12Reference Semba, Hughes, Darlington and Bendich14.

Vitamin A deficiency is associated with diminished phagocytic and oxidative burst activity of macrophages activated during inflammationReference Ramakrishnan, Web, Ologoudou, Gershwin, Nestel and Keen15, and a reduced number and activity of natural killer (NK) cellsReference Dawson, Li, Deciccio, Nibert and Ross16. The increased production of IL-12 (promoting T cell growth) and pro-inflammatory TNF-α (activating microbicidal action of macrophages) in a vitamin A deficient state may promote an excessive inflammatory response, but supplementation with vitamin A can reverse these effectsReference Aukrust, Mueller, Ueland, Svardal, Berge and Froland17.

Lymphocyte proliferation is caused by activation of retinoic acid receptors and therefore vitamin A is playing an essential role in the development and differentiation of Th1 and Th2 lymphocyte subsetsReference Halevy, Arazi, Melamed, Friedman and Sklan18. Vitamin A maintains the normal antibody mediated Th2 response by suppressing IL-12, TNF-α, and IFN-γ production of Th1 lymphocytes. As a consequence, in vitamin A deficiency there is an impaired ability to defend against extracellular pathogensReference Cantorna, Nashold and Hayes19. Antibody-mediated immunity is strongly impaired in vitamin A deficiencyReference Long and Santos20. Oral vitamin A supplementation increases delayed type hypersensitivity (DTH) in infants which may reflect vitamin A-related up-regulation of lymphocyte functionReference Rahman, Mahalanabis, Alvarez, Wahed, Islam and Habte21. In humans, vitamin A supplementation has been shown to improve antibody titre response to various vaccinesReference Semba22, Reference Semba, Calder, Field and Gill23.

Vitamin D

Besides the effects in calcium and bone metabolism, vitamin D and especially its biologically active metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D3) act as powerful immunoregulatorsReference Hayes, Nashold, Spach and Pedersen24Reference Cantorna, Zhu, Froicu and Wittke26. The discovery of significant quantities of vitamin D receptors in monocytes, macrophages, and thymus tissue suggests a specific role of vitamin D and its metabolites in the immune system. Most cells of the immune system except B cells express vitamin D receptorsReference Veldman, Cantorna and DeLuca27.

There is evidence from human epidemiological and animal studies that vitamin D status influences the occurrence of Th1-mediated autoimmunity diseases which is in accordance with the ability of 1,25(OH)2D3 to inhibit maturation of dendritic cells (DC) and down-regulate production of the immunostimulatory IL-12, and the observed increase in immunosuppressive IL-10Reference DeLuca and Cantorna28, Reference Lemire, Archer, Beck and Spiegelberg29. Human epidemiological studies indicate supplementation with 1,25(OH)2D3 as an independent protective factor influencing the occurrence of Th-1 mediated autoimmunityReference Hypponen, Laara, Reunanen, Jarvelin and Virtanen30, 31.

1,25(OH)2D3 acts as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the 'oxidative burst' potential of macrophages. Perhaps most importantly, it stimulates the expression of potent anti-microbial peptides, which exist in neutrophils, monocytes, NK cells, and in epithelial cells lining the respiratory tract where they play a major role in protecting the lung from infectionReference Cannell, Vieth, Umhau, Holick, Grant, Madronich, Garland and Giovannucci32. Volunteers inoculated with live attenuated influenza virus are more likely to develop fever and serological evidence of an immune response in the winter, a period of the year characterized by vitamin D insufficiencyReference Cannell, Vieth, Umhau, Holick, Grant, Madronich, Garland and Giovannucci32. Vitamin D deficiency predisposes children to respiratory infections. Ultraviolet radiation (either from artificial sources or from sunlight) reduces the incidence of viral respiratory infections, as does cod liver oil (which contains vitamin D)Reference Cannell, Vieth, Umhau, Holick, Grant, Madronich, Garland and Giovannucci32.

Vitamin E

Free radicals and lipid peroxidation are immunosuppressive and due to its strong lipid-soluble antioxidant activity vitamin E is able to optimise and enhance the immune response. Supplementation with vitamin E increases lymphocyte proliferation in response to mitogens, production of IL-2, NK cell cytotoxic activity, and phagocytic activity by alveolar macrophages, and causes an increased resistance against infectious agents indicating that higher vitamin E intake is promoting a Th1 cytokine mediated response and suppressing a Th2 responseReference Meydani, Han and Wu33.

