This is an overview of the immune system

Nutrition and Immunity

Overview of the Immune System

The immune system protects the body against infection and disease. It is a complex and integrated system of cells, tissues, and organs that have specialized roles in defending against foreign substances and pathogenic microorganisms, including bacteria, viruses, and fungi. The immune system also functions to guard against the development of cancer. For these actions, the immune system must recognize foreign invaders as well as abnormal cells and distinguish them from self (1). However, the immune system is a double-edged sword in that host tissues can be damaged in the process of combating and destroying invading pathogens. A key component of the immediate immune response is inflammation, which can cause damage to host tissues, although the damage is usually not significant (2). Inflammation is discussed in a separate article; this article focuses on nutrition and immunity.

Cells of the immune system originate in the bone marrow and circulate to peripheral tissues through the blood and lymph. Organs of the immune system include the thymus, spleen, and lymph nodes (3). T-lymphocytes develop in the thymus, which is located in the chest directly above the heart. The spleen, which is located in the upper abdomen, functions to coordinate secretion of antibodies into the blood and also removes old and damaged red blood cells from the circulation (4). Lymph nodes serve as local sentinel stations in tissues throughout the body, trapping antigens and infectious agents and promoting organized immune cell activation.

The immune system is broadly divided into two major components: innate immunity and adaptive immunity. Innate immunity involves immediate, nonspecific responses to foreign invaders, while adaptive immunity requires more time to develop its complex, specific responses (1).

Innate Immunity

Innate immunity is the first line of defense against foreign substances and pathogenic microorganisms. It is an immediate, nonspecific defense that does not involve immunologic memory of pathogens. Because of the lack of specificity, the actions of the innate immune system can result in damage to the body’s tissues (5). A lack of immunologic memory means that the same response is mounted regardless of how often a specific antigen is encountered (6).

The innate immune system is comprised of various anatomical barriers to infection, including physical barriers (e.g., the skin), chemical barriers (e.g., acidity of stomach secretions), and biological barriers (e.g., normal microflora of the gastrointestinal tract) (1). In addition to anatomical barriers, the innate immune system is comprised of soluble factors and phagocytic cells that form the first line of defense against pathogens. Soluble factors include the complement system, acute phase reactant proteins, and messenger proteins called cytokines (6). The complement system, a biochemical network of more than 30 proteins in plasma and on cellular surfaces, is a key component of innate immunity. The complement system elicits responses that kill invading pathogens by direct lysis (cell rupture) or by promoting phagocytosis. Complement proteins also regulate inflammatory responses, which are an important part of innate immunity (7-9). Acute phase reactant proteins are a class of plasma proteins that are important in inflammation. Cytokines secreted by immune cells in the early stages of inflammation stimulate the synthesis of acute phase reactant proteins in the liver (10). Cytokines are chemical messengers that have important roles in regulating the immune response; some cytokines directly fight pathogens. For example, interferons have antiviral activity (6). These soluble factors are important in recruiting phagocytic cells to local areas of infection. Monocytes, macrophages, and neutrophils are key immune cells that engulf and digest invading microorganisms in the process called phagocytosis. These cells express pattern recognition receptors that identify pathogen-associated molecular patterns (PAMPs) that are unique to pathogenic microorganisms but conserved across several families of pathogens (see figure). For more information about the innate immune response, see the article on Inflammation.

Adaptive Immunity

Adaptive immunity (also called acquired immunity), a second line of defense against pathogens, takes several days or weeks to fully develop. However, adaptive immunity is much more complex than innate immunity because it involves antigen-specific responses and immunologic “memory.” Exposure to a specific antigen on an invading pathogen stimulates production of immune cells that target the pathogen for destruction (1). Immunologic “memory” means that immune responses upon a second exposure to the same pathogen are faster and stronger because antigens are “remembered.” Primary mediators of the adaptive immune response are B lymphocytes (B cells) and T lymphocytes (T cells). B cells produce antibodies, which are specialized proteins that recognize and bind to foreign proteins or pathogens in order to neutralize them or mark them for destruction by macrophages. The response mediated by antibodies is called humoral immunity. In contrast, cell-mediated immunity is carried out by T cells, lymphocytes that develop in the thymus. Different subgroups of T cells have different roles in adaptive immunity. For instance, cytotoxic T cells (killer T cells) directly attack and kill infected cells, while helper T cells enhance the responses and thus aid in the function of other lymphocytes (5, 6). Regulatory T cells, sometimes called suppressor T cells, suppress immune responses (12). In addition to its vital role in innate immunity, the complement system modulates adaptive immune responses and is one example of the interplay between the innate and adaptive immune systems (7, 13). Components of both innate and adaptive immunity interact and work together to protect the body from infection and disease.

