Dietary carotenoids and human immune function. Hughes DA(1). Author information: (1)Immunology Group, Nutrition, Health and Consumer Science Division.
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- Dietary carotenoids and human immune function. - PubMed - NCBI
- The Effect of Nutritional Elements on the Immune System
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- How to boost your immune system
This article is a precis of uncomplicated ideas and strategies and is devoted to all these scholars who've been informed through their mentors, "Go forth and do two-dimensional gels and feature the consequences on my table day after today. New Insights, New Therapies: New Insights, New cures brings jointly contributions from a global workforce of specialists in different fields to contemplate how many of the pathways implicated in early and overdue sepsis have interaction, with a selected emphasis on novel recommendations and capability new healing approaches.
Topics lined comprise adaptive immunity, irritation, neuroendocrinology, bioenergetics and metabolism. Immunopharmacology is outlined as that a part of pharmacology that bargains with medications performing on the immune approach and, moreover, with the pharmacological activities of gear derived from the immune procedure. The light- and heavy-chain genes are carried on different chromosomes, and, as with other macromolecular systems, the genes are divided into coding segments exons and silent segments introns. The heavy-chain gene is on chromosome 14 and is composed of small groups of exons coding for the constant regions of the heavy chains and several V region genes Using the methods described here to assess changes in immune response in complex settings, such as postoperative recovery involving loss of enteral nutrition and potential risk of infection, require particular consideration of controls for setting and entails longitudinal design to clarify relationships Some nutrients can have direct effects on the pathogen, such as the vitamin C effect on HIV replication Many studies have shown that micronutrient status is profoundly affected in HIV infection, but the etiologic significance of these changes has been difficult to demonstrate However, assays of whole-blood cytokine production De Rijk et al.
The choice of techniques will depend on the investigator's resources and the availability and accessibility of tissue, blood, or biological fluid to be assayed. A number of examples exist of test panels that are in use or have been recommended by government agencies and private-sector scientists involved in immunologic field assessment Beisel and Talbot, ; Taylor, The outcomes of this workshop included recommendations for a panel of tests for assessment of immune deficiency as well as factors that must be considered in the design of field studies.
To provide an example, the tests comprising this panel are described in Appendix C. The desire to measure the influence of any stimulus on immune function, in this case the stresses of training and field operations, is based on two underlying assumptions presented by Cunningham-Rundles see Chapter Measurement of immune function, either in vitro or ex vivo following removal of cells from the body and placement in culture , reflects the internal status of the immune system;. These measures may be interpreted to predict future immune system response.
Dietary carotenoids and human immune function. - PubMed - NCBI
Among the problems cited are that relationships observed under various artificial conditions for example, in previous experiments on nutritional status and immune function conducted in a clinical or laboratory setting may not parallel those seen in training or deployment situations, particularly when clinical subjects were exposed to only one type Cunningham-Rundles, Chapter 9.
Many, but not all, of these observed responses are similar to those described in injured or infected patients Bessey et al. An additional problem is that recovery defined by Cunningham-Rundles as the ability to recover from a threat to the immune system may be the most critical parameter for assessing the likely response to future immune exposure but may not be predictable based on the magnitude of the immune response in a test situation.
Other problems include the fact that the response of an individual to a pathogen at any given time is influenced by a multitude of independent as well as interdependent factors. In addition to nutritional status, these factors include general health status, genetic predisposition, pharmacologic effects, presence of immunosuppressive diseases, neuroendocrine stress, and prior exposure. Therefore, it may be impossible to isolate the effect of a single nutrient or even nutritional status as a whole.
In addition, the nutritional effects may be those of a single nutrient as well as the effects of nutrient interactions, and each may manifest with a complicated time course which influences whether immune function assessments performed at isolated times will detect any effects. Cunningham-Rundles' recommendations include the need to document the type and range of alterations in immune function expected under typical training conditions, followed by careful design of studies allowing assessment at several levels of immune response.
One of the primary challenges of performing immune function assessments in field settings is that the necessity for the subjects to continue to perform physically challenging work significantly limits the amount of blood that can be sampled. Kramer see Chapter 10 describes the ongoing efforts of his laboratory to modify techniques for the assessment of immune indices in samples of whole blood.
According to Kramer, assaying whole blood samples, rather than isolating peripheral blood mononuclear cells PBMCs as is customarily done, has several advantages. First, additional indices of immune function can be assayed using smaller samples. Second, more samples can be processed in less time using less equipment and fewer technical staff because the requirement to purify cells has been eliminated.
Kramer shows that the coefficients of variation for measurement of mitogen-stimulated proliferation of cells compared favorably with those in PBMCs in a study of zinc-deficient women in Thailand Kramer et al. Shephard and coworkers b , in reviewing studies of the impact of exercise on the immune system, describe the finding of Shinkai et al. In contrast, Shephard et al. A study by Bocchieri and coworkers , comparing mitogen-induced proliferation in both whole-blood cultures and PBMCs to actual disease state and T-cell phenotype in HIV-seropositive individuals and controls, found stronger correlations between proliferation in whole-blood cultures and other disease indicators than between the same indicators and proliferation in PBMCs.
