Related Articles

Nutrition is a major determinant of host resistance. Both deficiencies and excesses impair immune responses and lead to increased risk of infection and other diseases. Changes in immunity occur early in the development of nutritional deficiency; thus immunocompetence can be used as a sensitive functional index of undernutrition and as a prognostic marker of post-operative complications. Nutritional support enhances antibody response to common immunization procedures in such populations at risk of malnutrition as the elderly.

The trace element zinc is essential for the immune system, and zinc deficiency affects multiple aspects of innate and adaptive immunity. There are remarkable parallels in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance toward T helper type 2 cells, decreased response to vaccination, and impaired functions of innate immune cells. Many studies confirm a decline of zinc levels with age. Most of these studies do not classify the majority of elderly as zinc deficient, but even marginal zinc deprivation can affect immune function. Consequently, oral zinc supplementation demonstrates the potential to improve immunity and efficiently downregulates chronic inflammatory responses in the elderly. These data indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence.

The relevance of zinc for proper functioning of the entire immune system is already well documented. However, the identification of individuals who really need zinc supplementation is still debated in view of the fact that excessive zinc may also be toxic. The risk of developing zinc deficiency in people from industrialized countries is relatively low, except for elderly subjects where zinc intake may be suboptimal and inflammation is chronic. Thus, the role of zinc on the immune system and on the health of European elderly people is becoming of paramount importance, considering also that the elderly population is rapidly increasing. In particular, the factors contributing to and the biochemical markers of zinc deficiency in the elderly are still remain to be established. Epidemiological, functional, and genetic studies aimed at formulating a rationale for the promotion of healthy ageing through zinc supplementation was the subject of an International Conference held in Madrid from 11–13 February 2006 (3rd ZincAge Meeting) at the CNIO Institute (local organizer: Maria Blasco, partner of ZincAge)

Background

Supplementation of nutritional deficiencies helps to improve immune function and resistance to infections in malnourished subjects. However, the suggested benefits of dietary supplementation for immune function in healthy well nourished subjects is less clear. Among the food constituents frequently associated with beneficial effects on immune function are micronutrients such as vitamin C, vitamin E, β-carotene and zinc, and colostrum. This study was designed to investigate the effects these ingredients on immune function markers in healthy volunteers.

Methods

In a double-blind, randomized, parallel, 2*2, placebo-controlled intervention study one hundred thirty-eight healthy volunteers aged 40–80 y (average 57 ± 10 y) received one of the following treatments: (1) bovine colostrum concentrate 1.2 g/d (equivalent to ~500 mg/d immunoglobulins), (2) micronutrient mix of 288 mg vitamin E, 375 mg vitamin C, 12 mg β-carotene and 15 mg zinc/day, (3) combination of colostrum and micronutrient mix, or (4) placebo. Several immune function parameters were assessed after 6 and 10 weeks. Data were analyzed by analysis of variance. Groups were combined to test micronutrient treatment versus no micronutrient treatment, and colostrum treatment versus no colostrum treatment.

Results

Overall, consumption of the micronutrient mix significantly enhanced delayed-type hypersensitivity (DTH) responses (p < 0.05). Adjusted covariance analysis showed a positive association between DTH and age. Separate analysis of younger and older age groups indicated that it was the older population that benefited from micronutrient consumption. The other immune function parameters including responses to systemic tetanus and oral typhoid vaccination, phagocytosis, oxidative burst, lymphocyte proliferation and lymphocyte subset distribution were neither affected by the consumption of micronutrients nor by the consumption of bovine colostrum concentrate.

Conclusion

Consumption of bovine colostrum had no effect on any of the immune parameters assessed. The micronutrient mix enhanced cellular immunity as measured by DTH, with an increased effect by incremental age, but did not affect any of the other immune parameters measured. Although correlations between decreased DTH and enhanced risk of certain infection have been reported, it remains unclear whether and enhanced DTH response actually improves immune defense. The present data suggests that improvement of immune parameters in a population with a generally good immune and nutritional status is limited and that improvement of immune function in this population may be difficult.

Objective

Zinc deficiency is common among populations at high risk for sepsis mortality, including elderly, alcoholic, and hospitalized patients. Zinc deficiency causes exaggerated inflammatory responses to endotoxin but has not been evaluated during bacterial sepsis. We hypothesized that subacute zinc deficiency would amplify immune responses and oxidant stress during bacterial sepsis [i.e., cecal ligation and puncture (CLP)] resulting in increased mortality and that acute nutritional repletion of zinc would be beneficial.

