Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage.

GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors.

Toenail concentrations of zinc, selenium and nickel in patients with chronic recurrent warts: A pilot two-group comparative study.

BACKGROUND: Normal immune functioning requires sufficient levels of trace elements including zinc and selenium, while elements such as nickel can be immunotoxic. AIM: To assess long-term abnormalities in zinc, selenium and nickel levels in patients with chronic recurrent warts. METHODS: Toenail samples were taken from 28 patients with chronic recurrent warts and 30 apparently healthy matching controls were analysed. Toenail concentrations of zinc, selenium and nickel were measured using inductively-coupled plasma-optical emission spectroscopy. RESULTS: Selenium levels were significantly higher in patients than in controls (P = 0.03). Levels of trace elements did not correlate with the number or duration of warts. Toenail nickel levels in all subjects were higher than globally reported values. LIMITATIONS: A small sample size and the absence of regional reference ranges for concentrations of trace elements in toenails. CONCLUSION: Zinc does not seem to be involved in the chronicity of warts, and it is unclear if selenium has a protective role against warts. Our finding of high concentrations of nickel in both patients and controls raises concerns about environmental exposure.

Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.

Selenium, Selenoproteins, and Immunity.

Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The immune system relies on adequate dietary selenium intake and this nutrient exerts its biological effects mostly through its incorporation into selenoproteins. The selenoproteome contains 25 members in humans that exhibit a wide variety of functions. The development of high-throughput omic approaches and novel bioinformatics tools has led to new insights regarding the effects of selenium and selenoproteins in human immuno-biology. Equally important are the innovative experimental systems that have emerged to interrogate molecular mechanisms underlying those effects. This review presents a summary of the current understanding of the role of selenium and selenoproteins in regulating immune cell functions and how dysregulation of these processes may lead to inflammation or immune-related diseases.

Modulation of urinary siderophores by the diet, gut microbiota and inflammation in mice.

Mammalian siderophores are believed to play a critical role in maintaining iron homeostasis. However, the properties and functions of mammalian siderophores have not been fully clarified. In this study, we have employed Chrome Azurol S (CAS) assay which is a well-established method for bacterial siderophores study, to detect and quantify mammalian siderophores in urine samples. Our study demonstrates that siderophores in urine can be altered by diet, gut microbiota and inflammation. C57BL/6 mice, fed on plant-based chow diets which contain numerous phytochemicals, have more siderophores in the urine compared to those fed on purified diets. Urinary siderophores were up-regulated in iron overload conditions, but not altered by other tested nutrients status. Further, germ-free mice displayed 50% reduced urinary siderophores, in comparison to conventional mice, indicating microbiota biotransformation is critical in generating or stimulating host metabolism to create more siderophores. Altered urinary siderophores levels during inflammation suggest that host health conditions influence systemic siderophores level. This is the first report to measure urinary siderophores as a whole, describing how siderophores levels are modulated under different physiological conditions. We believe that our study opens up a new field in mammalian siderophores research and the technique we used in a novel manner has the potential to be applied to clinical purpose.

Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut.

Selenium is an essential micronutrient that is incorporated into at least 25 selenoproteins encoded by the human genome, many of which serve antioxidant functions. Because patients with inflammatory bowel disease (IBD) demonstrate nutritional deficiencies and are at increased risk for colon cancer due to heightened inflammation and oxidative stress, selenoprotein dysfunction may contribute to disease progression. Over the years, numerous studies have analyzed the effects of selenoprotein loss and shown that they are important mediators of intestinal inflammation and carcinogenesis. In particular, recent work has focused on the role of selenoprotein P (SEPP1), a major selenium transport protein which also has endogenous antioxidant function. These experiments determined SEPP1 loss altered immune and epithelial cellular function in a murine model of colitis-associated carcinoma. Here, we discuss the current knowledge of SEPP1 and selenoprotein function in the setting of IBD, colitis, and inflammatory tumorigenesis.

Selenium Deficiency Attenuates Chicken Duodenal Mucosal Immunity via Activation of the NF-κb Signaling Pathway.