According to Cunningham-Rundles Chapter 9 , the whole-blood method has the advantage of reflecting the number of cells actually circulating as well as all plasma proteins and nutrients present in vivo. Whole blood is also a better medium for measurement of cytokine stimulation and glucocorticoid sensitivity ex vivo DeRijk et al. If an observed defect must be shown to be intrinsic to cell function, then isolation and study in a standardized test is needed. However, whole blood is a physiological medium that is well suited to testing under field conditions.
Whole blood also is currently preferred for phenotypic analysis of cellular subsets; it is advantageous for field studies to use both functional and phenotypic analysis. In summary , the design of an immune function assessment study is a significant challenge. According to Cunningham-Rundles and others, population research must move in the direction of identifying correlations among changes in individual parameters of immune function and patterns of immune responses, imposition of specific stressors, and disease outcome.
Table provides an outline of assessment methods for immune function. Most nondeployed military personnel live at home or in nonbarracked conditions, consuming a diet ad libitum. Depending on food preferences and the use of vitamin or mineral supplements, there may be great variations in the quantities of nutrients ingested. As these individuals are deployed and move from their self-selected diets to a constant ration, there may be profound alterations in nutrient intake, and these changes may result in altered host defense.
Part V of this report see Douglas W. Wilmore, Chapter 11 ; Richard D. Semba, Chapter 12 ; Laura C. Kelley, Chapter 14 ; Gerald T. Keusch, Chapter 15 ; and Melinda A. Beck, Chapter 16 discusses essential individual nutrients known to be important for sustaining immune system functions. However, it must not be forgotten that, worldwide, the most significant adverse impact of nutritional status on the immune system results from PEM. Its adverse effects on the immune system may be magnified by the deficiencies of essential single nutrients that almost always accompany PEM. These poorly defined nutritional interrelationships were undoubtedly of importance during the short-term effects of PEM associated with the sizable losses of weight and muscle mass experienced during Ranger I training and may have been major contributing factors in the immunological dysfunctions detected in these Rangers Beisel, Given the evidence that deficits in energy, protein, and certain fatty acids adversely affect immune function, it is also important to consider other nutrients such as vitamins and minerals more explicitly.
Finally, it must be emphasized that in many cases, an "overdose" of a nutrient, as well as a deficiency, can lead to negative consequences. Evidence demonstrates that severe protein or calorie malnutrition in humans results in impairment of both humoral and cell-mediated immune functions Bistrian et al.
There is also evidence that moderate energy restriction, such as that experienced by overweight individuals on weight loss diets, interferes with normal immune function Kelley et al. Protein deficiency is consistently observed to interfere with maintaining resistance to infection because most immune mechanisms are dependent on cell replication or the production of active protein compounds. As might be expected, deficiencies of essential amino acids can result in an altered humoral response, whereas deficiencies of single nonessential amino acids may have little effect on the immune system, although there are some exceptions.
Certain amino acids have been shown to play a direct role in immunity. Glutamine and arginine are two amino acids that have been shown to have immunoregulatory functions Kirk and Barbul, ; Reynolds et al. Glutamine is an abundantly available, nonessential or "conditionally essential" amino acid that functions in the regulation of both energy and nitrogen balance.
Most glutamine in the body is synthesized in skeletal muscle, from which it is released into the circulation and supplied to the visceral organs Souba et al. Glutamine appears to have numerous important functions within the body: In catabolic states such as stress, surgery, and disease, both synthesis and release of muscle glutamine increase Muhlbacher et al. The competition for glutamine increases among the visceral organs, the major consumers being the liver, gastrointestinal mucosa, kidney, and immunological tissues. Under such conditions, glutamine may become a conditionally essential amino acid, because the supply can no longer keep up with the demand.
In such cases, the diet may become an important source, although at present the extent to which dietary glutamine might supply the additional glutamine required is unknown. Wilmore see Chapter 11 focuses his discussion of glutamine on its role in immune function. Over the past decade, glutamine has been studied for its ability to promote immune cell proliferation and enhance immune function. Glutamine appears to promote lymphocyte proliferation and macrophage phagocytosis Parry-Billings et al.
Because of these effects, the amino acid has been studied for its potential use in reducing infection in patients undergoing surgical, chemotherapeutic, and cancer treatment procedures, where endogenous glutamine availability may become insufficient to supply increased metabolic needs. In several trials, some evidence has been obtained that glutamine administration can reduce infection and promote recovery see MacBurney et al. This effect is not uniformly positive, suggesting that glutamine may be efficacious in some, but not all, infectious conditions.
The gastrointestinal tract also has been the focus of study relating to the use of glutamine to improve host defenses and immune function. Under conditions of stress, infection, and injury, the permeability of the bowel to pathogens and toxic molecules increases, making the body more susceptible to disease. Glutamine is known to enhance intestinal mucosal growth and integrity and has been found to improve intestinal function in surgical patients Van der Hulst et al. Such findings suggest that glutamine ultimately may be found useful in promoting the recovery of patients from surgical treatments and disease states in which immune function may be compromised.
In a controlled clinical trial, the administration of glutamine to previously immune-suppressed bone marrow transplant patients was found to reduce the length of hospital stay significantly, primarily due to reductions in clinical infections Ziegler et al. A reduction in mortality was observed in patients with intra-abdominal sepsis who received glutamine Griffiths et al. Unfortunately, studies that have reported beneficial effects of glutamine have used a parenteral or enteral gastric tube route of administration.
