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Immune nutrition The importance of nutrition in immunity Anno 18 - No. 2 ■ March/April 2007 ■ AgroFOOD industry hi-tech 30 CHRISTINE GAERTNER Cognis Deutschland GmbH & Co KG, Nutrition & Health Rheinpromenade 1, Monheim, D-40789, Germany COMPONENTS OF THE IMMUNE SYSTEM The human immune system has developed over millions of years into what it is today: a highly efficient and complex system for defending the body against foreign infectious agents, such as bacteria, viruses and parasites, as well as malignant cells and other noxious agents. Physical barriers form the body's first line of defense, including the skin and mucous membranes in the airways and digestive tract. Innate ("non-specific") and adaptive ("specific" or "acquired") mechanisms together form the actual immune system. Unlike other organs, such as the liver or adipose tissue, the immune system extends throughout the body and comprises a network of highly specialized immune cells and small molecules. The immune cells are organized into lymphoid organs (spleen, lymph nodes - see Figure 1). They also circulate in the lymph and in the bloodstream, and are dispersed at various sites in the body such as the skin. A more detailed description of the various immune cells follows later in this article. The above mentioned "small molecules" include antibodies and cytokines. Produced by specialized immune cells (Blymphocytes), antibodies react with antigens (any substance triggering an immune response) to prepare the antigen for destruction. Cytokines are small soluble molecules, mainly peptides, which act as messengers between immune cells, as well as between immune cells and cells of other organs such as the liver, adipose tissue or the brain. Therefore, cytokines are essential for integrating and coordinating the immune responses. They include Tumor Necrosis Factor alpha (TNF-α), Interferon gamma (INF-γ), Interleukins (IL-1, IL-2, IL-6), and many more. The immune system is thus a highly complex and interrelated system, so that efficient communication between all elements is of key importance to ensure coordinated action. Table 1 summarizes its various components. ABSTRACT The human immune system is highly sophisticated, designed to ensure that it can protect the body against invasive foreign or dangerous substances. It can also be considered as the body's largest organ and, as such, has substantial energy and nutrient requirements. The link between nutrition and immunity has been established for many years and, in 1968, the WHO recognised that there is actually a synergism between infection and nutrition deficits (1). Since then, there has been an "explosion" of knowledge about interrelations between nutrition and immunity. This has confirmed the importance of optimal nutrition to support optimal immune status. The present paper gives a brief introduction into the human immune system, discusses factors which influence immune status, including nutrition, and finally reviews the evidence for immune modulating effects of selected nutrients. Figure 1 Table 1. Elements of the immune system CELLS OF THE IMMUNE SYSTEM All immune cells originate from bone marrow and are collectively named leukocytes, i.e., white blood cells. They develop from their bone marrow stem cell precursors and acquire their specific function in a multi-step process involving various lymphoid and other organs. The leukocytes can be broadly divided into two categories: phagocytes, which ingest and digest invading microorganisms and account for 70-80 percent of total leukocytes in the blood; and lymphocytes, which allow the body to remember and recognize previous invaders, and which account for the remaining 20-30 percent. Phagocytes include granulocytes, monocytes and macrophages. Monocytes circulate in blood and are both precursors of macrophages as well as having phagocytotic activity themselves. Monocytes migrate continuously from blood into tissues, where they differentiate into macrophages. Part of the first line of defense, macrophages KEEPING THE IMMUNE SYSTEM IN BALANCE Vitamin E Vitamin E is the most important fat-soluble antioxidant present in human and animal tissues, thus protecting lipids in biomembranes from oxidative damage. In addition to its antioxidative effects, it is involved in the modulation of cellular signalling: it inhibits protein kinase C (PKC) (14), a Anno 18 - No. 2 Following is a brief look at the immune effects of selected individual nutrients known for their immune-modulating effects. The selection is not intended to be complete and certain nutrients established for their "immune-boosting" effects, such as vitamin C, zinc, selenium, as well as proand prebiotics are not covered. However, excellent recent reviews covering these nutrients are available (9-13). ■ IMMUNE EFFECTS OF INDIVIDUAL NUTRIENTS 31 March/April 2007 Although different types of pathogenic micro-organisms are attacked and destroyed in slightly different ways, in general immune responses to invading micro-organisms follow a common pattern. If the pathogenic micro-organism has Since the human immune system can be