Immune function in humans declines with age (immunosenescence). Alterations include impaired T cell-dependent functions such as T-cell proliferation to mitogens, antibody response after primary immunization with T-cell dependent antigens, impaired DTH and IL-2 production, whereas IL-4 and IL-6 are elevated. These findings could indicate a shift from a pro-inflammatory Th1 to a more anti-inflammatory Th2 cytokine response due to ageingReference Castle34Reference Miller36. Since deregulation of the responses with age is associated with a higher morbidity and mortality from infections and neoplastic diseases, vitamin E has been investigated in human studies with regard to its potential to improve the overall immune response, especially in the elderlyReference Meydani, Meydani, Blumberg, Leka, Siber, Loszewski, Thompson, Pedrosa, Diamond and Stollar37Reference Lee and Wan46. Further support for a more specific role of vitamin E is provided by the finding that vitamin E supplementation increases IL-2 production of T cells and enhances a Th1 response and decreased the expression of IL-4, a stimulator of Th2 response. Other studies indicate that vitamin E causes a shift toward greater proportions of antigen-experienced memory T cells with fewer naive T cellsReference Han, Adolfsson, Lee, Prolla, Ordovas and Meydani47. Recent reviews comprehensively confirmed the role of vitamin E and immunity in man, especially in the elderlyReference Wintergerst, Maggini and Hornig4, Reference Meydani, Han and Wu33.

Vitamin C

Reactive oxygen species (ROS), generated by activated immune cells during the process of phagocytosis, can be scavenged by non-enzymatic antioxidants, such as vitamin C or by enzyme action. Whereas ROS play essential roles in intracellular killing of bacteria and other invading organisms, the immune system and other body's molecules may be vulnerable to oxidative attack. If ROS are produced in high concentrations, this fact can cause oxidative stress and lead to impaired immune response, loss of cell membrane integrity, altered membrane fluidity, and alteration of cell-cell communication. These alterations could contribute to degenerative disorders such as cancer and cardiovascular diseaseReference Calder and Jackson7, Reference Hughes, Calder, Field and Gill48, Reference Ames, Shigenaga and Hagen49.

The immune-enhancing role of vitamin C has recently been reviewedReference Wintergerst, Maggini and Hornig50. Vitamin C is highly concentrated in leukocytes and is used rapidly during infection. In fact, it has been defined as a stimulant of leukocyte functions, especially of neutrophil and monocyte movement. Vitamin C supplements have been shown to enhance neutrophil chemotaxis in healthy adults (1–3 g/day) and children (20 mg/kg/day)Reference Anderson, Oosthuizen, Maritz, Theron and Van Rensburg51. In addition, supplementation with vitamin C has been demonstrated to stimulate the immune system by enhancing T-lymphocyte proliferation in response to infection increasing cytokine production and synthesis of immunoglobulinsReference Jeng, Yang, Siu, Tsai, Liao and Kuo52. Vitamin C may also play a significant role in the regulation of the inflammatory responseReference Haertel, Strunk, Bucsky and Schultz53.

Administration of vitamin C results in improvement in several components of human immune response such as anti-microbicidal and NK cell activities, lymphocyte proliferation, chemotaxis, and DTH responseReference Johnston54Reference Kennes, Dumont, Brohee, Hubert and Neve57. Based on its immune-stimulating propertiesReference Anderson, Oosthuizen, Maritz, Theron and Van Rensburg51, vitamin C was postulated to be effective in ameliorating symptoms of upper respiratory tract infections, especially the common cold. Further, plasma and leukocyte vitamin C concentrations fall rapidly with the onset of the infection and return to normal with the amelioration of the symptoms suggesting dosage with vitamin C could be beneficial for the recovery processReference Hume and Weyers58. A review of the large numbers of studies on a potential effect of vitamin C on the common cold and respiratory infections concluded that administration of more than 1 g/day had no consistent effect on the incidence of common colds, but supported a moderate benefit on duration and severity of symptoms which may also be of economic advantageReference Douglas, Hemilä, Chalker and Treacy59.

Vitamin B6

Vitamin B6 is essential in nucleic acid and protein biosynthesis, hence an effect on immune function is logical, since antibodies and cytokines built up from amino acids and require vitamin B6 as coenzyme in their metabolism60, Reference Leklem, Rucker, Suttie, McCormick and Machlin61.

Human studies demonstrate that vitamin B6 deficiency impairs lymphocyte maturation and growth, and antibody production and T-cell activity. Lymphocyte mitogenic response is impaired by dietary vitamin B6 depletion in elderly subjects and restored by administration of vitamin B6. Effects of deficiency were seen in a decreased antibody DTH response, IL-1-β, IL-2, IL-2 receptor, NK cell activity, and in lymphocyte proliferationReference Chandra and Sudhakaran62Reference Trakatellis, Dimitriadou and Trakatelli64.

Marginal vitamin B6 deficiency alters the percentage of T-helper cells and slightly decreased serum immunoglobulin DReference Ockhuizen, Spanhaak, Mares, Veenstra, Wedel, Mulder and van den Berg65. Marginal vitamin B6 deficiency in the elderly is associated with decreased numbers and function of circulating T-lymphocytes which can be corrected by short-term (6 weeks) supplementation with 50 mg of vitamin B6/dayReference Miller and Kerkvliet66. Decreased IL-2 production, T lymphocyte numbers, and T lymphocyte proliferation is observed in subjects undergoing vitamin B6 depletion, indicating that vitamin B6 deficiency suppresses a Th1 and promotes a Th2 cytokine mediated activity, whereas repletion reverses itReference Long and Santos20.