This factor may explain the inability of Shippee and coworkers see Chapter 5 to observe any effect of oral glutamine supplements. In summary , the administration of exogenous glutamine appears to improve immune functions in patients, whose glutamine demands may not be met by endogenous production or dietary supply. Such effects may derive from one or more of the amino acid's many metabolic and cell proliferative effects in the body.
If additional work continues to show a positive effect of glutamine in reducing infection and disease, the amino acid ultimately may prove to be of value prophylactically in reducing sickness and speeding the recovery of soldiers from illness, although the adequacy of normal dietary glutamine will have to be assessed as well. The nonessential amino acid arginine, in addition to glutamine, should also be considered as a possible immune-enhancing nutrient. Arginine has multiple biological effects that are beneficial in a variety of situations, such as trauma, tumors, infections, and depressed immunity.
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Arginine is the sole precursor of nitric oxide, a newly recognized but important microbicidal molecule Koshland, that appears to be involved in macrophage killer function and in regulating interactions between macrophages and lymphocyte adhesion and activation Denham and Rowland, ; Kirk et al. Vitamin A and Carotenoids.
The effects of vitamin A deficiency on immune function are significant, and there is convincing evidence for a role of vitamin A in resistance to infection, although the mechanism is not known Kjolhede and Beisel, Epidemiologic studies, clinical trials, and experimental studies in animal models have firmly established that vitamin A deficiency is a nutritionally acquired immunodeficiency disorder that is characterized by widespread immune alterations and increased infectious disease and mortality Semba, Infections are known to accelerate the metabolic degradation of vitamin A and to increase its urinary excretion.
A hallmark of vitamin A deficiency is depressed antibody responses to T-cell-dependent and independent antigens, which may be mediated by alterations in the production of some cytokines. However, some viral infections do not reduce and may increase immunoglobulin G response, which may reduce or otherwise alter other immune responses Ross and Stephenson, It should be noted, however, that most of the data available are from children because vitamin A deficiency is relatively rare in adults especially in the United States and quite difficult to induce experimentally.
Trauma, or sterile inflammation, may cause a significant decrease in some plasma nutrients by reducing the biosynthesis of their transport proteins in liver, including retinol-binding protein and prealbumin, the transport proteins for retinol Aldred and Schreiber, A reduction in plasma retinol, into the range considered marginally vitamin A-deficient, has been produced in well-nourished rats following induction of acute inflammation Rosales et al.
Reviews of randomized, controlled epidemiological studies as well as clinical trials have led to the conclusion that although the incidence of infectious disease does not appear to be greatly increased by vitamin A deficiency, vitamin A supplementation to correct a deficiency can reduce the severity of some infections, including diarrheal diseases Beaton, ; Kirkwood, Because excess vitamin A can be toxic and is a suspected teratogen, no case can be made for supplementation of nondeficient individuals with amounts of preformed vitamin A significantly beyond the RDA level.
Provitamin A carotenoids vitamin A precursors from plant sources , however, are more limited in their toxicity and may have some effects on the immune system that are not seen with preformed vitamin A. Semba see Chapter 12 discusses the varying bioavailability of carotenoids from dietary fruits and vegetables. The predominant physiologic function of vitamin E is in its role as an antioxidant required for the protection of cellular as well as membrane polyunsaturated fatty acids.
Vitamin E also protects membrane-bound nucleic acids and thiol-rich proteins from oxidative damage. It is also known that antioxidants such as vitamin E are important for controlling signal transduction and genetic expression of the various cytokines and ultimately proliferation of the cells that synthesize them. This is particularly important for cells of the immune system because their membranes contain a high level of PUFAs that are exposed to high concentrations of free-radical products.
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So, not only are the levels of antioxidants reduced during normal cellular processes, but they also can be reduced by the presence of a pathogen itself. Because of the rare occurrence of symptomatic vitamin E deficiency in humans, most studies related to immunity have been conducted in either nondeficient subjects or laboratory animals, and in fact, animal studies have demonstrated improvements in immune function expressed through changes in cell proliferation Meydani and Hayek, Rall and Meydani see Chapter 13 describe a number of controlled clinical trials performed in Meydani's laboratory demonstrating that vitamin E supplementation of elderly subjects as well as healthy young subjects may enhance immune function Meydani et al.
Rall and Meydani also present some data interrelating the role of vitamin E to prostaglandins and immune function. Prostaglandins have a regulatory role in maintaining the function of T-cells as well as inhibiting lymphocyte proliferation, NK cell cytotoxicity, antibodies, and certain cytokines Meydani et al. For example, prostaglandin E 2 PGE 2 can downregulate the function of Th1 cells and also upregulate the function of Th2 cells.
Meydani hypothesized and later demonstrated in aged mice that vitamin E, acting as an antioxidant, would inhibit PGE 2 production by altering the cyclooxygenase pathway and would thus be effective in enhancing the immune response as monitored by T-cell-mediated functions Kramer et al. Meydani and coworkers have also demonstrated enhanced cell-mediated immune indices of DTH, lymphocyte proliferation to concanavalin A ConA , and IL-2 production in a group of healthy elderly subjects receiving IU of vitamin E daily for 30 days.
