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 has 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, makes antibodies and removes old and damaged red blood cells (4). 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 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 part of innate immunity (7-9). Acute-phase 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 proteins in the liver (10). Cytokines are chemical messengers that have key roles in regulating the immune response; some cytokines directly fight pathogens. For example, some 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 surface receptors that identify pattern recognition receptors that are unique to pathogenic microorganisms but conserved across several families of pathogens (Figure 1) (2, 11). For more information about the innate immune response, see the article on Inflammation.

Figure 1. Immune Cell Phagocytosis. Macrophages are specialized leukocytes that respond to invading pathogens by initiating phagocytosis and the synthesis and release of pro-inflammatory cytokines. Microorganisms like bacteria have pathogen-associated molecular patterns (PAMPs) that are identified by pattern recognition receptors on macrophages. The left side of the figure illustrates the process of phagocytosis, which involves engulfment of the bacterium into an intracellular vesicle called a phagosome, phagosome-lysosome fusion to form a phagolysosome, degradation of the bacterium by enzymes, and cellular release of the degraded material by exocytosis. The right side of the figure illustrates that bacterial binding to surface receptors of the macrophage also signals the transcription of pro-inflammatory cytokines in the cell’s nucleus. Cytokines are then produced in the cytoplasm and these pro-inflammatory proteins are secreted from the cell to affect behavior of nearby cells.

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 (4). 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, 12). 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 (reviewed in 13). 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).

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).


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, 21). According to the World Health Organization, more than one-third of the world’s underprivileged, preschool age children (80% living in Asia, 15% in Africa, and 5% in Latin America) are affected by PEM. This malnutrition stunts physical growth and mental development, with lasting effects into adulthood (22). 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 (23). 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 (23, 24). 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 (24). Thus, when treating PEM in connection with chronic disease, it is necessary to address the underlying cause of malnutrition, as well as correct the associated nutrient deficits (25, 26).

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, 27, 28). Such malnutrition disorders can also compromise the integrity of mucosal barriers, increasing vulnerability to infections of the respiratory, gastrointestinal, and urinary tracts (23). 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 (23, 28). 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 (28). 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 (23).

Dietary lipids

Experimental studies have shown that several types of dietary lipids (fatty acids) can modulate the immune response (29). 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) (30). 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 (For more information, see the article on Essential Fatty Acids) (30).

α-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 Figure 3 in the 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 (30). However, synthesis of EPA and, especially, DHA may be insufficient under certain conditions, such as during pregnancy and lactation (31, 32). EPA and DHA, like other PUFAs, modulate cellular function, including immune and inflammatory responses (33).

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 (33-35). 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 (33). 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 (34). 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 (34, 36). While eicosanoids derived from EPA are less biologically active than AA-derived eicosanoids (37), supplementation with EPA and other n-3 PUFAs may nevertheless have utility in treating various inflammatory diseases. This is currently an 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 (29, 38). Animal studies demonstrate that high dietary intake of EPA and DHA results in decreased pathogen clearance and increased susceptibility to experimental infections (39). In humans, a small number of randomized controlled trials (RCTs) indicate that EPA in particular may suppress some aspects of the immune response. Moreover, dose and participant age appear to be important modulating factors. In a randomized, double-blind, placebo-controlled trial in 46 healthy older men and women (ages 55 to 75 years), a moderate amount of EPA+DHA (720 mg EPA + 280 mg DHA/day in fish oil for 12 weeks) reduced NK cell activity (40) and T lymphocyte proliferation (41) but had no effect on inflammatory cell (neutrophil, monocyte, and macrophage) numbers, respiratory burst, or cytokine (TNF-α, IL-1β, and IL-6) production (42); DHA supplementation alone had no effect on any of the above-mentioned parameters.  On the other hand, an RCT in young men (N=93, ages 18 to 42 years) found that 12 weeks of daily supplementation with up to 4 g of EPA and 0.9 g of DHA had no effect on NK cell activity, T lymphocyte proliferation, or cytokine production (43). Directly comparing healthy young (N=93, ages 18 to 42 years) and older (N=62, ages 53 to 70 years) men, another RCT found that supplementation with increasing doses of EPA-rich oil (that also contained some DHA) for 12 weeks had differential effects on immune parameters (44). EPA was more readily incorporated into mononuclear cell membranes in older men, and a reduced neutrophil respiratory burst (approximate 20% impairment) was observed at the two higher doses of supplementation (2.7 g/day and 4.05 g/day of EPA) in older men only (44). Supplementation with 1.35 g/day of EPA + 0.3 g/day of DHA did not affect innate immune functions in either young or older men.