Role of Nutrition

Nutritional status can modulate the actions of the immune system; therefore, the sciences of nutrition and immunology are tightly linked. In fact, malnutrition is the most common cause of immunodeficiency in the world (14), and chronic malnutrition is a major risk factor for global morbidity and mortality (15). More than 800 million people are estimated to be undernourished, most in the developing world (16), but undernutrition is also a problem in industrialized nations, especially in hospitalized individuals and the elderly (17). Poor overall nutrition can lead to inadequate intake of energy and macronutrients, as well as deficiencies in certain micronutrients that are required for proper immune function. Such nutrient deficiencies can result in immunosuppression and dysregulation of immune responses. In particular, deficiencies in certain nutrients can impair phagocytic function in innate immunity and adversely affect several aspects of adaptive immunity, including cytokine production as well as antibody- and cell-mediated immunities (18, 19). Overnutrition, a form of malnutrition where nutrients, specifically macronutrients, are provided in excess of dietary requirements, also negatively impacts immune system functions (see Overnutrition and Obesity below).

Impaired immune responses induced by malnutrition can increase one’s susceptibility to infection and illness. Infection and illness can, in turn, exacerbate states of malnutrition, for example, by reducing nutrient intake through diminished appetite, impairing nutrient absorption, increasing nutrient losses, or altering the body’s metabolism such that nutrient requirements are increased (19). Thus, states of malnutrition and infection can aggravate each other and lead to a vicious cycle (14).

Macronutrients

Protein-energy malnutrition (PEM)

Protein-energy malnutrition (PEM; also sometimes called protein-calorie malnutrition) is a common nutritional problem that principally affects young children and the elderly (20). Clinical conditions of severe PEM are termed marasmus, kwashiorkor, or a hybrid of these two syndromes. Marasmus is a wasting disorder that is characterized by depletion of fat stores and muscle wasting. It results from a deficiency in both protein and calories (i.e., all nutrients). Individuals afflicted with marasmus appear emaciated and are grossly underweight and do not present with edema (21). In contrast, a hallmark of kwashiorkor is the presence of edema. Kwashiorkor is primarily caused by a deficiency in dietary protein, while overall caloric intake may be normal (21, 22). Both forms are more common in developing nations, but certain types of PEM are also present in various subgroups in industrialized nations, such as the elderly and individuals who are hospitalized (17). In the developed world, PEM more commonly occurs secondary to a chronic disease that interferes with nutrient metabolism, such as inflammatory bowel disease, chronic renal failure, or cancer (22).

Regardless of the specific cause, PEM significantly increases susceptibility to infection by adversely affecting aspects of both innate immunity and adaptive immunity (15). With respect to innate immunity, PEM has been associated with reduced production of certain cytokines and several complement proteins, as well as impaired phagocyte function (20, 23, 24). Such malnutrition disorders can also compromise the integrity of mucosal barriers, increasing vulnerability to infections of the respiratory, gastrointestinal, and urinary tracts (21). With respect to adaptive immunity, PEM primarily affects cell-mediated aspects instead of components of humoral immunity. In particular, PEM leads to atrophy of the thymus, the organ that produces T cells, which reduces the number of circulating T cells and decreases the effectiveness of the memory response to antigens (21, 24). PEM also compromises functions of other lymphoid tissues, including the spleen and lymph nodes (20). While humoral immunity is affected to a lesser extent, antibody affinity and response is generally decreased in PEM (24). It is important to note that PEM usually occurs in combination with deficiencies in essential micronutrients, especially vitamin A, vitamin B6, folate, vitamin E, zinc, iron, copper, and selenium (21).

Dietary lipids

Experimental studies have shown that several types of dietary lipids (fatty acids) can modulate the immune response (25). Fatty acids that have this role include the long-chain polyunsaturated fatty acids (PUFAs) of the omega-3 and omega-6 classes. PUFAs are fatty acids with more than one double bond between carbons. In all omega-3 fatty acids, the first double bond is located between the third and fourth carbon atom counting from the methyl end of the fatty acid (n-3). Similarly, the first double bond in all omega-6 fatty acids is located between the sixth and seventh carbon atom from the methyl end of the fatty acid (n-6) (26). Humans lack the ability to place a double bond at the n-3 or n-6 positions of a fatty acid; therefore, fatty acids of both classes are considered essential nutrients and must be derived from the diet (26). More information is available in the article on Essential fatty acids. Alpha-linolenic acid (ALA) is a nutritionally essential n-3 fatty acid, and linoleic acid (LA) is a nutritionally essential n-6 fatty acid; dietary intake recommendations for essential fatty acids are for ALA and LA. Other fatty acids in the n-3 and n-6 classes can be endogenously synthesized from ALA or LA (see the figure in a separate article on essential fatty acids). For instance the long-chain n-6 PUFA, arachidonic acid, can be synthesized from LA, and the long-chain n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can be synthesized from ALA (26). However, synthesis of EPA and, especially, DHA may be insufficient under certain conditions, such as during pregnancy and lactation (27, 28). EPA and DHA, like other PUFAs, modulate cellular function, including immune and inflammatory responses (29).