Design

Prospective, randomized, controlled animal study.

Setting

University medical center research laboratory.

Subjects

Adult male C57BL/6 mice.

Interventions

Ten-week-old, male, C57BL/6 mice were randomized into three dietary groups: 1) control diet, 2) zinc-deficient diet for 3 weeks, and 3) zinc-deficient diet for 3 weeks followed by oral zinc supplementation for 3 days (n = 35 per diet). Mice were then assigned to receive either CLP or sham operation (n = 15 each per diet). CLP and sham-operated treatment groups were further assigned to a 7-day survival study (n = 10 per treatment per diet) or were evaluated at 24 hours (n = 5 per treatment per diet) for signs of vital organ damage.

Measurements and Main Results

Sepsis mortality was significantly increased with zinc deficiency (90% vs. 30% on control diet). Zinc-deficient animals subject to CLP had higher plasma cytokines, more severe organ injury, including increased oxidative tissue damage and cell death, particularly in the lungs and spleen. None of the sham-operated animals died or developed signs of organ damage. Zinc supplementation normalized the inflammatory response, greatly diminished tissue damage, and significantly reduced mortality.

Conclusions

Subacute zinc deficiency significantly increases systemic inflammation, organ damage, and mortality in a murine polymicrobial sepsis model. Short-term zinc repletion provides significant, but incomplete protection despite normalization of inflammatory and organ damage indices.

Zinc may be a new risk factor for pneumonia in the elderly. In this special article, we reviewed the magnitude of the problem of pneumonia (its prevalence, morbidity and mortality) in the elderly, its etiology, and the dysregulation of the immune system associated with increasing age. In addition, we presented evidence from the literature, including work we did recently, that low zinc status (commonly reported in the elderly) impairs immune function, decreases resistance to pathogens, and is associated not only with increased incidence and duration of pneumonia, increased use and duration of antimicrobial treatment, but also with increased overall mortality in the elderly. Inadequate stores of zinc might therefore be a risk factor for pneumonia in the elderly. Randomized, double blind, controlled studies are needed to determine the efficacy of zinc supplementation as a potential low cost intervention to reduce morbidity and mortality due to pneumonia in this vulnerable population.

OBJECTIVES:

Both renal function and immune system function decline with age. Although controversial, a significant number of studies have shown that the decline in kidney function is associated with the worsening of the immune system. These findings are reinforced by the increased susceptibility to infections and deficient immunization coverage after vaccination both in patients with chronic renal disease and in elderly individuals. Our objective was to evaluate a non-institutionalized elderly population from São Paulo City and correlate the estimated glomerular filtration rate with the percentage of lymphocytes in circulation.

METHODS:

A random population of 237 individuals (107 men and 130 women), ranging in age from 60 to 101 years, who were enrolled in the Health, Well-Being and Aging Study was evaluated for renal function (Modification on Diet in Renal Disease formula) and lymphocyte percentage (flow cytometry).

RESULTS:

Aging was associated with a decrease in the estimated glomerular filtration rate in both male and female individuals. We did not identify a significant correlation between the estimated glomerular filtration rate and either the percentage of CD4, CD8, and B cells or CD4/CD8 ratio. The median percentage of CD8+ T cells was significantly lower in individuals with an estimated glomerular filtration rate ≥60 mL/min/1.73 m2.

CONCLUSIONS:

In this study, no statistical correlation was found between the estimated glomerular filtration rate and either the lymphocyte phenotype (CD4+, CD8+, and CD19+ cells) or the CD4/CD8 ratio in blood.

Malnutrition is common in patients with end-stage liver failure and hepatic encephalopathy, and is considered a significant prognostic factor affecting quality of life, outcome, and survival. The liver plays a crucial role in the regulation of nutrition by trafficking the metabolism of nutrients, their distribution and appropriate use by the body. Nutritional consequences with the potential to cause nervous system dysfunction occur in liver failure, and many factors contribute to malnutrition in hepatic failure. Among them are inadequate dietary intake, malabsorption, increased protein losses, hypermetabolism, insulin resistance, gastrointestinal bleeding, ascites, inflammation/infection, and hyponatremia. Patients at risk of malnutrition are relatively difficult to identify since liver disease may interfere with biomarkers of malnutrition. The supplementation of the diet with amino acids, antioxidants, vitamins as well as probiotics in addition to meeting energy and protein requirements may improve nutritional status, liver function, and hepatic encephalopathy in patients with end-stage liver failure.