thought of as the body's largest organ, it follows that its energy and nutrient requirements are considerable. It needs: - Glucose and glutamine for energy; - Amino acids for synthesis of cytokines, antibodies, as well as cell division and growth; - Fatty acids for energy, synthesis of eicosanoids, as well as cell membrane fluidity and thus functionality of receptors; - Vitamins as co-factors of enzymes, antioxidants, and for cell differentiation; - Minerals and trace elements as co-factors of enzymes. These nutrient requirements increase still further when the immune system is activated - in response to an infection, for example. Energy and protein are both needed for the synthesis of cytokines, antibodies, enzymes and others, as well as for the proliferation of immune cells, especially of Tand B-lymphocytes. Fever increases the body's energy needs (i.e. the basal metabolic rate) by as much as 13 percent for each 1°C, but even infections without fever provoke a consuming, decomposing reaction termed "catabolic response" (6). This relationship between nutritional status and infection can create a vicious circle: during infections, nutritional needs increase, but at the same time, appetite and nutrient absorption decrease. As the body draws on its resources, the likely result is a deficit in nutrients, thus further promoting susceptibility to infections. While nutrition deficits impair immune responses and thus increase the risk of infection, the same is also true for "overnutrition": incidence and severity of specific types of infections are higher in the obese, and lower antibody responses to antigens have been reported in overweight subjects (7, 8). Thus, optimal nutritional status supports an efficient immune response. This paper can only be intended as a very brief introduction into the highly complex human immune system and its relation with nutrition, a topic which is addressed in many excellent text books and monographs. ■ FIGHTING INFECTION NUTRITION, IMMUNITY AND INFECTION AgroFOOD industry hi-tech The human immune system is an extremely powerful tool, a fact which becomes especially apparent when it is thrown off balance: both failure - as in immunodeficiency states - and over-stimulation of the immune system - as in allergies - can be devastating. The same applies when the regulatory mechanisms controlling the distinction between "self" and "non-self" get out of control, so that the immune responses target the body's own tissues and cells, as in autoimmune diseases or chronic inflammatory conditions. The status or balance of an individual's immune system is determined by many factors including genetic and exogenous influences such as: Nutrition: the most important exogenous factor influencing the immune system, discussed in more detail below; Age: the immune system changes throughout life. While the immune system was previously believed to decline with age, it is accepted today that only some aspects decline, while others increase. This results in a progressive dysregulation of the immune system with decreased cell-mediated immunity and less appropriate antibody responses. These changes are particularly apparent in elderly people with suboptimal nutritional status and any type of disease (3). Further, age-related changes in the innate immune cells of the brain have implications both for the development of neurological diseases such as Alzheimer´s disease, as well as for the cognitive and behavioral impairments during infections, which are more pronounced in the Elderly (4). Stress: stress hormones such as glucocorticoids and catecholamines are potent modulators of immune function, and study results demonstrate an increased risk of infection with psychological stress (5). managed to cross the first line of defense - skin and mucous membranes - and has actually entered the human body, the innate immune system will respond and remove the pathogen. Most of the micro organisms to which we are exposed in daily life will be dealt with in this way. If exposure to the pathogen continues or the pathogen continues to multiply, overwhelming the innate responses, a more powerful response from the adaptive immune system is called to action in order to overcome the infection. Immune nutrition and other phagocytes initiate inflammatory responses by secreting cytokines, and they recruit further immune cells to the site of infection. Further, so-called dendritic cells have phagocytotic activity, but their role is not to destroy pathogens. Rather, they function as antigen-presenting cells, displaying elements of ingested antigens on their surface. They are involved in innate immune responses - by producing cytokines and mobilizing lymphocytes such as natural killer cells (NK-cells) - but also help to induce adaptive immune responses, especially T-cell mediated immunity (2). Lymphocytes can similarly be divided into three main sub-types: T-Lymphocytes, B-Lymphocytes and NK-cells. T-Lymphocytes are responsible for cell-mediated adaptive immunity and recognize antigens via receptors on their cells' surface. There are three types of T-lymphocytes (or "Tcells"): T-helper, T-suppressor and cytotoxic