Sen [ 19 ] has shown that political factors are responsible for nearly all famines. Conversely, the lymphocytes that mediate adaptive immunity have receptors that are narrowly tuned to a specific antigen and a diverse population of lymphocytes exists in order to identify a very large number of antigens Bonilla and Oettgen, However, nutritionists have generally been remiss in applying robust quantitative tools to tradeoffs between performance and immunity. Plant products also provide numerous resources through bioengineering for designing novel pharmaceuticals. However, nutrition does not influence all infections equally 3 , 4. Vitamin E is also very important in preventing fatty acid peroxidation Benedich Certain amino acids, specifically glutamine and arginine, may also play immune-related roles.
Stress: Its Effect on Nutrition and Immunity
Published as a World Health Organization monograph, the book discussed the nature of the interactions between nutritional status and infection, and implicated the immune system as the critical intermediary. However, consistent with the relatively rudimentary knowledge of the times, the lymphoid system was hardly mentioned, and, although the early underpinnings were being explored in murine models of tuberculosis, cell-mediated immunity was a concept still to be developed.
In this decade greater interest in the mechanisms underlying the malnutrition-infection cycle was facilitated by the increasing sophistication and availability of improved tools to assess immune function in humans. This work established the significant adverse impact of cyclical malnutrition-infection interactions on the complement system, mucosal immunity and cell-mediated immune responses.
Application of methods to distinguish between the T- and B-cell systems demonstrated that B-cells remained functionally intact if the proper help from mature T-cells could be provided. Part of the defect in antibody immunity in malnourished persons was shown to be attributed to the profound effect of these deficits on the maturation of T-cells, resulting in a reduction in fully functional mature T-cells and an excess of poorly functional immature T-cells.
Consumption of complement during infection and the inability to keep up with the needs by synthesis of new complement proteins were shown to result in a significant functional complement deficiency.
Because the initial events in phagocytosis and microbial killing are complement dependent, this deficiency resulted in a significant impairment in leukocyte microbicidal capacity, especially for gram-negative organisms, in the early stages of infection when complement was critical. In vitro studies demonstrated that addition of complement-rich sources from normal plasma restored the microbicidal capacity of polymorphonuclear leukocytes derived from PEM patients, compared to PEM cells incubated in autologous serum, indicating that humoral factors were of greater importance than cellular function in limiting microbicidal activity of neutrophils.
Insights gained from the observation of individuals with hereditary defects of specific limbs of the immune system revealed that these defects caused specific rather than generalized susceptibility for classes of infectious agents, and within classes, specific agents. Because all limbs of the immune system were affected in one way or another in PEM, the almost universal heightened susceptibility of these patients could be understood.
These descriptive immunological studies shed considerable light on the nature of the host defect, but did not provide an explanation for the mechanisms underlying them. A critical new insight by William Beisel and his colleagues at the Walter Reed Army Institute of Research, another contributor to this symposium, first suggested a role for leukocyte-derived mediators in initiating the catabolic changes and loss of nutrient stores characteristic of the infected host. These studies employed partially purified mixtures of the growth medium in which leukocytes were incubated and stimulated, which Beisel's group dubbed leukocyte endogenous mediator or LEM.
This product appeared to reproduce many of the critical metabolic changes occurring during the acute-phase response in infection. During this decade, the endogenous pyrogen derived from activated leukocytes and responsible for the febrile response during infection was purified, sequenced and the gene identified.
With this information, this protein was renamed interleukin 1 IL-1 , the first of a number of peptide mediators with different functions found in LEM to be clearly characterized.
These critical mediators of cell function and host response are now known as cytokines. When it was appreciated that many of these same cytokines were involved in the activation of the immune response, it became clear that the immune and metabolic responses to infection were intimately entwined, with common pathways of activation and regulation, suggesting that both responses had survival value, and that attempts to manipulate the metabolic response to diminish the deterioration of nutritional status during infection might have potential downsides.
These discoveries began to capture the interest of immunologists to study the effects of nutrition on immune function, and the initiation of greater collaborations between immunologists and nutritionists. For example, the decades-old observation that the thymus gland involuted during childhood malnutrition led immunologists to appreciate the role of the thymus gland in the differentiation of T-lymphocytes, and the relevance of thymic involution to the decrease in the number of mature, differentiated T-cells during malnutrition.
The consequence of this was functional impairment of cell-mediated immunity and diminished antibody responses to protein antigens dependent on T-cell help. Further analysis of the mechanisms by which the thymus gland triggers differentiation of T-cells suggests that secreted thymic peptides are involved, as well as still uncharacterized signals provided by interaction of immature lymphocytes with the thymic epithelium.