Selenium (Se) deficiency can cause intestinal mucosal inflammation, which is related to activation of nuclear transcription factor kappa-B (NF-κB) signaling pathway. However, the mechanism of inflammatory response in chicken duodenal mucosa caused by Se deficiency and its relationship with the NF-κB signaling pathway remain elusive. In this study, we firstly obtained Se-deficient chickens bred with 0.01 mg/kg Se and the normal chickens bred with 0.4 mg/kg Se for 35 days. Then, NF-κB signaling pathway, secretory immunoglobulin A (SIgA), inflammatory cytokines, oxidized glutathione, glutathione peroxidase, and glutathione activities were determined. The results showed that Se deficiency obviously enhanced p50, p65, and p65 DNA-binding activities. The phosphorylation of IκB-α and phosphorylation of kappa-B kinase subunit alpha (IKKα) and IKKα were elevated, but IκB-α was decreased (P < 0.05). Moreover, Se deficiency reduced SIgA amount in the duodenal mucosa but increased the level of interleukin-1ß (IL-1ß), IL-17A, tumor necrosis factor-α (TNF-α), and interferon gamma (IFN-γ). In contrast, anti-inflammatory cytokines, such as TGF-ß1 and IL-10, were significantly suppressed. Additionally, Se deficiency increased oxidized glutathione activity, whereas decreased glutathione peroxidase and glutathione activities (P < 0.05), suggesting that Se deficiency affected the regulation function of redox. Taken together, our results demonstrated that Se deficiency attenuated chicken duodenal mucosal immunity via activation of NF-κB signaling pathway regulated by redox activity, which suggested that Se is a crucial host factor involved in regulating inflammation.

Critical Thresholds of Antioxidant and Immune Function Parameters for Se deficiency Prediction in Dairy Cows.

The aim of this study was to determine the plasma selenium (Se) levels of lactating cows and to evaluate its association with antioxidant ability and immune function. In a descriptive study, 20 healthy Holstein cows with normal Se level (C) and 30 Holstein cows with subclinical Se deficiency (T) were randomly selected between 14 and 21 days postpartum from a dairy farm, according to a cutoff point of 70 mg/L Se in plasma. Analysis of biochemical parameters of antioxidant and immune function were performed on all the cows, and the risk prediction thresholds for subclinical Se deficiency were determined by area under receiver operating characteristic curve. Cows in the T group had significantly lower plasma Se concentrations compared with cows in the C group (52.16 ± 8.81 vs. 80.37 ± 8.46 µg/L, P = 0.02). There was a marked decrease in plasma glutathione peroxidase (GSH-Px) activity in the T group that correlated positively with the plasma Se level (R = 0.65, P = 0.00), and a significant increase of plasma methane dicarboxylic aldehyde (MDA), total nitric oxide synthase, and lipid peroxidation that correlated negatively with plasma Se levels (R = -0.47, P = 0.01; R = -0.33, P = 0.04; R = -0.40, P = 0.03). Furthermore, there were significantly lower plasma tumor necrosis factor-α and immunoglobulin G levels in the T group that correlated positively with plasma Se levels (R = 0.41, P = 0.01 and R = 0.45, P = 0.01), and a markedly lower plasma interleukin-6 level that correlated negatively with plasma Se levels (R = -0.38, P = 0.02). In addition, if plasma GSH-Px activity was less than 42.37 U/ml, the risk of Se deficiency was significantly increased in lactating cows. These results suggest that low plasma Se levels may reduce the antioxidant ability and immune function, and the risk of low plasma Se level may be predicted effectively by plasma GSH-Px activity in lactating cows.

Selenium and inflammatory bowel disease.

Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-κB and peroxisome proliferator-activated receptor-γ. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD.

Selenium and selenoproteins in inflammatory bowel diseases and experimental colitis.

Inadequate dietary intake of the essential trace element selenium (Se) is thought to be a risk factor for several chronic diseases associated with oxidative stress and inflammation. Biological actions of Se occur through low-molecular weight metabolites and through selenoproteins. Several key selenoproteins including glutathione peroxidases; selenoproteins M, P, and S; and selenium-binding protein 1 have been detected in the intestine. Interestingly, Se and antioxidant selenoproteins are known to modulate differentiation and function of immune cells and contribute to avoid excessive immune responses. This review discusses the role of Se and intestinal selenoproteins in inflammatory bowel diseases, based on data from human, animal, and in vitro studies. In humans, Se deficiency is commonly observed in patients with Crohn's disease. In animal models of experimental colitis, the Se status was negatively correlated with the severity of the disease. While the cause-effect relationship of these observations remains to be clarified, the beneficial outcome of dietary Se supplementation and an optimization of selenoprotein biosynthesis in murine inflammatory bowel disease models have led to investigations of targets and actions of Se in the gastrointestinal tract. The Se status affects gene expression, signaling pathways, and cellular functions in the small and large intestine as well as the gut microbiome composition. This data, particularly from animal experiments, hold promise that adequate dietary Se supply may counteract chronic intestinal inflammation in humans.

The immunostimulatory effect of biogenic selenium nanoparticles on the 4T1 breast cancer model: an in vivo study.