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 (45). 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 concentrations of IgA and IgM (46), 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 (46). Similar effects on the immune response have been observed in some animal studies (47, 48); however, a few other human studies have not found beneficial effects of CLA on various measures of immune status and function (49-51). 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 (34).


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 deficiencies are quite common in the general US population, but especially in the poor, the elderly, and those who are obese (see Overnutrition and obesity) (52, 53). According to data from the US National Health and Nutrition Examination Survey (NHANES), 93% of the US adult population does 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 (54). Moreover, vitamin D deficiency is a major problem in the US and elsewhere; it has been estimated that 1 billion people in the world have either vitamin D deficiency or insufficiency (55). 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 lymphocytes; thus, vitamin A is necessary for the generation of antibody responses to specific antigens (56).

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 (57). More than 500 genes are directly or indirectly regulated by retinoic acid (58). 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 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 (56). 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 (56). Subclinical vitamin A deficiency might increase risk of infection as well (59). 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 (60).

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 (61-67). 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 (56). 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 (68, 69). Vitamin A deficiency also affects B cell function; for example, animal experiments have shown that vitamin A deficiency impairs antibody responses (70-72). With respect to cell-mediated immunity, retinol is important in the activation of T cells (73), 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 (56).

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 43 randomized controlled trials (RCTs) that included approximately 215,633 children 6 months to 5 years of age found that vitamin A supplementation decreased the risk of all-cause mortality by 24% (RR: 0.76, 95% CI: 0.69 to 0.83); this analysis also found that vitamin A supplementation reduced the incidence of diarrhea (RR: 0.85, 95% CI: 0.82 to 0.87) and measles (RR: 0.50, 95% CI: 0.30 to 0.67) (56, 74-76). Vitamin A supplementation of mothers (during pregnancy or lactation), and early infants (1-5 months) does not appear to significantly affect child mortality, while supplementation of neonates (0 to 28 days) may reduce childhood mortality at 6 months of age (77, 78). Vitamin A supplementation is not beneficial in those with lower respiratory infections, such as pneumonia (77), and supplementation may actually aggravate the condition (56, 79-81). Although the effectiveness of vitamin A supplementation in children older than 6 months of age in low- and middle-income countries is now well established, the most effective dose and frequency of supplemental vitamin A delivery is still a matter of debate (56, 74, 78-80). For more information on vitamin A supplementation and childhood morbidity and mortality, see the article on Vitamin A. Because of potential adverse effects, vitamin A supplements should be reserved for undernourished populations and those with evidence of vitamin A deficiency (76). For information on vitamin A toxicity, see the 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) (82). 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. Thousands of VDREs have been identified throughout the genome, and VDR activation by 1,25-dihydroxyvitamin D is thought to directly and/or indirectly regulate 100 to 1,250 genes (83).

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 (84-87). Macrophages also produce the 25-hydroxyvitamin D3-1-hydroxylase enzyme, allowing for local conversion of vitamin D to its active form (88). 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 (89). AMPs also modulate immune functions through cell-signaling effects (90). The active form of vitamin D regulates two important antimicrobial proteins, cathelicidin and defensin (91-94). Vitamin D has also been shown to stimulate other components of innate immunity, including immune cell proliferation and cytokine production (95). 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 (96-98). Moreover, 1,25-dihydroxyvitamin D3 has been shown to modulate the functional phenotype of helper T cells and dendritic cells (90). 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 (4). Some studies have shown that 1,25-dihydroxyvitamin D3 inhibits the development and function of Th1 cells (99, 100) but enhances the development and function of Th2 cells (101, 102) and regulatory T cells (103, 104). 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 (105). Studies employing various animal models of autoimmune diseases and transplantation have reported beneficial effects of 1,25-dihydroxyvitamin D3 (reviewed in 100).

