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Research Newsletter-Spring/Summer 2010

NUTRITION AND IMMUNITY, PART I



Victoria J. Drake, Ph.D.
LPI Research Associate


The immune system functions to protect the body against infection and disease. It is a complex and integrated network of cells and organs that defends against pathogenic organisms and guards against the development of cancer. The immune system consists of the innate immune system and the adaptive immune system. This article explores the role of macronutrients and vitamins on immune function. An article in a forthcoming newsletter will address the role of minerals and other factors in immunity.

The innate immune system is an immediate, nonspecific response to harmful substances. It is composed of physical barriers, such as the skin, as well as chemical and microbiological barriers, including the mucous secretions of the respiratory tract and the normal microflora of the gastrointestinal tract. Primary components of the innate immune system include monocytes, macrophages, and neutrophils—immune cells that engulf and digest invading microorganisms in a process called phagocytosis. These cells express surface receptors that identify pattern-recognition molecules that are conserved among several families of pathogens but unique to pathogenic microorganisms. A key component of innate immunity is the complement system, a biochemical cascade of at least 20 serum proteins that functions to kill invading pathogens by direct lysis (cell rupture) or through the promotion of phagocytosis. Innate immunity also involves cells that mediate the inflammatory response. Thus, the innate immune response is a rapid, nonspecific response that serves as the first line of defense against invading micro-organisms. However, if the innate response doesn’t adequately eliminate microorganisms and resultant infections, the adaptive immune system is summoned to action through the signaling of messenger proteins called cytokines.

The adaptive or acquired immune system is a second line of defense against pathogens. This defense develops over a longer period of time, taking several days to even weeks to develop. Compared to the innate response, adaptive immunity is much more complex because it involves antigen-specific responses and immunologic "memory" of pathogenic organisms. Exposure to a specific antigen on an invading pathogen stimulates production of immune cells that target the pathogen for destruction; subsequent responses to the same pathogen are stronger and more efficient because the antigen is "remembered." The major mediators of the adaptive immune response are specialized white blood cells, namely B lymphocytes (B cells) and T lymphocytes (T cells). B cells produce antibodies and are responsible for humoral immunity, while T cells are responsible for cell-mediated immunity. Although the innate and adaptive immune systems have unique functions, their components interact and work together to protect the body from infection and disease.

The ability of the immune system to prevent infection and disease is strongly influenced by nutritional status of the host. In fact, malnutrition is the most common cause of immunodeficiency in the world. Poor overall nutrition can lead to inadequate intake of energy and macronutrients as well as selected micronutrient deficiencies. These nutrient deficiencies can cause immunosuppression and dysregulation of immune responses. Specifically, nutritional deficiencies can impair phagocyte function in innate immunity and cytokine production in adaptive immunity, as well as adversely affect certain aspects of humoral and cell-mediated immunity. Impairment of these responses can compromise the integrity of the immune system, thereby increasing one's susceptibility to infection. Because nutritional status can modulate the actions of the immune system, the sciences of nutrition and immunology are tightly linked.

Inadequate intake of macronutrients or selected micronutrients can lead to immune deficiency, impaired hostdefense mechanisms, and therefore, increased susceptibility to infection and disease. Protein-energy malnutrition (PEM), also called protein-calorie malnutrition, is a common nutritional problem worldwide. Primary PEM, which is caused by insufficient intake of protein and/or energy, is more common in developing nations but is also present in certain subgroups in industrialized nations, such as the elderly and individuals who are hospitalized. Secondary PEM is more common in developed countries, often occurring in the context of a chronic disease that interferes with nutrient metabolism, such as inflammatory bowel disease, chronic renal failure, or cancer. Regardless of the specific cause, PEM primarily affects cell-mediated immunity rather than 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. Humoral immunity is affected to a lesser extent, but antibody affinity and response is generally decreased in PEM. PEM also leads to decreased production of certain cytokines, reduced levels of several complement proteins, and phagocyte dysfunction. Additionally, PEM compromises the integrity of mucosal barriers, thereby increasing susceptibility to infections of the respiratory, gastrointestinal, and urinary tracts. PEM often occurs in combination with deficiencies in essential micronutrients, especially vitamin A, zinc, copper, selenium, and magnesium.

Several types of dietary lipids (fatty acids) have been shown to modulate immune function. Polyunsaturated fatty acids (PUFAs)—fatty acids with more than one double bond between carbons—are broadly divided into two main classes: omega-3 PUFAs and omega-6 PUFAs. Lipids of both classes are essential nutrients because they cannot be synthesized by the body; therefore, PUFAs must be obtained from the diet. Dietary sources of omega-3 PUFAs include oily fish, flaxseeds and their oil, walnuts and their oil, and canola oil. Food sources of omega-6 PUFAs include vegetable oils (e.g., soybean, safflower, and corn oil), nuts, and seeds.

Eicosanoids (20-carbon PUFA derivatives) are signaling molecules that play important roles in inflammatory and other immune responses. In general, eicosanoids derived from omega-3 PUFAs have anti-inflammatory and immunosuppressive effects, while eicosanoids derived from omega-6 PUFAs tend to have mostly pro-inflammatory and immunostimulatory effects, although some omega-6 PUFA derivatives (i.e., lipoxins) have anti-inflammatory properties. While high intakes of omega-3 PUFAs may benefit individuals with inflammatory or autoimmune diseases, increased omega-3 PUFA intakes, especially at supplemental doses, could impair host-defense mechanisms and increase vulnerability to infectious disease. Additionally, conjugated linoleic acid (CLA), a class of isomers of linoleic acid (an omega-6 fatty acid), has been shown in one human study to increase plasma levels of immunoglobulin antibodies IgA and IgM, decrease pro-inflammatory cytokines, and increase an anti-inflammatory cytokine. CLA is found naturally in meat and milk of ruminants but is also available in supplemental form. However, more research is needed to confirm the immune effects of CLA in humans.