The authors therefore believe that vitamin E supplements act to improve the immune response by decreasing the production of PGE 2 , which in turn moderates cyclooxygenase activity. Thus, benefits may be conferred on the elderly in the face of PGE 2 levels and oxidative tissue damage that tend to rise with age. Despite widespread coverage by the popular press of the influence of vitamin C on the common cold, its role in modulating immune function remains controversial.
Based on epidemiological studies of individuals consuming diets deficient in vitamin C and on administration of vitamin C supplements to injured and surgical patients, several mechanisms have been proposed for the apparent immunomodulatory effect, but none have been confirmed definitively. Vitamin C is known to function as an antioxidant and in this capacity may serve to protect the integrity of plasma, other extracellular fluids, plasma membranes, and intracellular spaces.
Neutrophil activity but not number is attributed to the high levels of vitamin C in these cells Khaw et al. A recent study in rats has shown that the antioxidant effect of vitamin C also serves to protect the level of cell energetics in burned tissues Lalonde and Boetz-Marquard, Other proposed mechanisms of vitamin C's role in immune function include stimulation of lymphocyte blastogenesis and synthesis of other immune modulators such as prostaglandins, prostacyclins, histamine Myrvik, , and IL Vitamin C is also essential for the locomotion of neutrophils and other phagocytic cells Beisel, Because the decrease in vitamin C status noted with smoking is associated with increased plasma values of IL-6 and TNF soluble receptors Borelli et al.
However, in the latter studies, cause and effect were not determined.
The Effect of Nutritional Elements on the Immune System
Attempts to show a relationship among dietary vitamin C intake or vitamin C supplementation, vitamin C status, and incidence of infection or cancer have provided controversial and often contradictory results, raising questions in the minds of some scientists regarding how requirements for the vitamin should be determined Levine et al.
Several types of surgical procedures as well as burn injuries, physical overtraining, and smoking are associated with decreased vitamin C status Ballmer and Staehlin, ; Lalonde and Boetz-Marquard, ; Peters et al. However, attempts to show that normalization of vitamin C status by dietary supplementation decreases the incidence of infection have resulted in contradictory observations. Although one study observed enhanced resistance to URIs in supplemented versus unsupplemented marathon runners Peters et al.
A significant amount of attention has recently focused on whether antioxidant nutrients, particularly vitamins E and C, may help to reduce oxidative stress and damage during exercise Cannon et al. Although antioxidant supplementation may attenuate oxidative stress following prolonged and strenous exertion, the effect of this attenuation on the exercise-induced immune response is uncertain see David C. In summary , the effects of vitamin A deficiency on immune function are significant, and infections can accelerate its loss of vitamin A. Vitamin A supplements have been shown to reduce the severity of some infections if a deficiency is present; however, an excess can be toxic.
The carotenoids are less toxic and may have some effects on the immune system that are not seen with preformed vitamin A. Vitamins C and E are both powerful antioxidants, have been shown to enhance the immune response, and are relatively nontoxic. However, data remain incomplete, particularly in terms of the optimal amount of supplementation that should be recommended to achieve these benefits.
The B vitamins are involved in a broad spectrum of cellular metabolic reactions and, as a group, have been shown to have an effect on cellular disease resistance and the immune response Bendich and Chandra, Vitamins B 6 , B 12 , and folate are particularly important for cell-mediated immunity CMI functions, and thiamine, is necessary for the synthesis of antibodies or the expression of humoral immunity Beisel, , Experimental vitamin B 6 deficiency in humans results in only slight impairment of antibody formation in response to a challenge by tetanus toxoid or typhoid Hodges et al.
Vitamin B 6 deficiency is not uncommon in humans, although when present, it is usually found in combination with PEM and a deficiency of other B vitamins such as riboflavin. Lymphocyte differentiation and maturation are altered by a deficiency of vitamin B6, DTH responses are reduced, and antibody production may be directly impaired Chandra, ; Rall and Meydani, Although repletion of vitamin B 6 restores these functions, megadoses do not produce benefits beyond those observed with moderate supplementation Rall and Meydani, Folate deficiency can lead to decreased responses of T-cells to phytohemagglutinin PHA as well as to decreased cytotoxic T-cell function Gross and Newberne, ; Hollingsworth and Carr, CMI is depressed in individuals with anemia due to folate deficiency Gross et al.
Folate and vitamin B 12 are both essential to cellular replication, and experimental deficiencies interfere with antibody formation and replication of stimulated leukocytes. In humans, neither phagocytosis nor the bactericidal capacity of neutrophils toward Staphylococcus aureus is altered by folate deficiency Gershwin et al. Among the fatty acids present in the diets of humans, the PUFAs are immunologically the most important. The PUFAs are substrates for the synthesis of two families of immunologically important products: These compounds affect many physiological functions including immunity and inflammation to varying degrees, depending on structure, amounts, and ratios.
Fatty acids affect immune function not only by the total amount of fat present, but also by the amounts of and ratio between the n-6 and n-3 types of PUFA that act primarily through prostaglandins and leukotriene production and activity, as depicted in Figure For example, linoleic acid On the other hand, soybean, linseed, and canola oils have a high concentration of linolenic acid Typical North American diets provide 7 percent of energy as linoleic acid, much more than is needed to prevent deficiency Lands, The n-6 and n-3 families of PUFAs are not metabolically interconvertible in mammals.