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), systemic lupus erythematosis (SLE), and rheumatoid arthritis (RA). Autoimmune diseases occur when the body mounts an immune response against its own tissue instead of a foreign pathogen. The targets of the inappropriate immune response are the insulin-producing β-cells of the pancreas in IDDM, the myelin-producing cells of the central nervous system in MS, multiple tissues and organs in SLE, and the collagen-producing cells of the joints in RA (106, 107).

Several case-control studies have found low serum 25-hydroxyvitamin D3 concentrations in individuals with IDDM, MS, and SLE; among these individuals, lower serum 25-hydroxyvitamin D3 concentrations have been associated with increased disease activity and relapse rates (108-110). Both genetic factors (e.g., VDR polymorphisms) and environment (e.g., low UVB exposure, low dietary vitamin D intake) may contribute to the low vitamin D status observed in these autoimmune diseases (110). For example, some observational studies have found the prevalence of various autoimmune conditions increases as latitude increases (111, 112). 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.

Low vitamin D intake has also been associated with an increased risk of MS (113), IDDM (114), and RA (115-121). Despite the well-documented relationship between low vitamin D status and autoimmune disease, few randomized controlled trials (RCTs) have been conducted, and the clinical efficacy of vitamin D supplementation in autoimmune prevention and treatment remains uncertain (108).  A 2013 meta-analysis of RCTs that tested the effect of high-dose vitamin D supplements on the risk of relapse in MS patients included only five RCTs (with a total of 129 patients and 125 controls) and found no significant effect (122). A 2013 systematic review similarly reported no effect of vitamin D supplementation on MS relapse (123). At this time, we await the results of three ongoing RCTs evaluating the efficacy of vitamin D supplementation on disease progression and activity in individuals with relapsing remitting MS (124-126). For more information on the specific autoimmune conditions discussed above, see the article on Vitamin D.

Vitamin C

Vitamin C is a highly effective antioxidant that protects the body’s cells against reactive oxygen species 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 (127-131) and function (132, 133) of leukocytes (white blood cells), especially neutrophils, lymphocytes, and phagocytes. Specific measures of functions stimulated by vitamin C include cellular motility (132), chemotaxis (132, 133), and phagocytosis (133). 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 (134-136). In support of vitamin C’s effect on neutrophil function, supplementation with vitamin C-rich SunGold Kiwifruit (2 kiwifruit/day, providing approximately 259 mg/day of vitamin C, for four weeks) increased plasma and neutrophil vitamin C concentration and improved neutrophil chemotaxis and oxidant generation in 14 young men considered to have suboptimal vitamin C status (<50 µmol/L) at baseline (137).  

Additionally, several studies have shown that supplemental vitamin C increases serum levels of antibodies (138, 139) and C1q complement proteins (140-142) 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 (143-146). 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 (131, 147, 148). In response to invading microorganisms, phagocytic leukocytes release non-specific toxins, such as superoxide radicals, hypochlorous acid (“bleach”), and peroxynitrite; these reactive oxygen species kill pathogens and, in the process, can damage the leukocytes themselves (149). Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from such effects of autooxidation (150). Phagocytic leukocytes also produce and release cytokines, including interferons that have antiviral activity (151). Vitamin C has been shown to increase interferon levels in vitro (152). Further, vitamin C regenerates the antioxidant vitamin E from its oxidized form (153).

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. A 2013 review identified six trials, only two of which were double-blind, placebo-controlled, randomized controlled trials, that could be used to evaluate the effect of vitamin C supplementation on the prevention or treatment of pneumonia (154). Overall, vitamin C supplementation had a mild beneficial effect compared to placebo. However, methodological shortcomings and the highly variable characteristics of the study populations prevent comparisons and firm conclusions from the available data. At this time, prophylactic use of vitamin C supplements for pneumonia prevention and treatment cannot be advocated for the general population. For a review of vitamin C and the common cold, see the 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 (155). In particular, the α-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 (156). 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 156). 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.