The elderly are particularly susceptible to influenza A virus infections, with increased occurrence, disease severity and reduced vaccine efficacy attributed to declining immunity. Experimentally, the age-dependent decline in influenza-specific CD8+ T cell responsiveness reflects both functional compromise and the emergence of ‘repertoire holes’ arising from the loss of low frequency clonotypes. In this study, we asked whether early priming limits the time-related attrition of immune competence. Though primary responses in aged mice were compromised, animals vaccinated at 6 weeks then challenged >20 months later had T-cell responses that were normal in magnitude. Both functional quality and the persistence of ‘preferred’ TCR clonotypes that expand in a characteristic immunodominance hierarchy were maintained following early priming. Similar to the early priming, vaccination at 22 months followed by challenge retained a response magnitude equivalent to young mice. However, late priming resulted in reduced TCRβ diversity in comparison with vaccination earlier in life. Thus, early priming was critical to maintaining individual and population-wide TCRβ diversity. In summary, early exposure leads to the long-term maintenance of memory T cells and thus preserves optimal, influenza-specific CD8+ T-cell responsiveness and protects against the age-related attrition of naïve T-cell precursors. Our study supports development of vaccines that prime CD8+ T-cells early in life to elicit the broadest possible spectrum of CD8+ T-cell memory and preserve the magnitude, functionality and TCR usage of responding populations. In addition, our study provides the most comprehensive analysis of the aged (primary, secondary primed-early and secondary primed-late) TCR repertoires published to date.

Author Summary

The elderly population is particularly susceptible to novel infections, especially the annual, seasonal epidemics caused by influenza viruses. Established T cell immunity directed at conserved viral regions provides some protection against influenza infection and promotes more rapid recovery, thus leading to better clinical outcomes. We asked whether priming early in life limits the time-related attrition of immune competence. We found that although influenza-specific T cell responses are compromised in the aged mice, vaccination with influenza early (but not late) in life ‘locks’ optimal T-cell responsiveness, maintains functional quality, persistence of preferred clones and a characteristic T cell hierarchy. Overall, our study supports development of vaccines that prime T cells early in life to elicit the broadest possible spectrum of pre-existing T cell memory and preserve the magnitude, functionality and clonal usage of responding populations for life-long immunity against influenza viruses.

A potential role for vitamin D as a therapeutic immunomodulator in tuberculosis (TB) has been recognised for over 150 years, but has only recently returned to the centre of the research arena due to the increasing awareness of the global vitamin D deficiency epidemic. As early as birth a child is often deficient in vitamin D, which may not only affect their bone metabolism but also modulate their immune function, contributing to the increased susceptibility to many infections seen early in life. Recent studies have begun to explain the mechanisms by which vitamin D affects immunity. Antimicrobial peptides are induced in conjunction with stimulation of innate pattern recognition receptors enhancing immunity to particular infections. In contrast the role of vitamin D within the adaptive immune response appears to be more regulatory in function, perhaps as a mechanism to reduce unwanted inflammation. In this paper we focus on the effect of vitamin D on immunity to TB. Where much of the attention has been paid by past reviews to the role of vitamin D in adult TB patients, this paper, where possible, focuses on research in paediatric populations.

Individuals at highest risk of zinc deficiency (children, elderly, pregnant and lactating women, morbidly ill, alcoholics) have a higher risk of infection. Whereas the essential role of zinc in maintaining adaptive immunity is well recognized, much less is known regarding the innate immune system. We recently reported that zinc deficiency significantly increases mortality in an animal model of sepsis. In particular, zinc-deficient mice had a decreased capacity to clear bacteria and a concomitant increase in NF-κB-mediated signaling across multiple vital organs. This occurred in tandem with exaggeration of the acute phase and innate immune response. Strikingly, sepsis patients revealed similar findings in that lower plasma zinc levels were associated with more inflammation and increased severity of illness. Through these investigations we have consistently observed that SLC39 A8 (Zip8) is unique, relative to other zinc transporters, in that its expression is significantly induced at the onset of infection. Moreover, induction of Zip8-mediated zinc transport into innate immune cells is vital for proper immune function. Whether Zip8 functions beyond the conventional role of a zinc transporter remains a work in progress, although new evidence has revealed that Zip8 expression itself is regulated by NF-κB. Taken together, these findings indicate that zinc is vital for proper innate immune function and that hZip8 is intricately involved in maintaining innate immune defense.