Long-chain PUFAs are incorporated into membrane phospholipids of immune cells, where they modulate cell signaling of immune and inflammatory responses, such as phagocytosis and T-cell signaling. They also modulate the production of eicosanoids and other lipid mediators (29, 30). Eicosanoids are 20-carbon PUFA derivatives that play key roles in inflammatory and immune responses. During an inflammatory response, long-chain PUFAs (e.g., arachidonic acid [AA] of the n-6 series and EPA of the n-3 series) in immune cell membranes can be metabolized by enzymes to form eicosanoids (e.g., prostaglandins, leukotrienes, and thromboxanes), which have varying effects on inflammation (29). Eicosanoids derived from AA can also regulate B- and T-cell functions. Resolvins are lipid mediators derived from EPA and DHA that appear to have anti-inflammatory properties (30). To a certain extent, the relative production of these lipid mediators can be altered by dietary and supplemental intake of lipids. In those who consume a typical Western diet, the amount of AA in immune cell membranes is much greater than the amount of EPA, which results in the formation of more eicosanoids derived from AA than EPA. However, increasing n-3 fatty acid intake dose-dependently increases the EPA content of immune cell membranes. The resulting effect would be increased production of eicosanoids derived from EPA and decreased production of eicosanoids derived from AA, leading to an overall anti-inflammatory effect (30, 31). While eicosanoids derived from EPA are less biologically active than AA-derived eicosanoids (32), supplementation with EPA and other n-3 PUFAs may nevertheless have utility in treating various inflammatory diseases. This is a currently active area of investigation; see the article on Essential fatty acids. While n-3 PUFA supplementation may benefit individuals with inflammatory or autoimmune diseases, high n-3 PUFA intakes could possibly impair host-defense mechanisms and increase vulnerability to infectious disease (for more information, see the article on Essential fatty acids) (25, 33).

In addition to PUFAs, isomers of LA called conjugated linoleic acid (CLA) have been shown to modulate immune function, mainly in animal and in vitro studies (34). CLA is found naturally in meat and milk of ruminant animals, but it is also available as a dietary supplement that contains two isomers, cis-9,trans-11 CLA and trans-10,cis-12 CLA. One study in 28 men and women found that CLA supplementation (3 g/day of a 50:50 mixture of the two main CLA isomers) was associated with an increase in plasma levels of IgA and IgM (35), two classes of antibodies. CLA supplementation was also associated with a decrease in levels of two pro-inflammatory cytokines and an increase in levels of an anti-inflammatory cytokine (35). Similar effects on the immune response have been observed in some animal studies (36, 37); however, a few other human studies have not found beneficial effects of CLA on various measures of immune status and function (38-40). More research is needed to understand the effects of CLA on the human immune response.

Further, lipids in general have a number of other roles in immunity besides being the precursors of eicosanoids and similar immune mediators. For instance, lipids are metabolized by immune cells to generate energy and are also important structural and functional components of cell membranes. Moreover, lipids can regulate gene expression through stimulation of membrane receptors or through modification of transcription factor activity. Further, lipids can covalently modify proteins, thereby affecting their function (30).

Micronutrients

Deficiencies in select micronutrients (vitamins and nutritionally-essential minerals) can adversely affect aspects of both innate and adaptive immunity, increasing vulnerability to infection and disease. Micronutrient inadequacies are quite common in the general U.S. population, but especially in the poor, the elderly, and those who are obese (see Overnutrition and Obesity below) (41, 42). According to data from the U.S. National Health and Nutrition Examination Survey (NHANES), 93% of the U.S. population do not meet the estimated average requirement (EAR) for vitamin E, 56% for magnesium, 44% for vitamin A, 31% for vitamin C, 14% for vitamin B6, and 12% for zinc (43). Moreover, vitamin D deficiency is a major problem in the U.S. and elsewhere; it has been estimated that 1 billion people in the world have either vitamin D deficiency or insufficiency (44). Because micronutrients play crucial roles in the development and expression of immune responses, selected micronutrient deficiencies can cause immunosuppression and thus increased susceptibility to infection and disease. The roles of several micronutrients in immune function are addressed below.

Vitamin A

Vitamin A and its metabolites play critical roles in both innate and adaptive immunity. In innate immunity, the skin and mucosal cells of the eye and respiratory, gastrointestinal, and genitourinary tracts function as a barrier against infections. Vitamin A helps to maintain the structural and functional integrity of these mucosal cells. Vitamin A is also important to the normal function of several types of immune cells important in the innate response, including natural killer (NK) cells, macrophages, and neutrophils. Moreover, vitamin A is needed for proper function of cells that mediate adaptive immunity, such as T and B cells; thus, vitamin A is necessary for the generation of antibody responses to specific antigens (45).