High intakes of As noted earlier in this chapter, increasing amounts of PUFAs in the diet increase the vitamin E requirement because of the propensity of PUFAs to undergo lipid peroxidation. The richest sources of vitamin E in the U. Clinical and experimental studies have demonstrated that the structural and functional properties of immune cells can be modified by dietary supplementation with n-3 PUFAs from fish oil or linolenic acid, and in vivo tests are the most appropriate approach for determining the effect of different dietary fatty acids on immune function and inflammation, but few studies have been reported in humans Calder, Metabolic pathways for conversion of dietary PUFAs to eicosanoids.
Depending on their concentration and type, prostaglandins and leukotrienes stimulate or inhibit the activity of immune cells. Other carbon fatty acids compete with arachidonic acid more The effect on immune function of reducing total fat intake has been studied in healthy men Kelley et al. In both groups, immune function improved as measured by such indices as the numbers of circulating T- and B-lymphocytes and their proliferation in response to specific mitogens.
Neutrophils and serum complement C3 decreased, and leukocyte counts and plasma concentrations of all major classes of immunoglobulins remained unchanged. In another study cited, Kelley and colleagues a measured the immune status of seven healthy women fed diets reduced in total fat with higher or lower levels of PUFA than the stabilization diet containing 5. The experimental diets contained either 3. In this study, a number of parameters reflecting immune status improved on the lower-fat diets. In contrast, no differences in these indices were observed between individuals consuming diets containing 9.
The authors suggested but did not conclude that immune function may have improved in response to the reduction of total fat intake. In the two studies cited above, changing the level of linoleic acid LA from 3 to 13 percent of energy but reducing total fat intake did not adversely affect the indices of immune function. In another study cited Barone et al. Inconsistencies apparent among studies measuring the effect of PUFA on immune function may be due to differences in total fat intake, antioxidants, duration of feeding, and the immune indices measured. Another obvious factor is the ratio of n-6 to n-3 PUFA in the diets.
To evaluate this more fully, Kelley et al. A number of studies have been carried out to evaluate the effect of n-3 PUFAs derived from plant sources Bjerve et al. These studies have suggested that consumption of n-3 PUFA reduces a number of indices of immune function and, because of this, has been reported to be beneficial in the management of autoimmune diseases such as arthritis in humans. The addition of flaxseed oil inhibited the proliferation of PBMCs in response to T- and B-cell-specific mitogens because of either the added n-3 PUFA or the higher fat level a control group receiving 30 percent of energy as total fat was not included.
In a study by Meydani et al. The low-fish-oil test diet, low in marine n-3 PUFA 0. In contrast, the high-fish-oil diet, high in marine n-3 PUFA 0. In another study, Kelley et al. In a recent study not previously cited, Hughes et al. Since these surface molecules are involved in the immune response to presenting antigens, the authors suggested that this is a potential mechanism by which n-3 PUFA may suppress the immune response.
A series of studies has examined the effects of fish oil medium-chain triglycerides so-called structured lipids on the incidence of postoperative infection and other indicators of renal, hepatic, and immune function. Bistrian and coworkers Swails et al. Mixtures of fish oils and arginine, with or without nucleic acids, have also been administered in the immediate postoperative period with mixed results.
Two large clinical trials, one in the United States and the other in Germany, have demonstrated significant decreases in postoperative infection and length of hospitalization following immediate postsurgical feeding with an enteral supplement Trade name: Impact, manufactured by Sandoz Bower et al. In a more recent study, patients given a mixture of nfatty acids contained in fish oils and arginine in the immediate postoperative period experienced no beneficial effects on immune function.
Calder has suggested that diets enriched in fish oil n-3 PUFAs may be of use in the therapy of acute and chronic inflammation and disorders involving inappropriately active immune responses such as autoimmune disorders. High-fat diets also have the potential to affect immune function adversely as evidenced by the fact that such diets were once used to delay or prevent transplant rejection Beisel, In summary , limited data suggest that moderate reductions in total fat calories i. To interpret data in this area, a number of caveats are important. These variables significantly interact with each other, and in human studies, the possible number of subjects does not allow for the kind of statistical analysis necessary to sort through all variables and interactions.
The most important caveat may be that in all of these studies, surrogates of immune function were measured, rather than immune function itself that is, immunity to disease and resistance to infection. Finally, it should be noted that although increasing the consumption of marine oils that supply eicosapentaenoic acid EPA and DHA may reduce the risk of heart disease and be useful in treating autoimmune disease and inflammation, such diets may well reduce immune function.
In Chapter 15 , Keusch provides an overview of iron metabolism and the role of iron in both host defense and the virulence of the invading pathogen. As with many other aspects of the immune system, iron has both positive and negative effects, promoting host defense or microbial virulence under differing circumstances. Iron is highly reactive, with considerable ability to generate free radicals that are toxic to both host and microbial cells.
The host and the invading organism both require the biological mechanisms to acquire and detoxify iron. The battle between host and pathogen is partly a battle of binding affinity in which the chelator protein that binds iron with greater affinity is able to strip it from the protein that binds it with less affinity. In the mammalian host, iron is bound primarily to protein complexes, including iron transport transferrin or lactoferrin and storage proteins ferritin , enzymes cytochrome c , and oxygen transport systems heme Griffiths, The mammalian iron acquisition system is very efficient, having the ability to compete for ferric iron even from insoluble ferric hydroxide.