Folate

Folate plays a crucial role in nucleic acid and protein synthesis by supplying in concert with vitamins B6 and B12 one-carbon units, and therefore inadequate folate significantly alters the immune response. Folate deficiency modulates immune competence and resistance to infections and affects cell-mediated immunity by reducing the proportion of circulating T lymphocytes and their proliferation in response to mitogen activation. This effect in turn decreases resistance to infectionsReference Dhur, Galan and Hercberg67.

In vitro data suggest that folate status may affect the immune system by inhibiting the capacity of CD8+T lymphocytes cells to proliferate in response to mitogen activation. This might explain the observation that folate deficiency enhances carcinogenesis, next to increased damage to DNA and altered methylation capacityReference Courtemanche, Elson-Schwab, Mashiyuama, Kerry and Ames68.

Folate supplementation of elderly individuals improves overall immune function by altering the age-associated decrease in NK cell activity supporting a Th1 response thus providing protection against infectionsReference Troen, Mitchell, Sorensen, Wener, Johnston, Wood, Selhub, McTiernan, Yasui, Oral, Potter and Ulrich69. Large intakes of folic acid (folate-rich diet and supplements >400 μg/day) were shown in one study to possibly impair NK cytotoxicityReference Troen, Mitchell, Sorensen, Wener, Johnston, Wood, Selhub, McTiernan, Yasui, Oral, Potter and Ulrich69, whereas another study reported no correlation between total plasma folate concentration and NK cell cytotoxicity in Italian elderlyReference Ravaglia, Forti, Maioli, Bastagli, Facchini, Mariani, Savarino, Sassi, Cucinotta and Lenaz70.

NK activity was followed in a trial with 60 healthy subjects aged over 70 years who received over 4 months in addition to the regular diet a special nutritional formula providing, among other nutrients, 400 μg folic acid, 120 IU vitamin E and 3·8 μg vitamin B12. NK cell cytotoxicity increased in supplemented subjects and decreased in non-supplemented participants. Supplemented subjects reported less infections, suggesting that this nutritional supplement increased innate immunity and provided protection against infections in elderly peopleReference Bunout, Barrera, Hirsch, Gattas, de la Maza, Haschke, Steenhout, Klassen, Hager, Avendano, Petermann and Munoz71.

Vitamin B12

Vitamin B12 is involved in carbon-1 metabolism and there are interactions with folate metabolism. In a vitamin B12-deficient state the irreversible reaction that forms 5-methyl tetrahydrofolate (THF) results in an inactive form of folate if it is not de-methylated by methionine synthase. The “trapping” of 5-methyl THF may result in a secondary folate deficiency with impairments in thymidine and purine synthesis and subsequently in DNA and RNA synthesis, leading to alterations in immunoglobulin secretionReference Bailey, Gregory, Bowman and Russel72.

A human study in vitamin B12 deficient patients evaluated the alterations of immunological indicators following administration of vitamin B12. In these patients, a significant decrease was found in the number of lymphocytes and CD8+ cells and in the proportion of CD4+ cells. In addition, findings showed an abnormally high CD4+/CD8+ ratio, and suppressed NK cell activity. Supplementation with vitamin B12 reversed these effects indicating that it may act as a modulatory agent for cellular immunity, especially in relation to CD8+ and NK cellsReference Tamura, Kubota, Murakami, Sawamura, Matsushima, Tamura, Saitoh, Kurabayashi and Naruse73.

In elderly subjects (aged >70 years) who received over 4 months in addition to the regular diet a special nutritional formula providing, among other nutrients, 120 IU vitamin E, 3·8 μg vitamin B12, and 400 μg folic acid, NK cell cytotoxic activity increased in supplemented subjects, indicating increased innate immunity in elderly peopleReference Bunout, Barrera, Hirsch, Gattas, de la Maza, Haschke, Steenhout, Klassen, Hager, Avendano, Petermann and Munoz71. Immunocompetent adults (aged >65 years) with low vitamin B12 serum concentrations, had an impaired antibody response to pneumococcal polysaccharide vaccineReference Fata, Herzlich, Schiffman and Ast74. These few studies demonstrate the importance of a sufficient vitamin B12 status to maintain an adequate immune response, especially in the elderly who have a high percentage (up to 15 %) of low serum vitamin B12 concentrationsReference Stabler, Lindenbaum and Allen75.

Trace elements and immune function

The role of trace elements is covered by other authors in this special issue and is only briefly sketched here.