This period also saw an increase in the number of studies conducted in humans, as the methodology continued to improve and new methods to obtain and purify relevant cell types from human peripheral blood and other tissues were developed, as well as new and better animal models. Some of this was ascribed to the full realization that malnutrition of a degree sufficient to impair immune function was not just confined to children in developing countries without access to nutritionally complete diets, but occurred in up to half of the adult patients hospitalized on medical or surgical services in the United States.
In fact, the same metabolic events induced by infection were found to be caused by trauma or surgery. Malnutrition was also common in the elderly, who often consumed inadequate diets because of a number of social and medical factors including disease and drug-induced anorexia. Nutritional rehabilitation during hospitalization and greater attention to nutrition and diet in general medical and surgical care became higher priorities.
In addition, there was a realization that the acute-phase response induced by infection was a closely regulated and highly complex set of events, and that further refinement in our understanding of the mechanisms and mediators involved might lead us to targeted interventions after all. This exciting period of discovery is further discussed by Michael Powanda in this symposium.
During this period the role of micronutrient deficiency as a conditioning factor in host response to infection became widely recognized, as multiple large field studies of vitamin A supplementation in different populations around the world demonstrated a marked decrease in childhood mortality attributed to all causes in children compared to those who were not supplemented.
Although it has been difficult to show that the reduction in deaths associated with supplementation of infants and young children was specifically attributable to an effect on susceptibility or the ability to respond to individual infectious diseases, with the exception of measles, there is no other plausible explanation for the large effects noted in these studies.
This discrepancy between the overall effect and the lack of an explanatory mechanism has triggered considerable discussion and some degree of skepticism. There are, however, plausible explanations that remain undocumented. For example, vitamin A deficiency is known to result in keratinization of the respiratory epithelium, leading to a decrease in mucus production and diminished capacity of the respiratory epithelium to clear bacterial pathogens.
These events have not been studied in vivo. In addition, vitamin A and other retinoids regulate the expression of the genes for multiple proteins involved in host defense; in fact, aside from its role in visual function, the major effect of vitamin A is through the regulation of genes. Although the specific pathways involved in the enhanced mortality associated with vitamin A-deficiency states remains elusive, major programs to provide vitamin A supplements to those at risk in developing countries have been initiated in many developing countries.
Deficiency of other minerals, including iron and zinc, are well documented to impair immune function in experimental animals, and to the extent studied, in humans as well. One postulated mechanism is that both of these metals are essential for the function of a number of metalloenzymes required for nucleic acid synthesis and cell replication. This is a particularly critical barrier to an effective immune response to infectious diseases that is based on the rapid reproduction of antigen-specific responsive clones of stimulated lymphocytes and the capacity of bone marrow to churn out increasing numbers of neutrophils and monocytes.
Without the ability to make new DNA and RNA for cell division the host response sputters, and this is clearly documented in a variety of in vitro studies. It has been more difficult to demonstrate these effects in vivo in humans, however, and the clinical importance of zinc and iron deficiency remains in doubt.
Interestingly, iron excess also appears to impair immune function, in this instance because of iron-catalyzed toxic oxidative reactions that physically damage immunocompetent cells. Interesting studies on Keshan disease, the cardiomyopathy ascribed to Coxsackie B virus infections in selenium-deficient individuals in Keshan province in China, demonstrated that the antioxidant deficiency acted to select for a more virulent form of the causative virus.
As is the case for many RNA viruses, including HIV, the relatively common infidelity of RNA replication leads to the production of an array of slightly different genotypes, commonly known as quasi-species. Famine, for example, is a disaster caused not only by agricultural failures or natural disasters but too often by politics. Sen [ 19 ] has shown that political factors are responsible for nearly all famines. Even with the droughts in Ethiopia and West Bengal, it was government policy, not agricultural failure, that was responsible for the human crisis [ 19 ].
Food supply, underlying health, and health care interact in important ways, and their combined effect is synergistic. The underlying causes may also change with the seasons. Rural households, for example, may experience an annual hunger season. Diarrheal diseases and malaria are more prevalent during rainy seasons, and respiratory tract infections are more prevalent during cold weather. The effects are poor growth, impaired intellect, and increased mortality and susceptibility to infection.
Micronutrients have a relationship to antibody formation and the development of the immune system. These ill effects are preventable by supplements, fortification, and diet change. The Copenhagen Consensus [ 20 ] project on hunger and malnutrition even suggested that efforts to provide vitamin A, iron, iodine, and zinc generates higher returns than do trade liberalization or malaria, water, and sanitation programs.