Most of the immune effects of vitamin A are carried out by vitamin A derivatives, namely isomers of retinoic acid. Isomers of retinoic acid are steroid hormones that bind to retinoid receptors that belong to two different classes: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). In the classical pathway, RAR must first heterodimerize with RXR and then bind to small sequences of DNA called retinoic acid response elements (RAREs) to initiate a cascade of molecular interactions that modulate the transcription of specific genes (46). More than 500 genes are directly or indirectly regulated by retinoic acid (47). Several of these genes control cellular proliferation and differentiation; thus, vitamin A has obvious importance in immunity.

Vitamin A deficiency is a major public health problem worldwide, especially in developing nations, where availability of foods containing preformed vitamin A is limited (for information on sources of vitamin A, see the separate article on Vitamin A). Experimental studies in animal models, along with epidemiological studies, have shown that vitamin A deficiency leads to immunodeficiency and increases the risk of infectious diseases (45). In fact, deficiency in this micronutrient is a leading cause of morbidity and mortality among infants, children, and women in developing nations. Vitamin A-deficient individuals are vulnerable to certain infections, such as measles, malaria, and diarrheal diseases (45). Subclinical vitamin A deficiency might increase risk of infection as well (48). Infections can, in turn, lead to vitamin A deficiency in a number of different ways, for example, by reducing food intake, impairing vitamin absorption, increasing vitamin excretion, interfering with vitamin utilization, or increasing metabolic requirements of vitamin A (49).

Many of the specific effects of vitamin A deficiency on the immune system have been elucidated using animal models. Vitamin A deficiency impairs components of innate immunity. As mentioned above, vitamin A is essential in maintaining the mucosal barriers of the innate immune system. Thus, vitamin A deficiency compromises the integrity of this first line of defense, thereby increasing susceptibility to some types of infection, such as eye, respiratory, gastrointestinal, and genitourinary infections (50-56). Vitamin A deficiency results in reductions in both the number and killing activity of NK cells, as well as the function of neutrophils and other cells that phagocytose pathogens like macrophages. Specific measures of functional activity affected appear to include chemotaxis, phagocytosis, and immune cell ability to generate oxidants that kill invading pathogens (45). In addition, cytokine signaling may be altered in vitamin A deficiency, which would affect inflammatory responses of innate immunity.

Additionally, vitamin A deficiency impairs various aspects of adaptive immunity, including humoral and cell-mediated immunity. In particular, vitamin A deficiency negatively affects the growth and differentiation of B cells, which are dependent on retinol and its metabolites (57, 58). Vitamin A deficiency also affects B cell function; for example, animal experiments have shown that vitamin A deficiency impairs antibody responses (59-61). With respect to cell-mediated immunity, retinol is important in the activation of T cells (62), and vitamin A deficiency may affect cell-mediated immunity by decreasing the number or distribution of T cells, altering cytokine production, or by decreasing the expression of cell-surface receptors that mediate T-cell signaling (45).

Vitamin A supplementation enhances immunity and has been shown to reduce the infection-related morbidity and mortality associated with vitamin A deficiency. A meta-analysis of 12 controlled trials found that vitamin A supplementation in children decreased the risk of all-cause mortality by 30%; this analysis also found that vitamin A supplementation in hospitalized children with measles was associated with a 61% reduced risk of mortality (63). Vitamin A supplementation has been shown to decrease the severity of diarrheal diseases in several studies (64) and has also been shown to decrease the severity, but not the incidence, of other infections, such as measles, malaria, and HIV (45). Moreover, vitamin A supplementation can improve or reverse many of the abovementioned, untoward effects on immune function, such as lowered antibody production and an exacerbated inflammatory response (65). However, vitamin A supplementation is not beneficial in those with lower respiratory infections, such as pneumonia, and supplementation may actually aggravate the condition (45, 66, 67). Because of potential adverse effects, vitamin A supplements should be reserved for undernourished populations and those with evidence of vitamin A deficiency (64). For information on vitamin A toxicity, see the separate article on Vitamin A.

Vitamin D

Like vitamin A, the active form of vitamin D, 1,25-dihydroxyvitamin D3, functions as a steroid hormone to regulate expression of target genes. Many of the biological effects of 1,25-dihydroxyvitamin D3 are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR) (68). Upon entering the nucleus of a cell, 1,25-dihydroxyvitamin D3 associates with the VDR and promotes its association with the retinoid X receptor (RXR). In the presence of 1,25-dihydroxyvitamin D3, the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs) and initiates a cascade of molecular interactions that modulate the transcription of specific genes. More than 200 genes in tissues throughout the body are known to be regulated either directly or indirectly by 1,25-dihydroxyvitamin D3 (44).