Because most iron is present in the bound form, the free iron pool is very small. Free radicals that are formed are destroyed by iron-containing enzymes such as catalase. Synthesis of the transferrin receptor and synthesis of ferritin for iron transport and storage are regulated reciprocally by iron concentration via a posttranscriptional mechanism Klausner et al. Iron influences immune functions via cytokines and nitric oxide Weiss et al. Lactoferrin, the milk protein, has a direct transcriptional role that may help explain the direct transmission of passive immunity from mother to child Fleet, Iron also is required for microbial growth; hence, microorganisms compete with the host for iron by using analogous systems of acquisition, transport, and detoxification.
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Many microbes make siderophores iron-binding chelators , which are high-affinity binding molecules for the ferric ion that have the ability to remove iron from host iron-binding proteins including ferritin Neilands, In response to low iron availability, E. Under anaerobic conditions, ferrous iron is more available because of its increased solubility. In addition, a ferrous iron transport gene has been demonstrated in E. It is clear that pathogenic microorganisms adapt to low iron availability through the regulation of gene transcription and translation by iron.
In Keusch's view, this raises doubts about enhancing immunity by withholding iron. Iron is needed by both pathogens and their hosts and is required for host immune function. Transferrin iron is required for the clonal expansion of lymphocytes via ribonucleotide reductase, and iron uptake also must precede DNA synthesis Kay and Benzie, ; Phillips and Azari, In addition, iron deficiency is associated with a decrease in delayed-type skin test reactivity to antigens and with impaired mitogen-stimulated lymphocyte proliferation in vitro Krantman et al.
Data from animal studies suggest that antibody production and CMI are likely to be impaired by iron deficiency because of the role of iron metalloenzymes in DNA synthesis and cell proliferation. Whether iron deficiency affects the host—pathogen relationship at the clinical level remains to be demonstrated conclusively. However, as discussed below, it is clear that iron deficiency does not and will not enhance immune responses.
Because invading microorganisms require iron and compete for it, it has been hypothesized that withholding therapeutic iron during infection will protect the host, and excess iron will enhance infection Weinberg, Any excess iron then can form loose complexes with albumin, thereby increasing the availability of iron to microorganisms Hershko and Peto, Increased infections and fatal outcomes have been associated with these conditions Barrett-Conner, ; Buchanan, and also have been observed in animal models of hemochromatosis.
However, it is difficult to attribute these adverse effects completely to free iron-related microbial growth and infection rather than to damage occurring to the reticuloendothelial system and disrupted cellular function resulting from iron-mediated oxidation or peroxidation effects Hershko et al. Nevertheless, free iron does increase oxidative damage to cells, and iron excess is, in fact, likely to impair immune function. A number of defects in immune mechanisms have been demonstrated in thalassemia patients.
The addition of increasing amounts of iron to T-lymphocytes diminishes clearing efficiency and reduces the proliferative response to mitogens Good et al. To clarify the conditions under which iron deficiency or iron excess is harmful, data obtained from well-controlled clinical studies are essential. In reviewing published clinical studies dealing with the effects of iron deficiency or overload on susceptibility to infection, Keusch concludes that most studies are flawed in design for one reason or another.
The most frequently cited studies showing a benefit of iron fortification are those that involve a comparison of infant formula with and without added iron Andelman and Sered, Unfortunately, in these studies, the morbidity data involving respiratory and intestinal disease were obtained by maternal recall rather than observation by trained personnel. Thus, the clinical consequences of iron deficiency with respect to immune function remain uncertain. Several clinical studies, however, have reported that iron overload can sometimes increase the severity of infections. These typically occur under conditions where the host does not compete well with the invading pathogen for protein-bound iron; thus the pathogen benefits from the increase in free iron that results from iron overload.
For example, life-threatening infections from low-virulence strains such as Yersinia enterocolitica have occurred in patients on iron chelation therapy or with iron overload following massive ingestion of iron Carniel et al. High plasma iron values following nutritional therapy have also induced lethal cerebral malaria in asymptomatic, parasitemic, malnourished African children Murray et al. Clearly iron in relation to infection has both positive and negative effects.
Iron Status of Military Personnel. According to data presented Friedl et al. A survey of a similar but not the same population of women at the end of BCT showed that by the end of training, 33 percent were iron deficient and 26 percent were anemic. Iron deficiency anemia can be expected to have adverse effects on military performance of both men and women depending in part on its severity. Performance deficits in both men and women due to compromised iron status have been demonstrated most clearly during exercise of prolonged duration such as long-distance running Newhouse and Clement, Iron deficiency anemia may also have an adverse impact on recovery from trauma, especially trauma involving significant blood loss.
However, data to support deficits in physical performance in iron-compromised individuals have not been systematically collected by the military. Some preliminary evidence suggests that iron supplementation of nonanemic women can improve aerobic capacity J. Haas, Cornell University, personal communication, After reviewing the data, the CMNR recommended to the Army that personnel with iron deficiency or iron deficiency anemia should receive appropriate medical treatment and monitoring until laboratory results show a return to normal values; a delay in deployment was also recommended for personnel with iron deficiency anemia.
If, after 4 weeks, the anemia does not respond to iron treatment despite compliance with supplementation and the absence of illness, further evaluation is warranted using other laboratory tests CDC, In summary , mechanistic data exist to suggest strongly that both iron deficiency and iron excess can increase susceptibility to infection, albeit by different mechanisms. It is important to note, however, that there is a fairly large range of iron intakes over which the immune system can function normally.