In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte–deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell–deficient mice have a 50– 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell–deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell–deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.

Age-associated deterioration in the immune system, which is referred to as immunosenescence, contributes to an increased susceptibility to infectious diseases, autoimmunity, and cancer in the elderly. A summary of major changes associated with aging in immune system is described in this paper. In general, immunosenescence is characterized by reduced levels of peripheral naïve T cells derived from thymus and the loss of immature B lineage cells in the bone marrow. As for macrophages and granulocytes, they show functional decline with advancing age as evidenced by their diminished phagocytic activity and impairment of superoxide generation. The indole melatonin is mainly secreted in the pineal gland although it has been also detected in many other tissues. As circulating melatonin decreases with age coinciding with the age-related decline of the immune system, much interest has been focused on melatonin's immunomodulatory effect in recent years. Here, we underlie the antioxidant and immunoenhancing actions displayed by melatonin, thereby providing evidence for the potential application of this indoleamine as a “replacement therapy” to limit or reverse some of the effects of the changes that occur during immunosenescence.

Nutrition is an important element of health in the older population and affects the aging process. The prevalence of malnutrition is increasing in this population and is associated with a decline in: functional status, impaired muscle function, decreased bone mass, immune dysfunction, anemia, reduced cognitive function, poor wound healing, delayed recovery from surgery, higher hospital readmission rates, and mortality. Older people often have reduced appetite and energy expenditure, which, coupled with a decline in biological and physiological functions such as reduced lean body mass, changes in cytokine and hormonal level, and changes in fluid electrolyte regulation, delay gastric emptying and diminish senses of smell and taste. In addition pathologic changes of aging such as chronic diseases and psychological illness all play a role in the complex etiology of malnutrition in older people. Nutritional assessment is important to identify and treat patients at risk, the Malnutrition Universal Screening Tool being commonly used in clinical practice. Management requires a holistic approach, and underlying causes such as chronic illness, depression, medication and social isolation must be treated. Patients with physical or cognitive impairment require special care and attention. Oral supplements or enteral feeding should be considered in patients at high risk or in patients unable to meet daily requirements.

The importance of Zn for optimal functioning of the immune system and antioxidant stress response is well documented. Zn homeostasis influences development and function of immune cells, activity of stress-related and antioxidant proteins [metallothioneins (MT), chaperones, ApoJ, Poly(ADP-Ribose) polymerase-1 (PARP-1) and Methionione Sulfoxide Reductase (Msr), Superoxide Dismutase (SOD)], and helps to maintain genomic integrity and stability. During ageing, the intake of Zn decreases due to inadequate diet and/or intestinal malabsorption, contributing to frailty, general disability and increased incidence of age-related degenerative diseases (cancer, infections and atherosclerosis). Although many factors contributing to Zn deficiency have been identified, the biochemical markers of Zn deficiency as well as the possibility to achieve relevant health benefits through Zn supplementation in the elderly are still a matter for evaluation. Taking into account that Zn homeostasis is regulated by proteins and enzymes for which polymorphisms have been previously found to be associated with successful/unsuccessful ageing, genetic screening might be of added value in evaluating the individual response to Zn supplementation. Biochemical, immunological, dietary and genetic studies aimed at understanding the impact of Zn in healthy ageing, the effect of Zn supplementation in the elderly and finally formulating a rationale for the promotion of correct Zn supplementation were discussed at the international Zincage conference held in Ancona in January 2007.

Infectious disease is the major cause of morbidity and mortality in developing countries, particularly in children. Increasing evidence suggests that protein-calorie malnutrition is the underlying reason for the increased susceptibility to infections observed in these areas. Moreover, certain infectious diseases also cause malnutrition, which can result in a vicious cycle. Malnutrition and bacterial gastrointestinal and respiratory infections represent a serious public health problem. The increased incidence and severity of infections in malnourished children is largely due to the deterioration of immune function; limited production and/or diminished functional capacity of all cellular components of the immune system have been reported in malnutrition. In this review, we analyze the cyclical relationship between malnutrition, immune response dysfunction, increased susceptibility to infectious disease, and metabolic responses that further alter nutritional status. The consequences of malnutrition are diverse and included: increased susceptibility to infection, impaired child development, increased mortality rate and individuals who come to function in suboptimal ways.