In addition to its effects on mineral homeostasis and bone metabolism, 1,25-dihydroxyvitamin D3 is now recognized to be a potent modulator of the immune system. The VDR is expressed in several types of immune cells, including monocytes, macrophages, dendritic cells, and activated T cells (69-72). Macrophages also produce the 25-hydroxyvitamin D3-1-hydroxylase enzyme, allowing for local conversion of vitamin D to its active form (73). Studies have demonstrated that 1,25-dihydroxyvitamin D3 modulates both innate and adaptive immune responses.

Antimicrobial peptides (AMPs) and proteins are critical components of the innate immune system because they directly kill pathogens, especially bacteria, and thereby enhance immunity (74). AMPs also modulate immune functions through cell-signaling effects (75). The active form of vitamin D regulates an important antimicrobial protein called cathelicidin (76-78). Vitamin D has also been shown to stimulate other components of innate immunity, including immune cell proliferation and cytokine production (79). Through these roles, vitamin D helps protect against infections caused by pathogens.

Vitamin D has mainly inhibitory effects on adaptive immunity. In particular, 1,25-dihydroxyvitamin D3 suppresses antibody production by B cells and also inhibits proliferation of T cells in vitro (80-82). Moreover, 1,25-dihydroxyvitamin D3 has been shown to modulate the functional phenotype of helper T cells as well as dendritic cells (75). T cells that express the cell-surface protein CD4 are divided into two subsets depending on the particular cytokines that they produce: T helper (Th)1 cells are primarily involved in activating macrophages and inflammatory responses and Th2 cells are primarily involved in stimulating antibody production by B cells (12). Some studies have shown that 1,25-dihydroxyvitamin D3 inhibits the development and function of Th1 cells (83, 84) but enhances the development and function of Th2 cells (85, 86) and regulatory T cells (87, 88). Because these latter cell types are important regulators in autoimmune disease and graft rejections, vitamin D is suggested to have utility in preventing and treating such conditions (89). Studies employing various animal models of autoimmune diseases and transplantation have reported beneficial effects of 1,25-dihydroxyvitamin D3 (reviewed in 84).

Indeed, vitamin D deficiency has been implicated in the development of certain autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM; type 1 diabetes mellitus), multiple sclerosis (MS), and rheumatoid arthritis (RA). Autoimmune diseases occur when the body mounts an immune response against its own tissues instead of a foreign pathogen. The targets of the inappropriate immune response are the insulin-producing beta-cells of the pancreas in IDDM, the myelin-producing cells of the central nervous system in MS, and the collagen-producing cells of the joints in RA (90). Some epidemiological studies have found the prevalence of various autoimmune conditions increases as latitude increases (91). This suggests that lower exposure to ultraviolet-B radiation (the type of radiation needed to induce vitamin D synthesis in skin) and the associated decrease in endogenous vitamin D synthesis may play a role in the pathology of autoimmune diseases. Additionally, results of several case-control and prospective cohort studies have associated higher vitamin D intake or serum levels with decreased incidence, progression, or symptoms of IDDM (92), MS (93-96), and RA (97). For more information, see the separate article on Vitamin D. It is not yet known whether vitamin D supplementation will reduce the risk of certain autoimmune disorders. Interestingly, a recent systematic review and meta-analysis of observational studies found that vitamin D supplementation during early childhood was associated with a 29% lower risk of developing IDDM (98). More research is needed to determine the role of vitamin D in various autoimmune conditions.

Vitamin C

Vitamin C is a highly effective antioxidant that protects the body’s cells against reactive oxygen species (ROS) that are generated by immune cells to kill pathogens. Primarily through this role, the vitamin affects several components of innate and adaptive immunity; for example, vitamin C has been shown to stimulate both the production (99-103) and function (104, 105) of leukocytes (white blood cells), especially neutrophils, lymphocytes, and phagocytes. Specific measures of functions stimulated by vitamin C include cellular motility (104), chemotaxis (104, 105), and phagocytosis (105). Neutrophils, which attack foreign bacteria and viruses, seem to be the primary cell type stimulated by vitamin C, but lymphocytes and other phagocytes are also affected (106). Additionally, several studies have shown that supplemental vitamin C increases serum levels of antibodies (107, 108) and C1q complement proteins (109-111) in guinea pigs, which—like humans—cannot synthesize vitamin C and hence depend on dietary vitamin C. However, some studies have reported no beneficial changes in leukocyte production or function with vitamin C treatment (112-115). Vitamin C may also protect the integrity of immune cells. Neutrophils, mononuclear phagocytes, and lymphocytes accumulate vitamin C to high concentrations, which can protect these cell types from oxidative damage (103, 116, 117). In response to invading microorganisms, phagocytic leukocytes release non-specific toxins, such as superoxide radicals, hypochlorous acid (“bleach”), and peroxynitrite; these ROS kill pathogens and, in the process, can damage the leukocytes themselves (118). Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from such effects of autooxidation (119). Phagocytic leukocytes also produce and release cytokines, including interferons, which have antiviral activity (120). Vitamin C has been shown to increase interferon levels in vitro (121). Further, vitamin C regenerates the antioxidant vitamin E from its oxidized form (122).