The natural age-related decline of the immune function is accompanied by an increased susceptibility to infections, a poorer response to immunization, and higher risks of developing cancers and autoimmune diseases. α-Tocopherol has been shown to enhance specifically the T cell-mediated immune response that declines with advancing age (reviewed in 157). T cell impaired response has been partly associated with a reduced capacity of naïve T cells to be activated during antigen presentation, and to produce interleukin-2 (IL-2) and proliferate as a result (158). However, very few studies have addressed the potential association between α-tocopherol and immune function in humans (157). In a small intervention study in older adults (mean age, 70 years), supplementation with 200 mg/day of all-rac-α-tocopherol (equivalent to 100 mg of RRR-α-tocopherol) for three months significantly improved natural killer (NK) cytotoxic activity, neutrophil chemotaxis, phagocytic response, and enhanced mitogen-induced lymphocyte proliferation and interleukin-2 (IL-2) production compared to baseline (159). In an earlier trial, daily supplementation of healthy older adults (≥65 years of age) with 200 mg of all-rac-α-tocopherol for 235 days also improved T lymphocyte-mediated immunity — as measured with the delayed-type hypersensitivity (DTH) skin test — and increased the production of antibodies in response to hepatitis B and tetanus vaccines (160).

Lower α-tocopherol doses failed to improve the DTH response compared to a placebo in another study in healthy participants (ages, 65-80 years) (161). A randomized, placebo-controlled trial in 617 nursing home residents (≥65 years of age) reported that daily supplementation with 200 IU of synthetic α-tocopherol (90 mg of RRR-α-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 (157, 160, 162-168). Yet, other trials have not reported an overall beneficial effect of vitamin E supplements on respiratory tract infections in older adults (161, 169-171). More research is needed to examine whether supplemental vitamin E might enhance immune function and reduce risk of infection in older adults.

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 of 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 (172-174). Correcting the vitamin deficiency restores the affected immune functions (174).

Additionally, several enzymatic reactions in the tryptophan-kynurenine pathway are dependent on vitamin B6coenzyme, pyridoxal 5’-phosphate (PLP). This pathway is known to be activated during pro-inflammatory immune responses and plays a critical role in immune tolerance of the fetus during pregnancy (175). Key intermediates in the tryptophan-kynurenine pathway are involved in the regulation of immune responses. Several tryptophan derivatives have been found to induce the death (apoptosis) or block the proliferation of certain types of immune cells, such as lymphocytes (in particular T-helper 1). They can also inhibit the production of pro-inflammatory cytokines (reviewed in 175). There is evidence to suggest that adequate vitamin B6 intake is important for optimal immune system function, especially in older individuals (176, 177). Furthermore, chronic inflammation that triggers tryptophan degradation and underlies many diseases (e.g., cardiovascular disease and cancer) may precipitate the loss of PLP and increase vitamin B6 requirements. Additional research is needed to evaluate whether vitamin B6 intakes higher than the current RDA could prevent and/or reverse immune system impairments.


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 (178, 179). Thus, folate has obvious importance in immunity. Animal studies and a few observational studies in humans indicate that folate deficiency is associated with an increased susceptibility to infection (180). Clinical folate deficiency, known as megaloblastic anemia, results in impaired immune responses, primarily affecting cell-mediated immunity; correcting the vitamin deficiency with folic acid supplementation restores the affected immune functions (181). Animal studies indicate that antibody responses of humoral immunity may also be impaired in folate deficiency, though human studies in this regard are lacking (180).

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 (182). Patients with diagnosed vitamin B12 deficiency (as pernicious anemia or megaloblastic anemia) have been reported to have suppressed natural killer cell activity and decreased numbers of circulating lymphocytes (183, 184). One study found that these immunomodulatory effects were corrected by treating the vitamin deficiency (183).


Zinc is critical for normal development and function of cells that mediate both innate and adaptive immunity (185). The cellular functions of zinc can be divided into three categories: (1) catalytic, (2) structural, and (3) regulatory (see the article on Zinc) (186). 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 (187). 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 (188-190). Zinc deficiency also compromises adaptive immune function, including lymphocyte number and function (191). T lymphocytes (T cells) are particularly vulnerable to zinc deficiency (reviewed in 192). Zinc deficiency causes thymic atrophy, which leads to low numbers of T cells, and creates an imbalance in T helper cell subsets, with a shift towards Th2. Additionally, altered cytokine production during zinc deficiency can contribute to oxidative stress and inflammation (193, 194; reviewed in 195).