Acute kidney injury (AKI) develops mostly in the context of critical illness and multiple organ failure, characterized by alterations in substrate use, insulin resistance, and hypercatabolism. Optimal nutritional support of intensive care unit patients remains a matter of debate, mainly because of a lack of adequately designed clinical trials. Most guidelines are based on expert opinion rather than on solid evidence and are not fundamentally different for critically ill patients with or without AKI. In patients with a functional gastrointestinal tract, enteral nutrition is preferred over parenteral nutrition. The optimal timing of parenteral nutrition in those patients who cannot be fed enterally remains controversial. All nutritional regimens should include tight glycemic control. The recommended energy intake is 20 to 30 kcal/kg per day with a protein intake of 1.2 to 1.5 g/kg per day. Higher protein intakes have been suggested in patients with AKI on continuous renal replacement therapy (CRRT). However, the inadequate design of the trials does not allow firm conclusions. Nutritional support during CRRT should take into account the extracorporeal losses of glucose, amino acids, and micronutrients. Immunonutrients are the subject of intensive investigation but have not been evaluated specifically in patients with AKI. We suggest a protocolized nutritional strategy delivering enteral nutrition whenever possible and providing at least the daily requirements of trace elements and vitamins.

Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8- and gamma interferon (IFN-γ)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-γ expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-γ production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-γ levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-γ. Additional characterizations of the signaling events that lead to enhanced innate IFN-γ production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.

Summary

Immune function declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. A diverse repertoire of T cells is essential for a vigorous immune response, and an important manifestation of immune aging is the progressive loss of repertoire diversity, predominantly among CD8 T cells in both mice and humans. Importantly, perturbations in the peripheral T cell repertoire, including reduction of the CD4:CD8 ratio and cytomegalovirus-driven T cell clonal expansions, make a major contribution to the “immune risk phenotype” defined for humans, which predicts two-year mortality in very old individuals.

Advances in modern medicine have led to an increase in the median life span and an expansion of the world’s population over the age of 65. With increasing numbers of the population surviving to the extreme of age, those at risk for the development of pneumonia will approach 2 billion by the year 2050. Numerous age-related changes in the lung likely contribute to the enhanced occurrence of pneumonia in the elderly. Inflammation in the elderly has been shown to increase risk prior to infection; age-associated inflammation enhances bacterial ligand expression in the lungs which increases the ability of bacteria to attach and invade host cells. Conversely, the elaboration of the acute inflammatory response during early infection has been found to decrease with age resulting in a delayed immune response and diminished bacterial killing. Finally, the resolution of the inflammatory response during the convalescent stage back to “baseline” is often prolonged in the elderly and associated with negative outcomes, such as adverse cardiac events. The focus of this review will be to discuss our current understanding of the potential mechanisms by which dysregulated inflammation (both prior to and following an infectious insult) enhances susceptibility to and severity of community acquired pneumonia (CAP) in the elderly with an emphasis on pneumococcal pneumonia, the leading cause of CAP.

Advances in modern medicine have led to an increase in the median life span and an expansion of the world’s population over the age of 65. With increasing numbers of the population surviving to the extreme of age, those at risk for the development of pneumonia will approach 2 billion by the year 2050. Numerous age-related changes in the lung likely contribute to the enhanced occurrence of pneumonia in the elderly. Inflammation in the elderly has been shown to increase risk prior to infection; age-associated inflammation enhances bacterial ligand expression in the lungs which increases the ability of bacteria to attach and invade host cells. Conversely, the elaboration of the acute inflammatory response during early infection has been found to decrease with age resulting in a delayed immune response and diminished bacterial killing. Finally, the resolution of the inflammatory response during the convalescent stage back to “baseline” is often prolonged in the elderly and associated with negative outcomes, such as adverse cardiac events. The focus of this review will be to discuss our current understanding of the potential mechanisms by which dysregulated inflammation (both prior to and following an infectious insult) enhances susceptibility to and severity of community acquired pneumonia (CAP) in the elderly with an emphasis on pneumococcal pneumonia, the leading cause of CAP.