Selenium salts as well as elemental selenium nanoparticles are attracting the attention of researchers due to their excellent biological properties. The aim of the present work was to study immunomodulation by applying elemental Se NPs to stimulate the immune response of mice bearing 4 T1 breast cancer tumors. Six- to 8-week-old female inbred BALB/c mice were divided into two groups of test and control, each containing 15 mice. Every day, for 2 weeks prior to tumor induction, selenium nanoparticles were orally administered to the mice at a dose of 100 µg/day. Then, 1 × 10(6) cells from a 4 T1 cell line were injected subcutaneously to each mouse. Oral nanoparticle administration was continued daily for 3 weeks after tumor induction. Different immunological parameters were then evaluated including cytokine level, delayed type hypersensitivity (DTH) response as well as tumor growth and the survival rates in all treated or nontreated animals. The production of Th1 cytokines, such as IFN-γ and IL-12, in spleen cell culture was increased in the test mice-administered selenium nanoparticles. The DTH response of test mice also showed a significant increase when compared to the control mice. The survival rate was notably higher for the selenium nanoparticle-treated mice compared to the control mice. Our results suggest that selenium nanoparticle administration can result in considerable induction of the Th1 platform of immune response through the elevation of IFN-γ and IL-12 and may be a cause for better prognosis in mice with tumors.

Effects of selenium source on measures of selenium status and immune function in horses.

The effects of selenium (Se) supplementation and source on equine immune function have not been extensively studied. This study examined the effects of oral Se supplementation and Se source on aspects of innate and adaptive immunity in horses. Fifteen horses were assigned to 1 of 3 groups (5 horses/group): control, inorganic Se (sodium selenite), organic Se (Se yeast). Immune function tests performed included: lymphocyte proliferation in response to mitogen concanavalin A, neutrophil phagocytosis, antibody production after rabies vaccination, relative cytokine gene expression in stimulated lymphocytes [interferon gamma (IFNγ), interleukin (IL)-2, IL-5, IL-10, tumor necrosis factor alpha (TNFα)], and neutrophils (IL-1, IL-6, IL-8, IL-12, TNFα). Plasma, red blood cell Se, and blood glutathione peroxidase activity were measured. Plasma and red blood cell Se were highest in horses in the organic Se group, compared with that of inorganic Se or control groups. Organic Se supplementation increased the relative lymphocyte expression of IL-5, compared with inorganic Se or no Se. Selenium supplementation increased relative neutrophil expression of IL-1 and IL-8. Other measures of immune function were unaffected. Dietary Se content and source appear to influence immune function in horses, including alterations in lymphocyte expression of IL-5, and neutrophil expression of IL-1 and IL-8.

Les effets d'un supplément de sélénium (Se) ainsi que sa source sur la fonction immunitaire équine n'ont pas été étudiés à fond. On examina dans la présente étude les effets d'un supplément oral en Se et les sources de Se sur des éléments de l'immunité innée et adaptative de chevaux. Quinze chevaux ont été assignés à un de trois groupes (5 chevaux/groupe); témoin, Se inorganique (sélénite de sodium), et Se organique (Se provenant de levures). Les tests de fonctions immunitaires effectués étaient : prolifération lymphocytaire en réponse au mitogène concanaviline A, phagocytose par les neutrophiles, production d'anticorps après vaccination anti-rabique, expression relative des gènes des cytokines de lymphocytes stimulés [interferon gamma (IFNγ), interleukine (IL)-2, IL-5, IL-10, facteur de nécrose tumorale alpha (TNFα)], et de neutrophiles (IL-1, IL-6, IL-8, IL-12, TNFα). Le Se plasmatique et des globules rouges, ainsi que l'activité de la glutathion peroxydase ont été mesurés. Le Se plasmatique et des globules rouges étaient plus élevés chez les chevaux dans le groupe de Se organique, comparativement au groupe recevant le Se inorganique ou le groupe témoin. Un supplément de Se organique entraîna une augmentation d'expression relative d'IL-5 par les lymphocytes, comparativement au Se inorganique ou aucun Se. Un supplément de Se augmenta l'expression relative d'IL-1 et IL-8 par les neutrophiles. Les autres mesures des fonctions immunitaires n'étaient pas affectées. Le contenu et les sources de Se alimentaire semblent influencer les fonctions immunitaires des chevaux, incluant des altérations dans l'expression d'IL-5 par les lymphocytes, et l'expression d'IL-1 et IL-8 par les neutrophiles.(Traduit par Docteur Serge Messier).

Influência do estado nutricional de selênio sobre a progressão da infecção pelo HIV / Influence of selenium nutritional status on the progression of HIV infection

Infection by the human immunodeficiency virus (HIV) is a public health problem of global scale, the nutritional status of infected individual shaving a great influence on the progression of HIV infection. In this context, the mineral selenium seems to play an important role. Therefore, this study aimed to discuss the influence of selenium status on HIV infection progression from a literature review. It was found that, among many approaches, in vivo and in vitro studies showed that seleniummay cause changes in health status of HIV patients, as well as suppress virus replication, respectively. However, the results of several studies are contradictory. Thus, we conclude that it is extremely important to develop further studies aiming to elucidate the way in which the effects of selenium can be achieved by improving the diet therapy of patients with HIV.