It is widely thought by the general public that vitamin C boosts the function of the immune system, and accordingly, may protect against viral infections and perhaps other diseases. While some studies suggest the biological plausibility of vitamin C as an immune enhancer, human studies published to date are conflicting. Controlled clinical trials of appropriate statistical power would be necessary to determine if supplemental vitamin C boosts the immune system. For a review of vitamin C and the common cold, see the separate article on Vitamin C.

Vitamin E

Vitamin E is a lipid-soluble antioxidant that protects the integrity of cell membranes from damage caused by free radicals (123). In particular, the alpha-tocopherol form of vitamin E protects against peroxidation of polyunsaturated fatty acids, which can potentially cause cellular damage and subsequently lead to improper immune responses (124). Several studies in animal models as well as humans indicate that vitamin E deficiency impairs both humoral and cell-mediated aspects of adaptive immunity, including B and T cell function (reviewed in 124). Moreover, vitamin E supplementation in excess of current intake recommendations has been shown to enhance immunity and decrease susceptibility to certain infections, especially in elderly individuals.

Aging is associated with immune senescence (125). For example, T-cell function declines with increasing age, evidenced by decreased T-cell proliferation and decreased T-cell production of the cytokine, interleukin-2 (126). Studies in mice have found that vitamin E ameliorates these two age-related, immune effects (127, 128). Similar effects have been observed in some human studies (129). A few clinical trials of alpha-tocopherol supplementation in elderly subjects have demonstrated improvements in immunity. For example, elderly adults given 200 mg/day of synthetic alpha-tocopherol (equivalent to 100 mg of RRR-alpha-tocopherol or 150 IU of RRR-tocopherol; RRR-alpha-tocopherol is also referred to as "natural" or d-alpha-tocopherol) for several months displayed increased formation of antibodies in response to hepatitis B vaccine and tetanus vaccine (130). However, it is not known if such enhancements in the immune response of older adults actually translate to increased resistance to infections like the flu (influenza virus) (131). A randomized, placebo-controlled trial in elderly nursing home residents reported that daily supplementation with 200 IU of synthetic alpha-tocopherol (equivalent to 90 mg of RRR-alpha-tocopherol) for one year significantly lowered the risk of contracting upper respiratory tract infections, especially the common cold, but had no effect on lower respiratory tract (lung) infections (132). Yet, other trials have not reported an overall beneficial effect of vitamin E supplements on respiratory tract infections in older adults (133-136). More research is needed to determine whether supplemental vitamin E may protect the elderly against the common cold or other infections.

Vitamin B6

Vitamin B6 is required in the endogenous synthesis and metabolism of amino acids—the building blocks of proteins like cytokines and antibodies. Animal and human studies have demonstrated that vitamin B6 deficiency impairs aspects adaptive immunity, including both humoral and cell-mediated immunity. Specifically, deficiency in this micronutrient has been shown to affect lymphocyte proliferation, differentiation, and maturation as well as cytokine and antibody production (137-139). Correcting the vitamin deficiency restores the affected immune functions (139).

Folate

The B vitamin, folate, is required as a coenzyme to mediate the transfer of one-carbon units. Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the endogenous synthesis and metabolism of nucleic acids (DNA and RNA) and amino acids (140, 141). Thus, folate has obvious importance in immunity. Folate deficiency results in impaired immune responses, primarily affecting cell-mediated immunity. However, antibody responses of humoral immunity may also be impaired in folate deficiency (142).

Vitamin B12

In humans, vitamin B12 functions as a coenzyme for two enzymatic reactions. One of the vitamin B12-dependent enzymes is involved in the synthesis of the amino acid, methionine, from homocysteine. Methionine in turn is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA. The other vitamin B12-dependent enzyme, L-methylmalonyl-CoA mutase, converts L-methylmalonyl-CoA to succinyl-CoA, a compound that is important in the production of energy from fats and proteins as well as in the synthesis of hemoglobin, the oxygen carrying pigment in red blood cells (143). Patients with diagnosed vitamin B12 deficiency have been reported to have suppressed natural killer cell activity and decreased numbers of circulating lymphocytes (144, 145). One study found that these immunomodulatory effects were corrected by treating the vitamin deficiency (144).

Zinc

Zinc is critical for normal development and function of cells that mediate both innate and adaptive immunity (146). The cellular functions of zinc can be divided into three categories: 1) catalytic, 2) structural, and 3) regulatory (see Function in the separate article on zinc) (147). Because zinc is not stored in the body, regular dietary intake of the mineral is important in maintaining the integrity of the immune system. Thus, inadequate intake can lead to zinc deficiency and compromised immune responses (148). With respect to innate immunity, zinc deficiency impairs the complement system, cytotoxicity of natural killer cells, phagocytic activity of neutrophils and macrophages, and immune cell ability to generate oxidants that kill invading pathogens (149-151). Zinc deficiency also compromises adaptive immune function, including lymphocyte number and function (152). Even marginal zinc deficiency, which is more common than severe zinc deficiency, can suppress aspects of immunity (148). Zinc-deficient individuals are known to experience increased susceptibility to a variety of infectious agents (see the separate article on Zinc).

