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IMMUNE SYSTEM REGULATION AND NUTRIENTS. Chicken soup, herbal tea, and vitamin C pills take on special meaning in cold and flu season. But beyond their possible role in treatment and comfort, nutrients are essential and fundamental parts of immune system function. To understand nutrient-immune interactions, it is helpful to understand how the body's immune system functions in general.

The human immune system has evolved to the state where it cannot only maintain continual vigilance against new challenges, but can "learn" from past challenges and "remember" more efficient means of resolving those challenges if they are ever encountered again. The numerous cooperative mechanisms by which the immune system addresses (but does not "remember") novel challenges are collectively termed "innate immunity." These mechanisms include proteins that can bind to or neutralize a wide variety of foreign particles, and cells that can phagocitize foreign particles to remove them from the body. In the process of neutralizing and removing foreign particles, other cells within the immune system (mainly dendritic cells) transport samples of the foreign particles (antigens) to specialized tissues and organs (spleen, lymph nodes, Peyer's patches) where naive cells (T cells and B cells) not previously exposed to foreign particles can adapt their surface molecules (through gene recombination) in order to increase the efficiency with which later encounters with the foreign particle can be resolved. These adapted cells and associated specialized proteins (immunoglobulins—proteins that function as antibodies) provide immunological memory of past encounters and form what is termed "acquired immunity."

The body's ability to resolve infections can be likened to the running of a race. The infectious agent must elude detection by the immune system until it can proliferate and establish itself within the body. The earlier the body can detect this infection (by maintaining a critical concentration of innate immune system cells and proteins throughout the body) and the faster the body can produce new protective cells and proteins, the better the chance of winning the race. The key steps in this process—efficient communication and rapid biosynthesis—are constrained by the availability of raw material, and in the body, raw material means nutrients. In this light, well-established nutritional principles can also be regarded as immunological paradigms.

Biosynthesis: Building New Cells and Proteins

The immune system is continually producing a remarkable number of new cells and proteins to provide a broad repertoire of potential immune responses and maintain functional concentrations in the periphery. An average adult has nearly six pounds of bone marrow, which produces about one trillion white blood cells per day, accounting for 8 percent or more of the total protein synthesis in the body. About 60 percent of bone-marrow biosynthesis is devoted to producing neutrophils (innate immune system phagocytes), amounting to about 100 billion cells a day, which then survive only one to two days in circulation. Studies in laboratory rats indicate that in the acquired immune system, cell turnover is ten times higher in the thymus than in the liver. Of the millions of naive T cells and B cells produced in the thymus and bone marrow every day, only about 3 to 5 percent of T cells and 10 to 20 percent of B cells pass positive and negative selection steps to reach the periphery and enter the "race" that was described.

As for proteins, more than two-thirds of the IgA (an acquired immune system protein useful in protecting mucosal surfaces—eyes, mouth, etc.) produced by the body every day (more than three grams per day for a 155-pound person) is secreted onto the body's mucosal surfaces for short-term disposal. Immunoglobulins also account for a significant fraction of total blood protein (second only to albumin) and must be replenished continually at a rate of about six grams of immunoglobulins per day for a 155-pound person. Clearly, maintaining the immune system is a demanding process for the human body.

On the cellular level, upon activation, a lymphocyte doubles the amount of intracellular energy (ATP—that is, adenosine triphosphate) committed to protein synthesis (up to 20 percent of total cell energy use), while nucleotide synthesis begins consuming about 10 percent of the cell's energy. This ATP is ultimately derived from dietary macronutrients (protein, carbohydrate, or fat) through metabolic steps that require thiamin, riboflavin, biotin, pantothenic acid, and niacin. When ATP supply is limited, protein and nucleotide syntheses are the first cellular processes to suffer. The building of proteins and nucleotides from amino acids also requires folate, vitamin B₆, and vitamin B₁₂ as the essential cofactors. Enzymes that build immunologically active proteins and cells also rely on diet-derived transitional metal atoms (iron, zinc, copper, etc.) for stability and to serve as functional centers. For example, ribonucleotide reductase is a rate-limiting enzyme in nucleotide synthesis, but the only way to maintain the loosely bound iron atom in its functional center is with adequate dietary iron intake. When deprived of multiple nutrients during malnutrition, these immunological processes are clearly compromised as exemplified by reduced thymus mass, lower IgA secretion, and poor proliferation of immune cells in vitro.

Signaling and Gene Regulation

The ability to expand or direct an immune response depends on communication between and within cells. In the innate immune system, various cells can produce signaling molecules (eicosanoids, chemokines, etc.) that attract phagocytes to the site of a challenge (inflammation) while alerting the rest of the immune system. In the acquired immune system, the adaptation of immune cells can be directed toward more efficacious products by signals between cells (cytokines, receptor interaction, etc.) and inside of cells (intracellular signaling molecules, nuclear binding factors, etc.).