Selenium

Selenium is essential for optimum immune response and influences the innate and acquired immune systems. It plays a key role in the redox regulation and antioxidant function through glutathione peroxidases that remove excess of potentially damaging radicals produced during oxidative stress. Thus, selenium plays an important role in balancing the redox state, and helping to protect the host from oxidative stress generated by the microbicidal effects of macrophages and during inflammatory reactions. The selenoenzyme thioredoxin reductase affects the redox regulation of several key enzymes, transcription factors and receptors, including ribonucleotide reductase, glucocorticoid receptors, anti-inflammatory protein AP-1, and nuclear factor-kappa B (NFκB), which binds to DNA and activates expression of genes encoding proteins involved in immune response (cytokines, adhesion molecules). Selenium deficiency decreases immunoglobulin titres and aspects of cell-mediated immunity. Selenium supplementation can counteract these effectsReference Wintergerst, Maggini and Hornig4, Reference Arthur, McKenzie and Beckett76Reference Klotz, Kroencke, Buchczyk and Sies79.

Zinc

The immune related functions of zinc have been reviewed in the last few yearsReference Wintergerst, Maggini and Hornig50, Reference Prasad80Reference Fraker and King82. Zinc is essential for highly proliferating cells, especially in the immune system and influences both innate and acquired immune functions. It is involved in the cytosolic defence against oxidative stress (superoxide dismutase activity) and is an essential cofactor for thymulin which modulates cytokine release and induces proliferation. Adequate zinc intake supports a Th1 response, and helps to maintain skin and mucosal membrane integrity and unbound zinc ions exert a direct antiviral effect on rhinovirus replication. Zinc supplementation increases cellular components of innate immunity (e.g. phagocytosis by macrophages and neutrophils, NK cell activity, generation of oxidative burst, DTH activity), antibody responses, and the numbers of cytotoxic CD8+T cells (Th1 response).

Copper

Copper has been shown to have a role in the development and maintenance of the immune system and a large number of experimental studies have demonstrated that copper status alters several aspects of neutrophils, monocytes and superoxide dismutase. Working together with catalase and glutathione peroxidase in the cytosolic antioxidant defence against ROS, copper is essential in the dismutation of superoxide anion to oxygen and H2O2, and diminishes damage to lipids, proteins, and DNA. Both copper deficiency and high intakes over longer periods can modulate several aspects of the immune responseReference Klotz, Kroencke, Buchczyk and Sies79, Reference Percival83Reference Pan and Loo87.

Iron

The immune related functions of iron have been subject to several reviews since 2001Reference Weiss, Hughes, Darlington and Bendich88Reference Oppenheimer91. Iron is essential for electron transfer reactions, gene regulation, binding and transport of oxygen, and regulation of cell differentiation and cell growth. Iron is a critical component of peroxide and nitrous oxide generating enzymes. It is involved in the regulation of cytokine production and mechanism of action, and in the activation of protein kinase C, which is essential for phosphorylation of factors regulating cell proliferation. In addition, iron is necessary for myeloperoxidase activity which is involved in the killing process of bacteria by neutrophils through the formation of highly toxic hydroxyl radicals. Therefore, any alteration in cellular iron homeostasis to either deficiency or overload has unfavourable functional consequences on the immune system. Since pathogens such as infectious microorganisms and viruses require iron and other micronutrients for replication and survival as well, it seems essential to restrict access of the infecting microorganism to iron, but to maintain a suitable concentration of iron that the host can mount an optimum immune response and avoid the possibility of excess amounts of iron which may induce free radical mediated damageReference Oppenheimer91.

Conclusions

Inadequate intake and status of vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates undernutrition. Evidence has accumulated that in humans certain nutrients selectively influence the immune response, induce dysregulation of a coordinated host response to infections in cases of deficiency and oversupply, and that deficiency may impact virulence of otherwise harmless pathogens. Thus, micronutrients are required at appropriate intakes for the immune system to function optimally. Available data indicate a role of vitamins (A, D, E, B6, B12, folate, and C), and trace elements (selenium, zinc, copper, and iron) on the immune response. They contribute to the body's natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A, C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Vitamin B6, selenium, copper and zinc have a direct impact on antibody production or B-cell proliferation, vitamins A, D and E stimulate Th2 response which in turn promotes humoral immunity, and the remaining micronutrients act indirectly by their roles in protein synthesis / cell growth. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected micronutrients can support the body's natural defence system by enhancing all three levels of immunity.

Conflict of interest statement

SB, SM and ESW are employees of Bayer Health Care, a manufacturer of multivitamins. DHH is a consultant for Bayer Consumer Care. SM, ESW, SB and DHH co-wrote the manuscript.