Selenium

Adequate selenium intake is essential for the host to mount a proper immune response because it is required for the function of several selenium-dependent enzymes known as selenoproteins (see the separate article on Selenium). For example, the glutathione peroxidases (GPx) are selenoproteins that function as important redox regulators and cellular antioxidants, which reduce potentially damaging reactive oxygen species, such as hydrogen peroxide and lipid hydroperoxides, to harmless products like water and alcohols by coupling their reduction with the oxidation of glutathione (see the diagram in the article on selenium) (153). These roles have implications for immune function and cancer prevention.

Selenium deficiency impairs aspects of innate as well as adaptive immunity (154, 155), adversely affecting both humoral immunity (i.e., antibody production) and cell-mediated immunity (156). Selenium deficiency appears to enhance the virulence or progression of some viral infections (see separate article on Selenium). Moreover, selenium supplementation in individuals who are not overtly selenium deficient appears to stimulate the immune response. In two small studies, healthy (157, 158) and immunosuppressed individuals (159) supplemented with 200 micrograms (mcg)/day of selenium as sodium selenite for eight weeks showed an enhanced immune cell response to foreign antigens compared with those taking a placebo. A considerable amount of basic research also indicates that selenium plays a role in regulating the expression of cytokines that orchestrate the immune response (160).

Iron

Iron is an essential component of hundreds of proteins and enzymes that are involved in oxygen transport and storage, electron transport and energy generation, antioxidant and beneficial pro-oxidant functions, and DNA synthesis (see Function in the article on iron) (161-163). Iron is required by the host in order to mount effective immune responses to invading pathogens, and iron deficiency impairs immune responses (164). Sufficient iron is critical to several immune functions, including the differentiation and proliferation of T lymphocytes and generation of reactive oxygen species (ROS) that kill pathogens. However, iron is also required by most infectious agents for replication and survival. During an acute inflammatory response, serum iron levels decrease while levels of ferritin (the iron storage protein) increase, suggesting that sequestering iron from pathogens is an important host response to infection (162, 165). Moreover, conditions of iron overload (e.g., hereditary hemochromatosis) can have detrimental consequences to immune function, such as impairments in phagocytic function, cytokine production, complement system activation, and T and B lymphocyte function (164). Further, data from the first National Health and Nutrition Examination Survey (NHANES), a U.S. national survey, indicate that elevated iron levels may be a risk factor for cancer and death, especially in men (167). For men and women combined, there were significant trends for increasing risk of cancer and mortality with increasing transferrin saturation, with risks being higher in those with transferrin saturation >40% compared to ≤30% (167).

Despite the critical functions of iron in the immune system, the nature of the relationship between iron deficiency and susceptibility to infection, especially with respect to malaria, remains controversial. High-dose iron supplementation of children residing in the tropics has been associated with increased risk of clinical malaria and other infections, such as pneumonia. Studies in cell cultures and animals suggest that the survival of infectious agents that spend part of their life cycle within host cells, such as plasmodia (malaria) and mycobacteria (tuberculosis), may be enhanced by iron therapy. Controlled clinical studies are needed to determine the appropriate use of iron supplementation in regions where malaria is common, as well as in the presence of infectious diseases, such as HIV, tuberculosis, and typhoid (168).

Copper

Copper is a critical functional component of a number of essential enzymes known as cuproenzymes (see the separate article on Copper). The mineral plays an important role in the development and maintenance of immune system function, but the exact mechanism of its action is not yet known. Copper deficiency results in neutropenia, an abnormally low number of neutrophils (169), which may increase one’s susceptibility to infection. Adverse effects of insufficient copper on immune function appear most pronounced in infants. Infants with Menkes disease, a genetic disorder that results in severe copper deficiency, suffer from frequent and severe infections (170, 171). In a study of 11 malnourished infants with evidence of copper deficiency, the ability of certain white blood cells to engulf pathogens increased significantly after one month of copper supplementation (172).

Immune effects have also been observed in adults with low intake of dietary copper. In one study, 11 men on a low-copper diet (0.66 mg copper/day for 24 days and 0.38 mg/day for another 40 days) showed a reduced proliferation response when white blood cells, called mononuclear cells, were isolated from blood and presented with an immune challenge in cell culture (173). While it is known that severe copper deficiency has adverse effects on immune function, the effects of marginal copper deficiency in humans are not yet clear (174). However, long-term high intakes of copper can result in adverse effects on immune function (175).