Vitamin A maintains the integrity of the epithelium in the respiratory and gastrointestinal tracts. The World Health Organization estimates that, worldwide, — million children are vitamin A deficient, causing 1. Vitamin A deficiency increases the risk of diarrhea, Plasmodium falciparum malaria, measles, and overall mortality. Although we have come a long way since then, in , Scrimshaw et al. Vitamin A deficiency and measles, which is estimated to kill 2 million children per year, are closely linked.
Measles in a child is more likely to exacerbate any existing nutritional deficiency, and children who are already deficient in vitamin A are at much greater risk of dying from measles.
Postmeasles diarrhea is particularly difficult to treat and has a very high mortality [ 22 ]. Vitamin A deficiency increases the risk of developing respiratory disease and chronic ear infections [ 22 ]. Vitamin A supplementation sustains gut integrity, lowers the incidence of respiratory tract infections, reduces mortality from diarrhea, and enhances immunity.
Measles also depletes the body's supply of vitamin A. Thus, vaccination against measles often includes a high dose of vitamin A. Vitamin E is an antioxidant that scavenges free radicals. Vitamin E supplementation has been shown to improve immune function in the elderly, with delayed hypersensitivity skin response and antibody production after vaccination.
Vitamin E increases both cell-dividing and interleukin-producing capacities of naive T cells but not of memory T cells.
This enhancement of immune function is associated with significant improvement in resistance to influenza virus infection in aged mice and a reduced risk of acquiring upper respiratory infections in nursing home residents [ 23 ]. Vitamin D supplements may offer a cheap and effective immune system boost against tuberculosis [ 24 ]. Vitamin D was used to treat tuberculosis in the preantibiotic era, when special sanatoria were built in sunny locations, such as the Swiss Alps. Investigators reported that a single 2.
These findings came from a study that identified an extraordinarily high incidence of vitamin D deficiency among tuberculosis-susceptible women in Muslim communities in London [ 25 ]. It is a cofactor in the formation of enzymes and nucleic acids and plays a critical role in the structure of cell membranes and in the function of immune cells.
Zinc deficiency reduces nonspecific immunity, including neutrophil and natural killer cell function and complement activity; reduces numbers of T and B lymphocytes; and suppresses delayed hypersensitivity, cytotoxic activity, and antibody production.
Inadequate zinc supply prevents normal release of vitamin A from the liver; clinically, it is associated with growth retardation, malabsorption syndromes, fetal loss, neonatal death, and congenital abnormalities.
Low blood zinc concentrations have also been found in patients with tuberculosis, Crohn disease, diarrheal disease, and pneumonia. Zinc deficiency is associated with abnormal pregnancy outcomes [ 26 ] and conditions of relative immunocompromise, including alcoholism, kidney disease, burns, inflammatory bowel disease, and HIV infection.
Many drugs, including corticosteroids, also cause excessive excretion. Zinc supplementation reduces the duration and intensity of diarrheal illness and pneumonia among children living in developing nations. It limits growth stunting in children affected by acute diarrheal illness and reduces clinical disease caused by P. In patients with sickle cell disease, it increases IL-2 production and decreases the number of infections and hospitalizations [ 29—31 ]. Resistance to infection and improved appetite were found with continuous potassium and magnesium as well as zinc supplementation [ 33 , 34 ].
It is associated with impairments in cell-mediated immunity and reductions in neutrophil action, with decreased bacterial and myeloperoxidase activity. It lowers the body's defenses against disease and diminishes body and brain functions.
Despite this, iron deficiency has unclear effects on infectious disease risk. In the treatment of malaria, correcting iron deficiency is important, because malaria causes hemolysis and anemia. Supplementation in some cases, however, may actually aggravate infection, because the malaria parasite requires iron for its multiplication in blood and thus may be less infective in the iron-deficient person.
The mechanism for this may also be related to the inhibition of zinc absorption [ 37 ]. Many microorganisms require trace elements, such as iron and zinc, for survival and replication in the host and may increase in pathogenicity with supplementation [ 38 ]; thus, there is a concern about iron supplementation in malaria chemoprophylaxis programs.
In general, iron preferably with folate should be administered to all pregnant women undergoing malaria chemoprophylaxis [ 39 ], much like the need for pyridoxine B 6 supplementation during isoniazid treatment.
One billion people are infected with soil-transmitted helminths e. Humans can host as many as different types of parasites, and 1 worm can produce an average of 20, eggs per day. Intestinal parasites may be associated with a reduction in food intake, malabsorption, endogenous nutrient loss, and anemia. Although it is understood that parasites may lead to malnutrition, the extent to which malnutrition itself causes increased parasite infestation is not clearly known.