References

1Parkin, J & Cohen, B (2001) An overview on the immune system. Lancet 357, 17771789.Google Scholar
2Mackay, I & Rosen, FS (2000) The immune system. Part I. N Engl J Med 343, 3749.Google Scholar
3Mackay, I & Rosen, FS (2000) The immune system. Part II. N Engl J Med 343, 108117.Google Scholar
4Wintergerst, ES, Maggini, S & Hornig, DH (2007) Contribution of selected vitamins and trace elements to immune function. Ann Nutr Met 51, 301323.CrossRefGoogle ScholarPubMed
5Calder, PC & Kew, S (2002) The immune system: a target for functional foods? Br J Nutr 88, Suppl. 2, S165S177.Google Scholar
6Scrimshaw, NS, Taylor, CE & Gordon, JE (1968) Effects of infections on nutritional status. In Interactions of Nutrition and Infection, pp. 4446. Geneva: World Health Organization, Monograph Series 57, .Google Scholar
7Calder, PC & Jackson, AA (2000) Under-nutrition, infection and immune function. Nutr Res Rev 13, 329.CrossRefGoogle Scholar
8Stephensen, CB (2001) Vitamin A, infection, and immunity. Annu Rev Nutr 21, 167192.Google Scholar
9Villamor, E & Fawzi, WW (2005) Effects of vitamin A supplementation on immune responses and correlation with nutritional outcome. Clin Microbiol Rev 18, 446464.CrossRefGoogle Scholar
10Sommer, A, Katz, J & Tarwotjo, I (1984) Increased risk of respiratory disease and diarrhea in children with preexisting mild vitamin A deficiency. Am J Clin Nutr 40, 10901095.Google Scholar
11Barreto, ML, Santos, LMP, Assis, AMO, Araujo, MP, Farenzena, GG, Santos, PA & Fiaccone, RL (1994) Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory tract infections in young children in Brazil. Lancet 344, 228231.CrossRefGoogle ScholarPubMed
12Beaton, GH, Martorell, R, Aronson, KJ, Edmonston, B, McCabe, G, Ross, AC & Harvey, B (1993) Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. Geneva: Subcommittee on Nutrition, Administrative Committee on Coordination; World Health Organization; State of the Art Discussion Paper No 13.Google Scholar
13The Vitamin A and Pneunomia Working Group (1995) Potential interventions for the prevention on childhood pneumonia in developing countries: a meta-analysis of data from field trials to assess the impact of vitamin A supplementation on pneumonia morbidity and mortality. Bull WHO 73, 609619.Google Scholar
14Semba, RD (2004) Vitamin A. In Diet and Human Immune Function, chapter 6, pp. 105131 [Hughes, DA, Darlington, LG and Bendich, A, editors]. Totowa, NJ: Humana Press.CrossRefGoogle Scholar
15Ramakrishnan, U, Web, AL & Ologoudou, K (2004) Infection, immunity, and vitamins. In Handbook of Nutrition and Immunity, pp. 93115 [Gershwin, NE, Nestel, P and Keen, CL, editors]. Totoja, NJ: Humana Press.Google Scholar
16Dawson, HD, Li, NQ, Deciccio, KL, Nibert, JA & Ross, AC (1999) Chronic marginal vitamin A status reduces natural killer cell number and activity and function in aging Lewis rats. J Nutr 129, 15101517.CrossRefGoogle ScholarPubMed
17Aukrust, P, Mueller, F, Ueland, T, Svardal, A, Berge, R & Froland, SS (2000) Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses. Eur J Clin Invest 30, 252259.CrossRefGoogle ScholarPubMed
18Halevy, O, Arazi, Y, Melamed, D, Friedman, A & Sklan, D (1994) Retinoic acid receptor-alpha gene expression is modulated by dietary vitamin A and by retinoic acid in chicken T lymphocytes. J Nutr 124, 21392146.CrossRefGoogle ScholarPubMed
19Cantorna, MT, Nashold, FE & Hayes, C (1994) In vitamin A deficiency multiple mechanism establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J Immunol 152, 15151522.CrossRefGoogle ScholarPubMed
20Long, KZ & Santos, JL (1999) Vitamins and the regulation of the immune response. Ped Inf Dis J 18, 283290.CrossRefGoogle ScholarPubMed
21Rahman, MM, Mahalanabis, D, Alvarez, JO, Wahed, MA, Islam, MA & Habte, D (1997) Effect of early vitamin A supplementation on cell-mediated immunity in infants younger than 6 months. Am J Clin Nutr 65, 144148.CrossRefGoogle Scholar
22Semba, RD (1999) Vitamin A as “anti-infective” therapy. J Nutr 129, 783791.CrossRefGoogle ScholarPubMed