Even marginal zinc deficiency, which is more common than severe zinc deficiency, can suppress aspects of immunity (187). The elderly may be particularly at risk for marginal zinc deficiency given that there is a high prevalence of inadequate dietary zinc intake among those 60 years of age and older (196, 197) and that plasma zinc concentration declines with age (198, 199). It is not known why plasma zinc declines, but impaired absorption, alterations in cellular uptake, and epigenetic dysregulation may be contributing factors (reviewed in 200). Several randomized controlled trials demonstrate that supplementation with low to moderate doses of zinc (ranging from 10 to 45 mg zinc/day) in healthy elderly individuals improves several aspects of immune function, such as restoration of thymulin activity, increased numbers of cytotoxic T lymphocytes, reduced numbers of activated T helper cells (which can contribute to autoimmunity), increased NK cell cytotoxicity, and reduced incidence of infections (193, 201-205). For more information on zinc supplementation and the susceptibility to infectious diseases, such as diarrhea, pneumonia, and malaria, see the article on Zinc.


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 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 Figure 2 in the article on selenium) (206). These roles have implications for immune function and cancer prevention.

Selenium deficiency impairs aspects of innate and adaptive immunity (207, 208), adversely affecting both humoral immunity (i.e., antibody production) and cell-mediated immunity (209). Selenium deficiency also appears to enhance the virulence or progression of some viral infections (see the article on Selenium) (210-212). Selenium affects different types of immune responses in different ways, and the selenium status of the host is an important factor when considering selenium supplementation (213). For example, selenium supplementation improves cell-mediated immunity in deficient individuals and enhances the immune response to viruses; on the other hand, selenium supplementation may worsen allergic asthma and impair the immune response to parasites (213, 214). A considerable amount of basic research also indicates that selenium plays a role in regulating the production of cytokines and eicosanoids that orchestrate the immune response (215, 216).


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 the article on Iron) (217-219). Iron is required by the host in order to mount effective immune responses to invading pathogens, and iron deficiency impairs immune responses (220). 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 (218, 221, 222). 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 (see the article on Iron) (220, 223, 224).

Concern that iron administration could increase susceptibility to malaria and the risk of adverse events has received a lot of well-deserved attention (225). A large, randomized controlled trial (RCT) in Pemba, Zanzibar, where malaria is endemic, reported an increase in serious adverse events (hospital admissions and deaths) among young children (ages, 1-35 months) receiving iron plus folic acid supplements compared to those receiving placebo [RR: 1.12, 95% CI: 1.02-1.23]; notably, a substudy within the main Pemba trial determined that the detrimental effect was confined to children who were iron-replete at baseline (226). A 2011 Cochrane review found that oral iron supplementation alone did not influence the risk of clinical malaria (fever plus parasitemia) (13 trials), death (13 trials), or hospital admissions (4 trials) in malaria-endemic areas (227). However, a subgroup analysis revealed that the risk for clinical malaria was higher with iron supplementation in settings that lacked malaria surveillance and treatment [RR: 1.16, 95% CI: 1.03 to 1.31], suggesting that access to malaria diagnostic and treatment services is a critical component of iron supplementation efforts in malaria-endemic regions.

With respect to other infections, the Cochrane review found no beneficial or adverse effects of iron supplementation on respiratory tract infections (11 RCTs) or diarrheal episodes (13 RCTs) (227).


Copper is a critical functional component of a number of essential enzymes known as cuproenzymes (see the 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 has antimicrobial properties, accumulates at sites of inflammation, and may play a role in the innate immune response to bacterial infections (reviewed in 228). Copper deficiency results in neutropenia, an abnormally low number of neutrophils (229), 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 (230, 231). 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 (232).

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 (233). 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 (234). However, long-term high intakes of copper can result in adverse effects on immune function. In a small feeding study conducted in nine healthy young men, long-term high intake of copper (7.8 mg/day for approximately 5 months) blunted antibody production in response to an influenza vaccine (235).


Probiotics are usually defined as live microorganisms that, when administered in sufficient amounts, benefit the overall health of the host (236). 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 (237). 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 (238). Immune modulation requires regular consumption because probiotics have not been shown to permanently alter intestinal microflora (239).

Probiotics have been shown to benefit both innate and adaptive immune responses of the host (240). Proposed mechanisms by which probiotics may influence immunity include the maintenance of the antimicrobial barrier, production of metabolic products that inhibit the growth of pathogens and influence host immune cell activity, and competition with pathogenic bacteria for available resources (13, 241). 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 (242). Probiotics can also stimulate the production of antibodies and T lymphocytes, which are critical in the adaptive immune response (240). Several immune effects of probiotics are mediated through altering cell-signaling cascades that modify cytokine and other protein expression (242). 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 (243).