T-cells. B-Lymphocytes are responsible for humoral adaptive immunity. They produce antibodies (Immunoglobulins, Ig's) upon stimulation, or become memory cells. There are five different classes of antibodies (IgA, IgD, IgE, IgG, and IgM), each of which has its own function. Natural killer cells (NKcells) belong to the innate immune system and destroy virus-infected or malignant cells directly and in a nonspecific way. Thus, natural killer cells are often the body's first line of defense against viral infections. Immune nutrition Anno 18 - No. 2 ■ March/April 2007 ■ AgroFOOD industry hi-tech 32 key player in the signalling of growth factors, cytokines and hormones. Many animal and human studies suggest that supplementation with doses higher than the RDAs (100 IU/d and above) has beneficial effects on immunity, especially in the elderly (15). In humans, vitamin E has been shown to improve cellmediated immunity, as assessed by delayed type hypersensitivity (DTH) responses and lymphocyte proliferation (16-19). These effects are mediated by increasing production of the "T-cell growth factor" Interleukin 2 (IL-2), and by reducing the production of T-cell suppressive factor prostaglandin E2 (PGE2), the latter increasing with age. Further, vitamin E supplementation increased antibody titers upon vaccination (17), and reduced the risk of acquiring respiratory infections or common colds at doses of at least 200 IU (20). Beneficial effects were not observed in all studies conducted to date. However, in those studies showing no effect, lower doses of vitamin E were used (21-23). Lack of observed effects may also be due to the study design and methodology (24, 25), and/or effects might not have been expected in the specific study population (21-23, 26). The findings in humans are supported by a wealth of data from animal studies, as reviewed by Meydani et al. (15). Beta-carotene Beta-carotene is probably the best known member of the large family of carotenoids, which are yellow to red lipophilic plant pigments. In the human body, beta-carotene acts both as an antioxidant and as a precursor to vitamin A. Vitamin A has long been recognized for its importance in maintaining immune responses: in vitamin A deficiency, susceptibility to and mortality from infections are increased. However, later research established that beta-carotene itself also acts as an immune-modulating agent (27). Higher beta-carotene plasma levels have been correlated with a lower risk of infection (28). Beta-carotene generally seems to support innate immunity, especially NK-cell activity, rather than adaptive immunity: in humans, higher intakes of beta-carotene via foods or supplements increased the number of NK-cells and/or NK-cell activity (29-34). Low NK-cell activity is associated with increased cancer risk and increased mortality in the elderly (35, 36). To improve NK-cell activity, sufficiently high doses, duration of supplementation and beta-carotene status at baseline are all important determinants of efficacy. Further, beta-carotene supplementation has been demonstrated to prevent immuno-suppression induced by UV-light exposure (37-39). CLA Conjugated linoleic acid (CLA) refers to a class of conjugated isomers of linoleic acid. The form typically used in research and commercial products is a 50:50 mixture of two isomers known to be biologically active: the cis-9, trans11 isomer (c9, t11), which is also the predominant form in the diet; and the trans-10, cis-12 isomer (t10, c12). The beneficial health effects of CLA only became known in the early 1980s (40) - relatively recently compared to other nutrients. While most data currently available on its immune effects are therefore based on research in animals, human intervention studies have demonstrated that CLA may increase antibody titers upon vaccination (results approaching statistical significance) (41), and increase levels of IgA and IgM (42), which are instrumental in activating further components of the immune system and protecting mucosal barriers against infectious invaders. In addition, CLA reduced common cold symptoms, specifically cough and sore throat (43). There is a multitude of data from animal studies supporting these observations in humans (40). Other human trials did not observe immune-stimulating effects, most probably because of the forms of CLA and/or the doses applied (44-46). CONCLUSIONS The relation between nutrition and immunity is complex. It is established that nutrient deficiencies impair immune responses. For some nutrients such as vitamin E, C or zinc, intakes higher than the current RDAs have been shown to "boost" immunity resulting in lower risk of infections and/or symptom severity. However, this may not be true for other nutrients, so that the effects of each nutrient need to be considered individually. Overall, improving immunity by optimizing nutritional status may considerably improve the health status and thus have significant benefits, both for an individual as well as from a public health perspective. REFERENCES AND NOTES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 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