There is a consensus that nutritional support, which must be provided to patients in intensive care, influences their clinical outcome. Malnutrition is associated in critically ill patients with impaired immune function and impaired ventilator drive, leading to prolonged ventilator dependence and increased infectious morbidity and mortality. Enteral nutrition is an active therapy that attenuates the metabolic response of the organism to stress and favorably modulates the immune system. It is less expensive than parenteral nutrition and is preferred in most cases because of less severe complications and better patient outcomes, including infections, and hospital cost and length of stay. The aim of this work was to perform a review of the use of enteral nutrition in critically ill patients.

Under appropriate conditions, deficiencies of certain minerals and vitamins as well as high intakes of dietary fat increase the toxicity of a given dose of lead in experimental animals. The severity of lead poisoning can also be increased by the consumption of either deficient or excessive levels of protein. Mineral deficiencies appear to have some of the most profound effects on lead toxicity, since the consequences of plumbism can be exaggerated by feeding diets low in calcium, phosphorus, iron, zinc, and in some cases, copper. Evidence for an antagonism between lead and nutritional levels of selenium is inconclusive. Vitamin E deficiency and lead poisoning interact to produce an anemia in rats that is more severe than that caused by either treatment alone. Lead apparently exerts a pro-oxidant stress on the red cell, thereby causing its accelerated destruction. One of the biochemical mechanisms of lead poisoning may be the disruption of normal membrane architecture, thereby leading to peroxidative damage. Epidemiological surveys have suggested a negative correlation between the poor nutritional status of children with regard to calcium and the concentration of lead in blood. Other examples of potential interactions of mineral status and lead poisoning in humans include the hypothesized hazards of soft water to public health in areas with lead plumbing and the possible role of mineral deficiencies in the etiology of pica. Experimental studies have shown that in some situations combined nutritional deficiencies can have an additive effect in potentiating lead toxicity.

The effect of progressive long term dietary protein depletion on viral susceptibility was investigated in 2 host-virus systems: (1) swine influenza in the male CF1 mouse, and (2) Rous sarcoma virus in the New Hampshire red chicken. Data are presented demonstrating a relationship between host protein nutrition and susceptibility to virus infection. This relationship is shown to be cyclic in character, involving phases of increased and decreased viral susceptibility. The relative resistance of the host on low protein intake is a function of the duration on incomplete diet administration before virus inoculation, and consequently a function of the host's state of depletion. As illustrated in Fig. 6, the cyclic susceptibility change demonstrated by these animals on low protein diet was characterized by an initial phase of increased susceptibility, a secondary phase of increased resistance, and a final phase of increased susceptibility. It is proposed that these alterations in relative viral susceptibility result from metabolic changes occurring within the host during the process of dietary protein depletion. The resistance changes are roughly correlated to periods of depot fat utilization (increased susceptibility), reserve protein utilization (decreased susceptibility), and tissue breakdown subsequent to protein starvation (increased susceptibility). Many previously published concepts of the interplay of viral susceptibility and host nutrition maintained that host malnourishment led to increased host resistance. The cyclic change in resistance, reported herein, is given as evidence that the effect of host deficiency cannot be explained simply on the basis of an inhibition of virus growth due to retarded cellular metabolism in the host. Protein deficiency is shown not to produce an "all-or-none" effect, but a series of reproducible phases of increased and decreased resistance. From the aforementioned results it is proposed that the phases of viral susceptibility seen in the protein-deficient host are demonstrative of the dynamic interrelationship between the physiologic state and the resistance of the host. Dietary influences in the normal host, by producing similar metabolic changes, could have analogous implications on innate resistance. It is believed that the foregoing leads to a more clear and dynamic concept of viral resistance in the normal individual.

Infectious diseases contribute to significant morbidity and mortality in elderly populations. One of the major contributing factors to this is age-related declines in the immune system that diminish the response o both infections and vaccinations. In order to understand how specific changes in the immune system influence the generation of immunity in older individuals, immunologists have developed aging mouse models that allow for experimental manipulation of immune system components. These models have shown that there are dramatic age-related changes in naive CD4 T cell function that have the potential to impact a myriad of immune responses. In this review, we will summarize these findings on the intrinsic changes in CD4 T cell function and discuss how these changes influence immunity.