A 2013 Cochrane review of 23 randomized controlled trials (RCTs) reported that probiotics reduce the risk of Clostridium difficile-associated diarrhea (CDAD) by 64% (95% CI: 26 to 51%) in participants taking antibiotics (244). Specifically, the incidence of CDAD in the probiotic group was 2.0% compared to 5.5% in the placebo or no treatment control group. This effect applied to both children and adults and was evident regardless of the dose or strain of administered probiotic. Another 2013 systematic review and meta-analysis, which focused on hospitalized adults (ages 33 to 79 years), reported a significant reduction in antibiotic-associated diarrhea (RR: 0.61, 95% CI 0.47 to 0.79) and Clostridium difficile infection (RR: 0.37, 95% CI: 0.22 to 0.61) in adults randomly assigned to co-administration of probiotics with antibiotics compared to co-administration of placebo with antibiotics (245). At this time, the scientific evidence is too weak to advocate the use of probiotics to reduce respiratory infections and improve vaccination response, especially in the elderly (reviewed in 246, 247). Probiotics may have utility in the prevention of inflammatory bowel disorders, allergic diseases, gastrointestinal and other types of infections, and certain cancers, but the clinical efficacy of probiotic administration for these applications is unknown at this time (240).

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 disease, type 2 diabetes mellitus, liver and gallbladder disease, osteoarthritis, sleep apnea, and certain cancers (248). Obesity has also been linked to increased risk of mortality (249).

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 (250). Studies in mouse models of genetic and high-fat diet-induced obesity have documented a marked upregulation in expression of inflammation and macrophage-specific genes in white adipose tissue (251). 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. A number of changes occur in hypertrophied adipose tissue that might contribute to this inflammatory state: (1) altered adipokine secretion, namely increased leptin (pro-inflammatory) and reduced adiponectin (anti-inflammatory) secretion; (2) release of free fatty acids that induce systemic inflammation; (3) increased endoplasmic reticulum stress (leading to oxidative stress and inflammation) triggered by adipocyte expansion; and (4) increased inflammatory gene expression and immune cell activation in hypoxic regions (252). Alterations in the numbers, proportions, and activity of resident adipose tissue immune cells also help explain the pro-inflammatory phenotype of obesity (253, 254). Notably, visceral fat accumulation (central adiposity) appears to be more strongly associated with inflammation and adverse metabolic risk factors than subcutaneous fat, displaying increased macrophage infiltration, lower adiponectin gene expression, and increased inflammatory gene expression (252, 253).

Adipose tissue secretes fatty acids and other molecules, including various hormones and cytokines (called adipocytokines or adipokines), that trigger inflammatory processes (250). Leptin is one such hormone and adipokine that plays a key role in the regulation of food intake, body weight, and energy homeostasis (255, 256). 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 (257). 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 (257). 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 (255, 258). 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 258). 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 (259). Th1 cells are primarily involved in activating macrophages and inflammatory responses (4, 257).

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 (260, 261; reviewed in 262). Obesity has been linked to poor wound healing and increased occurrence of skin infections (263-265). A higher body mass index (BMI) may also be associated with increased susceptibility to respiratory, gastrointestinal, liver, and biliary infections (reviewed in 262). Several epidemiological studies have reported obesity to be an independent risk factor for increased morbidity and mortality following infection with the 2009 influenza A (H1N1) virus (266). 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 (267). Deficiencies or inadequacies of other vitamins, including the B vitamins and vitamins A, C, D, and E, have also been associated with obesity (52). 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 (reviewed in 266).

Authors and Reviewers

Written in August 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2015 by:
Giana Angelo, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2016 by:
Adrian F. Gombart, Ph.D.
Associate Professor
Department of Biochemistry and Biophysics
Principal Investigator, Linus Pauling Institute
Oregon State University

Reviewed in August 2010 by:
Malcolm B. Lowry, Ph.D.
Assistant Professor
Department of Microbiology
Oregon State University

Copyright 2010-2016   Linus Pauling Institute


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