23Semba, RD (2002) Vitamin A, infection and immune function. In Nutrition and Immune Function (Frontiers in Nutritional Science, No. 1) chapter 8, pp. 151170 [Calder, PC, Field, CJ and Gill, HS, editors]. Oxford: CABI Publishing.CrossRefGoogle Scholar
24Hayes, CE, Nashold, FE, Spach, KM & Pedersen, LB (2003) The immunological functions of the vitamin D endocrine system. Cell Molec Biol 49, 277300.Google Scholar
25Griffin, MD, Xing, N & Kumar, R (2003) Vitamin D and its analogs as regulators of immune activities and antigen presentation. Annu Rev Nutr 23, 117145.CrossRefGoogle ScholarPubMed
26Cantorna, MT, Zhu, Y, Froicu, M & Wittke, A (2004) Vitamin D status, 1,25-dihydroxy- vitamin D3, and the immune system. Am J Clin Nutr 80, 1717S1720S.CrossRefGoogle Scholar
27Veldman, CM, Cantorna, MT & DeLuca, HF (2000) Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system. Arch Biochem Biophys 374, 334338.CrossRefGoogle ScholarPubMed
28DeLuca, HF & Cantorna, MT (2001) Vitamin D: its role and uses in immunology. FASEB J 15, 25792585.Google Scholar
29Lemire, JM, Archer, DC, Beck, L & Spiegelberg, HL (1995) Immunosuppressive actions of 1,25(OH)2D3: preferential inhibition of Th1 functions. J Nutr 125, 1704S1708S.Google ScholarPubMed
30Hypponen, E, Laara, E, Reunanen, A, Jarvelin, MR & Virtanen, SM (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 15001503.CrossRefGoogle ScholarPubMed
31The EURODIAB substudy 2 study group (1999) Vitamin D supplement in early childhood and risk for type I (insulin-dependent) diabetes mellitus. Diabetologia 42, 5154.CrossRefGoogle Scholar
32Cannell, JJ, Vieth, R, Umhau, JC, Holick, MF, Grant, WB, Madronich, S, Garland, CF & Giovannucci, E (2006) Epidemic influenza and vitamin D. Epidemiol Infec 134, 11291140.CrossRefGoogle ScholarPubMed
33Meydani, SN, Han, SN & Wu, D (2005) Vitamin E and immune response in the aged: molecular mechanism and clinical implications. Immunol Rev 205, 269284.Google Scholar
34Castle, S (2000) Clinical relevance of age-related immune dysfunction. Clin Inf Dis 31, 578585.CrossRefGoogle ScholarPubMed
35Burns, EA & Goodwin, JS (2004) Effect of aging on immune function. J Nutr Health Aging 8, 918.Google ScholarPubMed
36Miller, RA (1996) The aging immune system: primer and prospectus. Science 273, 7074.CrossRefGoogle ScholarPubMed
37Meydani, SN, Meydani, M, Blumberg, JB, Leka, LS, Siber, G, Loszewski, R, Thompson, C, Pedrosa, MC, Diamond, RD & Stollar, BD (1997) Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. J Am Med Assoc 277, 13801386.CrossRefGoogle ScholarPubMed
38Meydani, SN, Barklund, MP, Liu, S, Miller, RA, Cannon, JG, Morow, FD, Rocklin, R & Blumberg, JB (1990) Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 53, 557563.CrossRefGoogle Scholar
39Pallast, E, Schouten, E, de Waart, F, Fonk, H, Doekes, G, von Blomberg, B & Kok, FJ (1999) Effect of 50- and 100-mg vitamin E supplements on cellular immune function in non-institutionalized elderly persons. Am J Clin Nutr 69, 12731281.CrossRefGoogle Scholar
40Meydani, SN, Leka, LS, Fine, BC, Dallal, GE, Keusch, GT, Singh, MF & Hamer, DH (2004) Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. J Am Med Assoc 292, 828836.CrossRefGoogle ScholarPubMed
41Graat, JM, Schouten, EG & Kok, FJ (2002) Effect of daily vitamin E and multivitamin/multimineral supplementation on acute respiratory tract infections in elderly persons. J Am Med Assoc 288, 715721.Google Scholar
42De la Fuente, M, Ferrandez, MD, Burgos, MS, Soler, A, Prieto, A & Miquel, J (1998) Immune function in aged women is improved by ingestion of vitamins C and E. Can J Physiol Pharmacol 76, 373380.CrossRefGoogle ScholarPubMed
43Park, OJ, Kim, HYP, Kim, WK, Kim, YJ & Kim, SH (2003) Effect of vitamin E supplementation on antioxidant defense systems and humoral immune response in young, middle-aged and elderly Korean women. J Nutr Sci Vitaminol 49, 9499.CrossRefGoogle ScholarPubMed
44DeWaart, FG, Portengen, L, Doekes, G, Verwaal, CJ & Kok, FJ (1997) Effect of 3 months vitamin E supplementation on indices of the cellular and humoral immune response in elderly subjects. Br J Nutr 78, 761774.Google Scholar