Probiotics

Probiotics are usually defined as live microorganisms that, when administered in sufficient amounts, benefit the overall health of the host (176). Common examples belong to the Lactobacilli and Bifidobacteria species; these probiotics are consumed in yogurt and other fermented foods. Ingested probiotics that survive digestion can transiently inhabit the lower part of the gastrointestinal tract (177). Here, they can modulate immune functions by interacting with various receptors on intestinal epithelial cells and other gut-associated immune cells, including dendritic cells and M-cells (178). Immune modulation requires regular consumption because probiotics have not been shown to permanently alter intestinal microflora (179). Probiotics have been shown to benefit both innate and adaptive immune responses of the host (180). For example, probiotics can strengthen the gut epithelial barrier—an important innate defense—through a number of ways, such as by inhibiting apoptosis and promoting the survival of intestinal epithelial cells (181). Probiotics can also stimulate the production of antibodies and T lymphocytes, which are critical in the adaptive immune response (180). Several immune effects of probiotics are mediated through altering cell-signaling cascades that modify cytokine and other protein expression (181). However, probiotics exert diverse effects on the immune system that are dependent not only on the specific strain but also on the dose, route, and frequency of delivery (182). Probiotics may have utility in the prevention of inflammatory bowel disorders, diarrheal diseases, allergic diseases, gastrointestinal and other types of infections, and certain cancers. However, more clinical research is needed in order to elucidate the health effects of probiotics (180).

Overnutrition and Obesity

Overnutrition is a form of malnutrition where nutrients are supplied in excess of the body’s needs. Overnutrition can create an imbalance between energy intake and energy expenditure and lead to excessive energy storage, resulting in obesity (15). Obesity is a major public health problem worldwide, especially in industrialized nations. Obese individuals are at increased risk of morbidity from a number of chronic diseases, including hypertension and cardiovascular diseases, type 2 diabetes, liver and gallbladder disease, osteoarthritis, sleep apnea, and certain cancers (183). Obesity has also been linked to increased risk of mortality (184).

Overnutrition and obesity have been shown to alter immunocompetence. Obesity is associated with macrophage infiltration of adipose tissue; macrophage accumulation in adipose tissue is directly proportional to the degree of obesity (185). Studies in mouse models of genetic and high-fat diet-induced obesity have documented a marked up-regulation in expression of inflammation and macrophage-specific genes in white adipose tissue (186). In fact, obesity is characterized by chronic, low-grade inflammation, and inflammation is thought to be an important contributor in the pathogenesis of insulin resistance—a condition that is strongly linked to obesity. Adipose tissue secretes fatty acids and other molecules, including various hormones and cytokines (called adipocytokines or adipokines), that trigger inflammatory processes (185). Leptin is one such hormone and adipokine that plays a key role in the regulation of food intake, body weight, and energy homeostasis (187, 188). Leptin is secreted from adipose tissue and circulates in direct proportion to the amount of fat stores. Normally, higher levels of circulating leptin suppress appetite and thereby lead to a reduction in food intake (189). Leptin has a number of other functions as well, such as modulation of inflammatory responses and aspects of humoral and cell-mediated responses of the adaptive immune system (187, 190). Specific effects of leptin, elucidated in animal and in vitro studies, include the promotion of phagocytic function of immune cells; stimulation of pro-inflammatory cytokine production; and regulation of neutrophil, natural killer (NK) cell, and dendritic cell functions (reviewed in 190). Leptin also affects aspects of cell-mediated immunity; for example, leptin promotes T helper (Th)1 immune responses and thus may have implications in the development of autoimmune disease (191). Th1 cells are primarily involved in activating macrophages and inflammatory responses (12). Obese individuals have been reported to have higher plasma leptin concentrations compared to lean individuals. However, in the obese, the elevated leptin signal is not associated with the normal responses of reduced food intake and increased energy expenditure, suggesting obesity is associated with a state of leptin resistance. Leptin resistance has been documented in mouse models of obesity, but more research is needed to better understand leptin resistance in human obesity (189).

Obese individuals may exhibit increased susceptibility to various infections. Some epidemiological studies have shown that obese patients have a higher incidence of postoperative and other nosocomial infections compared with patients of normal weight (192, 193; reviewed in 194). Obesity has been linked to poor wound healing and increased occurrence of skin infections (195-197). A higher body mass index (BMI) may also be associated with increased susceptibility to respiratory, gastrointestinal, liver, and biliary infections (reviewed in 194). In obesity, the increased vulnerability, severity, or complications of certain infections may be related to a number of factors, such as select micronutrient deficiencies. For example, one study in obese children and adolescents associated impairments in cell-mediated immunity with deficiencies in zinc and iron (198). Deficiencies or inadequacies of other micronutrients, including the B vitamins and vitamins A, C, D, and E, have also been associated with obesity (41). Overall, immune responses appear to be compromised in obesity, but more research is needed to clarify the relationship between obesity and infection-related morbidity and mortality.