Although the evidence for iron excess may be compelling, it is likely that for the military, the potential reduction in immune function due to iron deficiency is of more immediate and consequential importance than iron overload. The negative consequences of low iron status are especially dire for women in the military. Zinc is clearly the most important trace element with respect to immune function.
Many animal studies have shown that zinc deficiency leads to decreased T-cell function, impaired antibody response, reduced thymus size, and depletion of macrophages and lymphocytes in the spleen Beisel, The inherited defect in intestinal zinc absorption, acrodermatitis enteropathica, causes a severe but treatable zinc deficiency state in afflicted infants, resulting in similar widespread immunological dysfunctions.
There also is evidence that zinc deficiency in elderly persons can result in heightened susceptibility to infectious disease Chandra, Conversely, excess intakes of zinc also have been reported to be immunosuppressive so that both excess and deficient zinc status can have adverse effects on immune function Chandra, Given that zinc is a vital cofactor for many different enzymes, regulates some immune-related genes, influences cytokine effects in some situations, and may play a key role as a component of thymic hormones that help regulate all T-cell functions, it is not surprising that deficiency of this essential trace element results in numerous immunological impairments, but its precise role in proper immune system functioning has yet to be clarified fully.
Clinically, zinc deficiency is almost impossible to prove in individual patients, in contrast to groups, by any current, clinically available, diagnostic methods. However, zinc deficiency almost always coexists with severe PEM, and it is difficult to separate the overlapping effects of these two states on immune system function.
Animal data show that unifactorial, experimental zinc deficiency leads to a greatly heightened susceptibility to infection and immune system dysfunctions similar to those seen in PEM Fraker, Zinc deficiency also impairs the body's ability to mobilize its stores of vitamin A Udomkesmalee et al. In contrast, excess intakes of zinc can have an adverse impact on the immune system Chandra, Long-term clinical studies Tang et al. Furthermore, excess zinc intake can interfere with intestinal absorption of copper Kramer et al. Imbalances between zinc and copper may occur because of either deficient or excessive copper intake, or excessive zinc intake relative to copper.
There is some evidence to suggest that the interactive effects of zinc and copper on the immune response may involve differential cytokine stimulation Scuderi, In studies with children, zinc has been shown to reduce the morbidity associated with secretory diarrhea Rosado et al. This effect of supplemental zinc is of unknown mechanistic basis but could be related to enhanced immune function of the intestine. An effect on diarrheal disease in the field is possible.
Copper, like zinc, is a necessary constituent of numerous metalloenzymes, and deficiency of this essential trace element results in an increased susceptibility of animals to a wide range of infectious agents. Copper deficiency in a variety of animal models has caused a decreased antibody response to a number of antigens, decreased T-cell proliferative response, decreased NK-cell activity, and thymic atrophy Bala, ; Blakley and Hamilton, ; Prohaska et al. Copper deficiency is rare in human adults and, if present, is characterized by leukopenia and anemia Prasad et al.
How to boost your immune system
Moreover, children suffering from Menkes disease, an inborn error that results in failure to absorb copper, normally die of infectious bronchopneumonia. A well-controlled human metabolic feeding study showed that lymphoproliferative responses to mitogens were markedly impaired in healthy adult men fed a low-copper diet for 66 d Hopkins and Failla, Despite compelling evidence that copper is required for a normal immune system, more research is needed to clarify its role in proper immune function.
Selenium is now known to be a part of several mammalian enzymes including four glutathione peroxidases Burk, , three deiodinases Arthur and Beckett, ; Berry and Larsen, ; Croteau et al. Selenium also is found in a number of selenoproteins selenoprotein P, selenoprotein W whose enzymatic activities have yet to be determined. Many of selenium's effects can be explained most simply on the basis that it is a required constituent of the glutathione peroxidase family of enzymes.
Selenium deficiency has been associated with an increased susceptibility to certain infectious pathogens, perhaps because of decreased antibody production and impaired lymphoproliferative responses in the deficient state Kiremidjian-Schumacher and Stotzky, In China, selenium deficiency also has been associated with an endemic juvenile cardiomyopathy known as Keshan disease. This association has led to the discovery that the selenium status of the host may have an effect on the genetic makeup of a pathogen.
Because of pronounced seasonal and annual variations in the incidence of Keshan disease, an infectious component may be involved in its etiology. In fact, a number of enteroviruses were isolated from Keshan disease patients, and one of these, a coxsackievirus B4, was tested by the Chinese for its cardiotoxic effects in mice fed diets of varying selenium content Bai et al. Beck see Chapter 16 and Orville A.
Similar changes in Coxsackievirus virulence i. All of these dietary effects selenium deficiency, vitamin E deficiency, fish oil supplementation can be explained most readily on the basis of an increased oxidative stress imposed on the host by the diet. The biochemical mechanisms responsible for these dietary effects on viral virulence in mice are not known, but defects in certain host immune functions were observed impaired mitogen- and antigen-stimulated T-cell proliferation. Other immune parameters antibody production, NK-cell function were not affected by selenium or vitamin E deficiency.
This observation appears to be the first report that the nutritional status of the host might affect the genetic makeup of a pathogen. As pointed out by Morse see Appendix D , soldiers often must perform in crowded and unsanitary environments, which increases their vulnerability to infection by a variety of pathogenic agents.