45Hara, M, Tanaka, K & Hirota, Y (2005) Immune response to influenza vaccine in healthy adults and the elderly: association with nutritional status. Vaccine 23, 14571463.CrossRefGoogle ScholarPubMed
46Lee, CYJ & Wan, JMF (2000) Vitamin E supplementation improves cell-mediated immunity and oxidative stress of Asian men and women. J Nutr 130, 29322937.CrossRefGoogle ScholarPubMed
47Han, SN, Adolfsson, O, Lee, CK, Prolla, TA, Ordovas, J & Meydani, SN (2004) Vitamin E and gene expression in immune cells. Ann NY Acad Sci 1031, 96101.CrossRefGoogle ScholarPubMed
48Hughes, DA (2000) Antioxidant vitamins and immune function. In Nutrition and Immune Function, pp. 171191 [Calder, PC, Field, CJ and Gill, HS, editors]. Wallingford: CAB International.Google Scholar
49Ames, BN, Shigenaga, MK & Hagen, TM (1993) Oxidants, antioxidants, and the degenerative disease of aging. Proc Natl Acad Sci USA 90, 79157922.CrossRefGoogle Scholar
50Wintergerst, ES, Maggini, S & Hornig, DH (2006) Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann Nutr Met 50, 8594.Google Scholar
51Anderson, R, Oosthuizen, R, Maritz, R, Theron, A & Van Rensburg, AJ (1980) The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers. Am J Clin Nutr 33, 7176.Google Scholar
52Jeng, KC, Yang, CS, Siu, WY, Tsai, YS, Liao, WJ & Kuo, JS (1996) Supplementation with vitamin C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults. Am J Clin Nutr 64, 960965.CrossRefGoogle Scholar
53Haertel, C, Strunk, T, Bucsky, P & Schultz, C (2004) Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine 27, 101106.CrossRefGoogle Scholar
54Johnston, CS (1991) Complement component C1q unaltered by ascorbate supplementation in healthy men and women. J Nutr Biochem 2, 499501.Google Scholar
55Jacob, RA, Kelley, DS, Pianalto, FS, Swendseid, ME, Henning, SM, Zhang, JZ, Ames, BN, Fraga, CG & Peters, JH (1991) Immunocompetence and oxidant defense during ascorbate depletion of healthy men. Am J Clin Nutr 54, 1302S1309S.Google Scholar
56Panush, RS, Delafuente, JC, Katz, P & Johnson, J (1982) Modulation of certain immunologic responses by vitamin C. III. Potentiation of in vitro and in vivo lymphocyte response. Int J Vitam Nutr Res 23, 3547.Google Scholar
57Kennes, B, Dumont, I, Brohee, D, Hubert, C & Neve, P (1983) Effect of vitamin C supplements on cell-mediated immunity in older people. Gerontology 29, 305310.Google Scholar
58Hume, R & Weyers, E (1973) Changes in leukocyte ascorbic acid during the common cold. Scot Med J 18, 37.CrossRefGoogle ScholarPubMed
59Douglas, RM, Hemilä, H, Chalker, E & Treacy, B (2007) Vitamin C for preventing and treating the common cold. In Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD000980. DOI: 10.1002/14651858.CD000980.pub3.Google Scholar
60Institute of Medicine (1998) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, D.C.: Food and Nutrition Board, Institute of Medicine, National Academy Press, chapter 7: Vitamin B6, pp. 150195.Google Scholar
61Leklem, JE (2001) Vitamin B6. In Handbook of Vitamins, 3rd ed, revised and expanded. chapter 10, pp. 339396 [Rucker, RB, Suttie, JW, McCormick, DB and Machlin, LJ, editors]. New York: Marcel Dekker Inc.Google Scholar
62Chandra, RK & Sudhakaran, L (1990) Regulation of immune responses by vitamin B6. Ann NY Acad Sci 585, 404423.Google Scholar
63Rall, LC & Meydani, SN (1993) Vitamin B6 and immune competence. Nutr Rev 51, 217225.CrossRefGoogle ScholarPubMed
64Trakatellis, A, Dimitriadou, A & Trakatelli, M (1997) Pyridoxine deficiency: new approaches in immunosuppression and chemotherapy. Postgr Med J 73, 617622.CrossRefGoogle ScholarPubMed
65Ockhuizen, T, Spanhaak, S, Mares, N, Veenstra, J, Wedel, M, Mulder, J & van den Berg, H (1990) Short-term effects of marginal vitamin B deficiencies on immune parameters in healthy young volunteers. Nutr Res 10, 483492.CrossRefGoogle Scholar
66Miller, LT & Kerkvliet, NT (1990) Effect of vitamin B6 on immune competence in the elderly. Ann NY Acad Sci 587, 4954.Google Scholar
67Dhur, A, Galan, P & Hercberg, S (1991) Folate status and the immune system. Progr Food Nutr Sci 15, 4360.Google Scholar