Perhaps the clearest relationship between essential nutrients and immune system signaling is the transformation of dietary essential fatty acids into eicosanoids. Certain kinds of fat, which synthesize polyunsaturated fatty acids, are essential to life. These fatty acids are classified as omega-3 or omega-6 fatty acids based on their chemical structure. These fatty acids are used by the body to manufacture eicosanoids (prostaglandins, thromboxanes, and leukotrienes) that regulate inflammation and other body functions. At a molecular level, the distinction between dietary intake of omega-3 versus omega-6 fats is functionally important since eicosanoids derived from omega-3 fats do not produce as much inflammation as omega-6 fats.

An area of immunological research that has rapidly expanded in recent years is the discovery and characterization of proteins that carry signals between the cell surface and nucleus as well as where these proteins bind within various genes. Both vitamin A and vitamin D regulate gene expression by binding to specific gene sequences including, for example, the genes that regulate production of the antiviral protein interferon-gamma. A deficiency of either of these vitamins can impair immune function. Pharmacological doses of vitamin D have been investigated for their therapeutic potential in autoimmune disorders.

Immune system cells also initiate intracellular signals in response to oxidation. Oxidative stress induces expression of intracellular proteins (AP-1 and NF-kB), which leads to increased production of pro-inflammatory signaling molecules (such as cytokines and chemokines) and their receptors. Vitamin E, vitamin C, and other antioxidants can reduce NF-kB expression, which may contribute to their wide variety of effects on the immune system. Intracellular oxidation state also may alter acquired immune responses, but further research is needed to determine if dietary antioxidants can modify oxidation-sensitive genes and proteins.

Life-Cycle Stages

Different stages of the life cycle have unique nutritional demands and are characterized by unique immunological functionality. Both young children and the elderly have clear age-related immune function deficiencies. In addition, many children in the United States do not meet their daily requirements for several immunologically relevant nutrients, including vitamin E, iron, zinc, and vitamin B₆. The elderly may also have difficulty meeting their requirements for vitamin B₁₂, zinc, vitamin E, iron, vitamin D, and vitamin B₆ as a result of physiological changes due to aging or to inadequate dietary intakes. Pregnant and lactating women are remarkable because they produce acquired immune system products for the sole apparent purpose of export to the infant. Likewise, pregnant and lactating women frequently do not meet their nutritional demands for folate, vitamin B₆, iron, and zinc. Few studies have examined the interaction between nutrients and life-cycle–dependent immune outcomes in otherwise healthy people, but the available data indicate that these interactions have immunological impact—for example, vitamin E among the elderly and iron among postpartum women. Given the susceptibility of these populations to infectious disease, a better understanding of nutrient-immune life-cycle interactions is needed to promote optimal immune status through adequate nutrition.

Nonnutritive Food Components and the Immune Response

For immunologists, developing more efficacious vaccines and certain anticancer agents is a process of improving immune system performance. As nutritional paradigms have shifted from preventing deficiency to promoting optimal health, nutrition scientists have also sought to improve immune system performance. Many in vivo studies have examined more or less purified food components like phytochemicals (polyphenols), herbs, and carotenoids. Such studies frequently use classic immunological tests—cell proliferation, blood lymphocyte counts, skin hypersensitivity responses, etc.—but the results of these tests should be interpreted with caution. For example, a food component that increases cell proliferation may be beneficial if it is the protective cells that proliferate more readily. Conversely, increased cell proliferation would be harmful if autoreactive T-cell or B-cell clones were expanded or inflammatory responses were boosted inappropriately. Although these measures are useful for preliminary identification of nutrient-immune interactions, additional studies using efficacy-related immune measures (infectious disease risk, vaccine titers, etc.) are needed before such phenomena can be termed beneficial.

Summary

To maintain immunological competence, the immune system must quickly alert the body to foreign challenges and rapidly manufacture the cells and proteins needed to stop exponentially dividing infectious organisms. It is apparent that some essential nutrients are signaling molecules. Others can be rate-limiting factors in cell division and protein synthesis. The brevity of this review has prohibited the exploration of many other important nutritional immunology topics: nutrient interactions with infectious agents, treatment of autoimmune disorders, cancer biology, and metabolic functions of nutrients unrelated to biosynthesis or signal transduction. Clearly, the most venerable nutritional paradigms of growth and development are important for shaping the magnitude and character of immune responses.

See also Fats; Gene Expression, Nutrient Regulation of; Iron; Nutrients; Vitamins: Overview; Vitamins: Water-Soluble and Fat-Soluble Vitamins.

J. Paul Zimmer