If, for any reason, the nutritional well-being of military personnel is compromised, they could become unwitting incubators of novel viruses with unpredictable properties. In summary , dietary deficiencies of a variety of nutritionally essential trace elements zinc, copper, selenium have all been shown to have an adverse impact on a number of immune functions in laboratory animals.
However, excessive intake of some trace elements for example, zinc may lead to immunosuppressive effects; so there clearly exists an optimal range of nutritional status for proper immune function. Excessive alcohol consumption is a major health problem in the United States, and high rates of excessive consumption have been observed among military personnel Bray et al. Although data were not presented at the workshop, it is important to discuss the various mechanisms by which alcohol interferes with the complex mechanisms of nutritional immunomodulation. Alcohol acts directly on mechanical barriers in the gastrointestinal tract and increases the permeability of the intestinal wall, which results in a greater absorption of immunogenic material in the intestine.
Alcohol further affects granulocytopoiesis and suppresses various immune functions Watzl and Watson, Indirect effects on immune response also can be caused by alcohol-induced malnutrition. Heavy alcohol intake abuse is associated with a high percentage of total energy intake being contributed by alcohol and sometimes with an inadequate intake of protein, vitamins, and minerals.
In addition, alcohol abuse impairs absorption, utilization, storage, and excretion of nutrients, which in combination with inadequate nutrient intake results in nutritional immunosuppression. The nutrients most likely at risk of becoming depleted are folate, thiamine, vitamins A and B 6 , and zinc. In Chapter 17 , David C. Nieman discusses how the immune system responds to chronic exercise of varying intensity and duration, both in health and during periods of compromised health.
Kapcala review the role of the neuroendocrine system in moderating immune function. Reichlin describes the hypothalamic—pituitary—adrenal, thyroid, and gonadal system interrelationships and responses to inflammatory disease conditions, whereas Kapcala discusses the involvement of individual cytokines in stimulating the hypothalamic—pituitary—adrenal axis. Superimposed on the demands of exercise and neurohormonal or neuroimmunological activation, an individual's innate biologic rhythms also may affect changes in the body's immune response, as described by Erhard Haus in Chapter The interaction of exercise and immunity has two facets: In Chapter 17 , Nieman addresses both of these issues.
The effect of exercise on the immune system depends on a variety of factors, the most important of which seem to be the intensity and duration of exercise and the immune component being discussed. The acute response within 1—2. This response is probably due to an exercise-induced increase in stress hormones especially cortisol and increased cytokine concentrations. Increased levels of cortisol are associated with neutrophilia, eosinophilia, lymphocytopenia, and a suppression of NK- and T-cell activity Cupps and Fauci, Mitogen-induced lymphocyte proliferation Eskola et al.
Other stresses such as chronic mental stress and anxiety have been associated with similar suppression of immune function, probably through the same hormonal mechanism. Highly trained endurance athletes, both young and old, appear to have enhanced NK-cell activity and decreased neutrophil function in comparison to age- and sex-matched sedentary controls Nieman et al. However, measurements taken after 8—15 weeks of moderate exercise show that this exercise does not seem to affect either parameter. Mitogen-induced lymphocyte proliferative response a measure of T-cell activity does not appear to be changed by moderate physical activity, although strenuous activity may negatively affect the immune system in the young.
Swedish studies indicated that moderate physical training stimulates the immune system, whereas exhaustive and long-lasting exercise is followed by a temporary immunodeficiency and an increased susceptibility to respiratory tract infections Friman et al. In the elderly, intense physical training is associated with an increase in NK- and T-cell activity Shinkai et al.
However, moderate activity does not seem to have the same effect, and training may have to be sufficient to induce changes in body weight and fitness to be effective in stimulating the immune system in the elderly as well as the young. A J curve of risk has been proposed by Nieman, which means that at moderate activity, the risk to the individual of developing a URI is lower than in a sedentary or strenuously active situation Nieman, In addition, the symptoms associated with any URI are diminished in those who are moderately active regardless of age; however, he points out the dearth of well-controlled studies of this phenomenon.
Infection does decrease various measures of performance. Nieman suggests that mild exercise during infection with localized symptoms is not contraindicated, but exercise should be curtailed for 2 to 4 weeks after severe infections with systemic involvement. The military relevance of the interaction between nutrition and physical activity and the effect of this interaction on the immune system are pointed out by Nieman see Chapter Low energy intake, weight reduction, and increased levels of circulating glucocorticoids often associated with field maneuvers see Shippee and Wiik, Chapters 5 and 6 , respectively may suppress the immune system independently, and superimposing physical activity may increase vulnerability.
The use of flu shots to minimize risk in exercising troops is recommended by Nieman. In addition, the use of immunomodulator drugs, such as indomethacin, aspirin, and ibuprofen, could be considered; however, studies on these compounds are ongoing, and no clear conclusions are available at present. Studies of glutamine see Wilmore, Chapter 11 , vitamin C see Rall and Meydani, Chapter 13 , n-acetylcysteine, and carbohydrate-containing beverages by way of their ability to decrease cortisol levels suggest that these may be candidates for prophylactic agents.
Repeated bouts of strenuous activity may put individuals at risk for infection especially URIs because of suppression of neutrophil activity.