PNAS December 10, 93 25 ; https: When an immune response occurs from challenge by a pathogen, a systemic acute phase or inflammatory response results that is considered to be the foundation of non-specific immunity. It is important to be able to distinguish between a stressor and stress. The effects of chronic non-communicable diseases on labour force outcomes: Selenium works with vitamin E in tissues to protect biological membranes from oxidative damage. Scopus Google Scholar. Integrative and Comparative Biology
Stage I: the dark ages, before 1959
During the first day of an immune response to a pathogen challenge the liver transitions from maintaining homeostasis and supporting the nutritional demands of growth or reproduction to the production of proteins such as complement, mannan binding protein, and C-reactive protein that aid in the detection and neutralization of pathogens.
During the acute phase response against a successful pathogen, the liver becomes the most important organ of the immune system when using nutritional demands as the metric. By five to seven days of a typical immune response the production of lymphocytes and immunoglobulin become quantitatively greater than the production of acute phase proteins.
Overall the innate and adaptive immune systems work mutually to provide an immediate response to infection via innate processes, while slowly developing a specific response that is mediated by lymphocytes. This temporal division serves to spread the nutritional costs of a response over a longer period of time but a global accounting of the innate and adaptive responses is needed to determine if there are nutritionally important implications. Nutritionist have rigorously applied quantitative theory and modeling to nutrient needs for growth and reproduction as influenced by dietary and environmental factors.
However, nutritionists have generally been remiss in applying robust quantitative tools to tradeoffs between performance and immunity. We have endeavored to make quantitative estimates of the size of these tradeoffs as well as each of the underlying processes that siphon nutrients away from growth and reproduction. To do this we have assessed the amount of nutrients needed for mounting an immune response using both direct and indirect estimates.
Indirect estimates were made by quantifying the magnitude of growth depression that occurs during the periods of time that growing broiler chicks mount an initial innate response and also a subsequent adaptive immune response.
About two-thirds of the growth depression during the acute phase response is due to a decrease in appetite and about a third is due to nutrient diversions or losses related to the immune response.
Direct estimates were made by quantifying the whole body dynamics and nutrient content of the myriad of cells and proteins responsible for protective immunity during the innate and adaptive responses to a simulated infection with E. Although energy expenditure or any one of the dozens of dietary essential nutrients might be used as a metric for nutritional expenditures by the immune system relative to other tissues, the essential amino acid lysine was initially used as a reference nutrient.
This is because lysine is the reference amino acid in the ideal protein system used commonly in non-ruminant nutrition because it functions almost exclusively as a substrate for protein synthesis and cannot be stored or synthesized.
The immune system has both systemic and mucosal components; however, we limited this investigation to the systemic system due to the extreme difficulty of quantifying the diffusely organized mucosal immune system. A summary of the data is shown in Figure 1 and indicates that the amount of lysine in protective proteins, such as the acute phase proteins and immunoglobulins, greatly exceed that in the cellular component of the immune system, regardless of whether the immune system is responding or not.
During the acute phase of the immune response the liver hypertrophies markedly for the rapid production of acute phase proteins. Because the liver is recruited to become part of the immune defenses during the acute phase response, it is the most expensive part of the response.
The amount of lysine needed for the adaptive phase of the response antibody production and new lymphocytes is much less than that needed for the acute phase of the response and is incurred following the acute phase response i. During the transition from the acute phase response to the time when the adaptive response begins to utilize significant quantities of lysine, the size of the liver and levels of protective proteins return toward normal.
The lysine liberated from protein catabolism of hepatic tissue and acute phase proteins would provide a surplus of lysine to provision the anabolic processes of the adaptive response. This means that the cost of an immune response is mostly due to protective processes and physiological adjustments that are unrelated to the needs of leukocytes or the production of protective proteins.
Even when the hypertrophy of the liver and the massive production of acute phase proteins are included, the amount of nutrients diverted to protective processes accounts for very little of the depression in growth or reproduction that occurs during the response. More recently we have examined the ideal balance of amino acids for the immune response to a pathogen and found that lysine needs are lower for immunity relative to growth or egg production and use of sulfur amino acids, especially cysteine, gives a better estimate Table 1.
This large difference in the balance of amino acids needed for the immune response relative to accretion of body tissue or egg protein greatly increases the protein cost of an immune response. Ongoing research indicates that fever, decreased intake of food, and less efficient digestion that accompanies a robust immune response are, together, more important than the diversion of nutritional resources to the immune system Figure 2.
Quantitatively, a decrease in digestion of nutrients, especially fat and some amino acids Table 2 is the most important physiological change when the nutritional impact is used as a metric. Appropriation of nutrients when the immune system responds. In the initial stages of an immune response against a novel pathogen, phagocytes are the early responders and release pro-inflammatory cytokines in sufficient amounts that they have endocrine-like effects throughout the body.
This cytokine storm induces metabolic changes, including increased protein degradation and insulin resistance, which divert nutrients from skeletal muscle and other tissues so that they become available for the increased demands of the liver and responding leukocytes Sirimongkolkasem, In the case of amino acids, the balance of essential and semi-essential amino acids is very different in leukocytes, protective proteins and the hypertrophying liver compared to the balance in muscle and other tissues.
Recent work indicates that cysteine is the most limiting amino acid during the acute phase response in chickens Table 1. Iseri and Klasing, ; Sirimongkolkasem, and also in rats Breuille et al. This is due to a mismatch between muscle cysteine release and hepatic demand for the markedly enhanced production of acute phase proteins and glutathione, which serves as an antioxidant. There was a three-pronged impetus for systematic studies of immune responses in undernourished individuals.
First, there was a plethora of public health data indicating an interaction, usually synergistic but occasionally antagonistic, between malnutrition and infection 3. Second, new concepts and novel techniques in immunology emerged in the s and s. Third, dramatic human stories and demographic data stimulated individual scientists, as the following example shows 7. My interest in nutrition-immunity interactions was kindled by two cases: Eighteen-month-old Kamala was thin, her skin pale as wax, and her lungs screaming for air.
She wore a spectral white death-mask in a frame of black hair. Her shrivelled body and swollen legs were typical of marasmic kwashiorkor, and she had an obvious fulminant infection. 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 Would deficiencies of other nutrients result in impaired anti-mycobacterial immunity similar to that observed in mice on low-protein diet?
For instance, deficiencies of vitamin A 1 , 21 , 22 and zinc 1 , 23 — 25 alter a wide range of immune responses. Both in small-for-gestation low-birth-weight infants 26 , 27 and in animal models of intrauterine undernutrition or zinc deficiency 28 , 29 , the immunologic impairment is profound and long lasting.
What is the status of other immunologic mechanisms that play an important role in defense against intracellular pathogens, e. Neutralizing antibodies 42 , gene knockout mice 43 , and adoptive transfer assays 19 with bone marrow chimeric or transgenic rodent hosts can be deployed to study the specific role of individual immune processes. What is the impact of genetic host factors on antigen recognition and immunologic defense 44? Finally, it would be useful to confirm the interesting observations reported in the study by Chan et al.
There is exciting new information on another face of host—parasite interaction. Viruses can mutate and show altered virulence because of nutritional deficiencies in the hosts they infect. Beck and coworkers 45 showed that selenium deficiency enhanced the heart-damaging potential of coxsackievirus. Virus strain recovered from selenium-deficient animals was capable of inducting damage in well-nourished animals. Most interestingly, there were six nucleotide changes between the avirulent input virus strain and the virulent virus recovered from selenium-deficient animals.