68Courtemanche, C, Elson-Schwab, I, Mashiyuama, ST, Kerry, N & Ames, BN (2004) Folate deficiency inhibits the proliferation of primary human CD8+T lymphocytes in vitro. J Immunol 173, 31863189.Google Scholar
69Troen, AM, Mitchell, B, Sorensen, B, Wener, MH, Johnston, A, Wood, B, Selhub, J, McTiernan, A, Yasui, Y, Oral, E, Potter, JD & Ulrich, CM (2006) Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 136, 189194.Google Scholar
70Ravaglia, G, Forti, P, Maioli, F, Bastagli, L, Facchini, A, Mariani, E, Savarino, L, Sassi, S, Cucinotta, D & Lenaz, G (2000) Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged ≧90 years. Am J Clin Nutr 71, 590598.Google Scholar
71Bunout, D, Barrera, G, Hirsch, S, Gattas, V, de la Maza, MP, Haschke, F, Steenhout, P, Klassen, P, Hager, C, Avendano, M, Petermann, M & Munoz, C (2004) Effects of a nutritional supplement on the immune response and cytokine production in free-living Chilean elderly. J Parenteral Enteral Nutr 28, 348354.Google Scholar
72Bailey, LB & Gregory, JF III (2006) Folate. In Present Knowledge in Nutrition, 9th ed., chapter 22, pp. 278301 [Bowman, BA and Russel, RM, editors]. Washington, DC: ILSI Press.Google Scholar
73Tamura, J, Kubota, K, Murakami, H, Sawamura, M, Matsushima, T, Tamura, T, Saitoh, T, Kurabayashi, H & Naruse, T (1999) Immunomodulation by vitamin B12: augmentation of CD8+T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clin Exp Immunol 116, 2832.CrossRefGoogle ScholarPubMed
74Fata, FT, Herzlich, B, Schiffman, G & Ast, AL (1996) Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels. Ann Intern Med 124, 299304.CrossRefGoogle ScholarPubMed
75Stabler, SP, Lindenbaum, J & Allen, RH (1997) Vitamin B12 deficiency in the elderly: current dilemmas. Am J Clin Nutr 66, 741749.CrossRefGoogle ScholarPubMed
76Arthur, JR, McKenzie, R & Beckett, GJ (2003) Selenium in the immune system. J Nutr 133, 1457S1459S.CrossRefGoogle ScholarPubMed
77Ferencik, M & Ebringer, L (2003) Modulatory effects of selenium and zinc on the immune system. Folia Microbiol 48, 417426.CrossRefGoogle ScholarPubMed
78Ryan-Harshman, M & Aldoori, W (2005) The relevance of selenium to immunity, cancer, and infectious/inflammatory diseases. Can J Diet Prac Res 66, 98102.Google Scholar
79Klotz, LO, Kroencke, KD, Buchczyk, DP & Sies, H (2003) Role of copper, zinc, selenium, and tellurium in the cellular defense against oxidative and nitrosative stress. J Nutr 133, 1448S1451S.Google Scholar
80Prasad, AS (2000) Effects of zinc deficiency on immune functions. J Trace Elem Exp Med 13, 130.3.0.CO;2-2>CrossRefGoogle Scholar
81Ibs, KH & Rink, L (2003) Zinc-altered immune function. J Nutr 133, 1452S1456S.Google Scholar
82Fraker, PJ & King, LE (2004) Reprogramming of the immune system during zinc deficiency. Ann Rev Nutr 24, 277298.Google Scholar
83Percival, SS (1988) Copper and immunity. Am J Clin Nutr 67, 1064S1085S.CrossRefGoogle Scholar
84Bonham, M, O'Connor, JM, Hannigan, BM & Strain, JJ (2002) The immune system as a physiological indicator of marginal copper status? Br J Nutr 87, 393403.CrossRefGoogle ScholarPubMed
85Minatel, L & Carfagnini, JC (2000) Copper deficiency and immune response in ruminants. Nutr Res 2010, 15191529.CrossRefGoogle Scholar
86Linder, MC & Hazegh-Azam, M (1996) Copper biochemistry and molecular biology. Am J Clin Nutr 63, 797S811S.Google ScholarPubMed
87Pan, YJ & Loo, G (2000) Effect of copper deficiency on oxidative DNA damage in Jurkat T-lymphocytes. Free Rad Biol Med 28, 824830.CrossRefGoogle ScholarPubMed
88Weiss, G (2004) Iron. In Diet and Human Immune Function, chapter 11, pp. 203215 [Hughes, DA, Darlington, LG and Bendich, A, editors]. Totowa, NJ: Humana Press.CrossRefGoogle Scholar
89Schaible, UE & Kaufmann, SHE (2004) Iron and microbial infection. Nature Rev Microbiology 2, 946953.Google Scholar
90Weiss, G (2002) Iron and immunity: a double-edged sword. Eur J Clin Invest 32, Suppl 1, 7078.Google Scholar
91Oppenheimer, SJ (2001) Iron and its relation to immunity and infectious disease. J Nutr 131, 616S635S.Google Scholar
Figure 0

Table 1 Summary of the sites of action of micronutrients on the immune system