Nonetheless, the conditions so frequently coexist that they need to be considered together [ 22 ]. The evidence demonstrating that parasites damage a child's health is unambiguous. Helminth infections in school-aged children are associated with cognitive deficits [ 40 ].
Several worm infections, including hookworm, schistosomes, and Giardia , are associated with iron-deficiency anemia and a significant loss of micronutrients. Children free of parasites have better nutritional status, grow faster, learn more, and are freer of infections than are children with parasites. Nutritional deficiencies associated with pregnancy may induce disturbances between the generation of free oxygen radicals and the production of antioxidants that scavenge free radicals, thus being associated with poor immune response to infection.
This immune deficiency is partially made up for by breast-feeding. All of these strengthen the intrinsic immune response. Thus, breast milk actively enhances the immune system via transfer of antibodies and lymphocytes.
Lung aspirate revealed the opportunistic organism Pneumocystis carinii. Despite our best efforts, we lost the child. I speculated that malnutrition had robbed Kamala of her defenses against infection and led to premature demise. The tears shed on her death were not my first and would not be my last. There would be another Kamala, and another, and another. The second case was of the poor nations of the world, with high infant mortality, poor sanitation, contaminated food and water, a low literacy rate, and short life expectancy.
Widespread malnutrition and infection were obvious shackles to development. Research into their interactions became a necessity. Tuberculosis is a major cause of death in underprivileged populations. It has been estimated that 3 million to 4 million individuals die of the disease every year. In addition to environmental factors such as overcrowding, host immunity plays a crucial role in determining the final outcome.
A number of innate and adaptive mechanisms are responsible for killing Mycobacteria 8 , 9. The major role played by macrophages has been reviewed extensively Infection occurs commonly through the respiratory tract. Bacteria that survive mucociliary escalator of the upper respiratory tract are ingested by alveolar macrophages that contain numerous acidic phagocytic vacuoles and hydrolytic enzymes.
Macrophage activation results in a drastic reduction in the number of viable bacteria that may be completely eradicated.
However, some mycobacteria may survive the powerful microbicidal onslaught and escape into the cytoplasm where they multiply unhindered, leading ultimately to cell death, and release into the tissues where they enter other cells including macrophages.
Persistent organisms provide the antigenic stimulation and cell-mediated hypersensitivity reaction that leads to local accumulation of inflammatory cells and formation of granulomas.
This process limits the spread of mycobacteria but is associated with tissue necrosis, fibrosis, and functional impairment. This stereotypic hide-and-seek game of evasion, activation, attack, and death is played out in response to many intracellular pathogens, e. Bloom and colleagues 12 — 16 have conducted a number of studies to elucidate the principal mechanisms by which murine mononuclear phagocytes kill M.
Now, Bloom and colleagues take us one major step forward by examining the effects of a low protein diet on anti-mycobacterial immunity Interestingly, these changes were observed in the lungs but not in the liver, and the effects wore off after 2 weeks after challenge. There was no significant effect on total nitric acid production in vivo. Granulomatous inflammation was studied at the light, immunohistochemical, and electron microscopic levels, and was impaired in the low-protein group, confirming and extending earlier observations The immunologic changes and risk of death could be reversed by reverting to a normal high-protein diet.
The seminal work of Bloom and colleagues raises many new questions. Are the findings nutrient-specific? Did body weight and lymphoid organ weight differ in the two animal groups?
It is possible that at least some of the observed effects may be the result of concomitant deficiencies of micronutrients such as zinc. It is recognized that inadequate diets result in poor appetite, malabsorption, and decreased growth. Thus, the consumption and absorption of nutrients that are critical for optimum immune responses e.
This confounding variable can be sorted out by including a pair-fed comparison group. Would the quality of dietary protein make a difference? In general, animal proteins are superior to vegetable proteins in sustaining growth and maintaining immunity; there are subtle differences in immune responses of animals fed casein-based and whey-based diets.
What is the threshold of nutritional deficiency that results in a significant impairment of anti-mycobacterial defenses? What is the explanation for the marked heterogeneity of survival time in genetically similar mice challenged with the same mycobacterial burden? What is the basis of tissue specificity of macrophage handling of the microorganisms?
It has been shown that CD8 T cells specific for listeriolysin O mediate significant immunity in the liver but not in the spleen Is one cell type essential for antibacterial defense at one site but not at another location, as has been shown for neutrophils and Listeria