In addition to macronutrients, deficiencies in certain micronutrients (vitamins and nutritionally-essential minerals) adversely affect both the innate and adaptive immune systems. Micronutrients play crucial roles in the development and expression of the immune response, and certain micronutrient deficiencies lead to immunosuppression and increased susceptibility to infection and disease. Select micronutrient deficiencies are common, especially in cigarette smokers, alcoholics, pregnant and lactating women, and the elderly. Micronutrient deficiencies often occur in the context of general malnutrition; however, common isolated micronutrient deficiencies include vitamin A, vitamin D, zinc, and iron.

Vitamin A and its metabolites are required for normal functioning of the immune system. The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) function as a barrier and form the body's first line of defense against infection. Vitamin A maintains the integrity and function of these cells; therefore, deficiency in this micronutrient results in loss of integrity of the mucosal barriers and increased vulnerability to respiratory and diarrheal diseases and other infections. The vitamin A derivative, retinoic acid, functions as a hormone to regulate more than 500 genes, several of which are involved in controlling the production, proliferation, and differentiation of immune cells, including neutrophils, monocytes, and lymphocytes. Thus, vitamin A deficiency compromises the function of cell-mediated immunity and also impairs antibody responses to antigens, adversely affecting humoral immunity. Additionally, vitamin A deficiency adversely affects components of innate immunity, such as phagocyte function and the activity of so-called natural killer cells, and alters cytokine signals that influence various immune responses. Vitamin A deficiency is common worldwide, especially in developing nations, and has detrimental effects on maternal and child health. Severe vitamin A deficiency in children increases morbidity and mortality related to measles, malaria, and diarrheal infections; mild vitamin A deficiency may increase rates of certain infections, as well. Vitamin A supplementation can enhance immunity, decrease susceptibility to infection, and significantly reduce infection-related morbidity and mortality in children.

The active form of vitamin D—1,25-dihydroxyvitamin D—is a potent modulator of the immune system. Within a cell's nucleus, 1,25-dihydroxyvitamin D associates with the vitamin D receptor (VDR), a transcription factor that regulates gene expression. The VDR is expressed in most cells of the immune system; thus, vitamin D status can profoundly impact immunity. Vitamin D can affect aspects of both innate and adaptive immunity, including phagocytosis, cytokine production, lymphocyte differentiation, and antibody production. Additionally, the active form of vitamin D stimulates the expression of antimicrobial peptides, which are synthesized by various immune cells and function as critical components of the innate immune system. Vitamin D deficiency has been linked to an increased risk of autoimmune diseases (e.g., type 1 diabetes, multiple sclerosis, and rheumatoid arthritis) and certain cancers (colorectal, breast, and prostate). For more information about vitamin D and immunity, see the interview with Dr. Adrian Gombart in this newsletter.

Other vitamins play critical roles in immunity, such as the antioxidant vitamins C and E. 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. Immune cells accumulate vitamin C in high concentrations, which protects them against oxidative damage. Some studies have shown that vitamin C stimulates the production and function of neutrophils, lymphocytes, and phagocytes. Cell culture studies have demonstrated a direct antiviral effect of vitamin C, but clinical studies have had mixed results. Vitamin C also regenerates vitamin E, a lipid-soluble antioxidant that protects the integrity of cell membranes, from its oxidized form. Vitamin E supplementation in the elderly has been shown to improve age-related declines in immune function, particularly aspects of cell-mediated immunity. Some studies have found that this translates to an increased resistance against infections. In addition to the antioxidant vitamins, several B vitamins, such as vitamin B6, folate, and vitamin B12, are important in immunity. Vitamin B6 deficiency impairs aspects of both humoral and cell-mediated immunity due to its requirement in the biosynthesis and metabolism of amino acids—the building blocks of proteins like cytokines and antibodies. Deficiencies in either folate or vitamin B12 can also adversely affect immune responses because these B vitamins are needed in the biochemical reactions that synthesize the nucleic acids DNA and RNA.

Poor overall nutrition can lead to nutritional deficiencies that compromise immunity and increase susceptibility to infection and disease. Even subclinical deficiencies in various nutrients may have adverse effects on the immune system. Infection and illness can, in turn, exacerbate states of malnutrition in many different ways, for example, by reducing nutrient intake, impairing nutrient absorption, increasing nutrient losses, or altering the body's metabolism such that nutrient requirements are increased. Immune function also declines with age. For example, older people often exhibit decreased vitamin D synthesis in the skin and may have impaired vitamin C uptake. States of malnutrition and infection can aggravate each other and lead to a vicious cycle. Eating a healthful diet and taking a daily multivitamin-mineral supplement as nutritional insurance will help to maintain optimal immune function. Single nutrient supplements, such as vitamin D, may also be necessary.

Last updated June 2010

For more detailed information on nutrition and immunity, see the article in the Micronutrient Information Center.