La infección por el virus de la inmuno deficiencia humana (VIH) es un problema de salud pública de escala global, siendo que el estado nutricional de los individuos infectados por elvirus tiene gran influencia en el desarrollo de la enfermedad. En este contexto, el mineral selenio parece desempeñar un papel destacado. Por lotanto, este estudio tuvo por objetivo discutir la influencia del estado nutricional de selenio en el avance de la infección por el VIH por medio de una revisión de la literatura. Se encontró que, diversos estudios, "in vivo" e "in vitro" muestran que el micronutriente puede ejercer modificaciones en la salud de los portadores de VIH, bien como suprimir la replicación del virus, respectivamente. Pero, los resultados de los estudios muestran contradicciones. Portanto, es importante la realización de más investigación destinada a aclarar la influencia del selenio en la evolución de los pacientes con VIH, lo cual podría ayudar a mejorar el tratamiento dietoterápico de los portadores.

A infecção pelo vírus da imunodeficiência humana (HIV) é um problema de saúde pública de escala global, sendo que o estado nutricional dos indivíduos infectados pelo vírus exerce grande influência na progressão da infecção pelo HIV. Nesse contexto, o mineral selênio parece desempenhar papel de destaque. Com isso, este trabalho teve como objetivo discutir a influência do estado nutricional de selênio sobre a progressão da infecção pelo HIV a partir de revisão da literatura. Verificou-se que, entre muitas abordagens, estudos in vivo e in vitro mostraram que o micronutriente pode exercer modificações no estado de saúde de portadores do HIV, bem como suprimir a replicação do vírus, respectivamente. Porém, os resultados de vários trabalhos se mostram contraditórios. Assim, conclui-se que é de extrema necessidade a realização de mais estudos com o objetivo de elucidar a forma pela qual os efeitos do uso de selênio podem ser alcançados, aprimorando o tratamento dietoterápico dos pacientes portadores do HIV.

The pathogenicity of an enteric Citrobacter rodentium Infection is enhanced by deficiencies in the antioxidants selenium and vitamin E.

The pathogenesis of a Citrobacter rodentium infection was evaluated in mice fed diets with a single deficiency in either selenium or vitamin E or with a double deficiency in both selenium and vitamin E compared to mice on nutritionally adequate diets. Mice fed the selenium- and vitamin E-deficient diet for 6 weeks had increased loads of C. rodentium in the colon and spleen, which were not observed in mice fed either of the singly deficient diets or the adequate diet. Infected mice fed the doubly deficient diet had increased colon crypt hyperplasia and an influx of infiltrating cells along with gross changes to crypt architecture, including ulceration and denuding of the epithelial layer. Cytokine and chemokine mRNA levels in the colon were measured by real-time PCR. Expression of proinflammatory cytokines and chemokines was upregulated on day 12 after infection with C. rodentium in mice fed the doubly deficient diet compared to mice fed the control diet. Heme oxygenase 1, an enzyme upregulated by oxidative stress, also was more highly induced in infected mice fed the doubly deficient diet. Production of C. rodentium antigen-specific IgM and IgG antibodies was not affected by feeding the doubly deficient diet. The results indicated that selenium and vitamin E play an important role in host resistance and in the pathology induced by C. rodentium, an infection that mimics disease caused by common food-borne bacterial pathogens in humans.

Role of selenium-containing proteins in T-cell and macrophage function.

Selenium (Se) has been known for many years to have played a role in boosting the immune function, but the manner in which this element acts at the molecular level in host defence and inflammatory diseases is poorly understood. To elucidate the role of Se-containing proteins in the immune function, we knocked out the expression of this protein class in T-cells or macrophages of mice by targeting the removal of the selenocysteine tRNA gene using loxP-Cre technology. Mice with selenoprotein-less T-cells manifested reduced pools of mature and functional T-cells in lymphoid tissues and an impairment in T-cell-dependent antibody responses. Furthermore, selenoprotein deficiency in T-cells led to an inability of these cells to suppress reactive oxygen species production, which in turn affected their ability to proliferate in response to T-cell receptor stimulation. Selenoprotein-less macrophages, on the other hand, manifested mostly normal inflammatory responses, but this deficiency resulted in an altered regulation in extracellular matrix-related gene expression and a diminished migration of macrophages in a protein gel matrix. These observations provided novel insights into the role of selenoproteins in the immune function and tissue homeostasis.

Molecular cloning, characterization and mRNA expression of selenium-binding protein in abalone (Haliotis discus hannai Ino): Response to dietary selenium, iron and zinc.

Selenium-binding protein (SEBP) is believed to play crucial role in controlling the oxidation/reduction in the physiological processes. In this study, the cDNA of selenium-binding protein from abalone Haliotis discus hannai Ino (HdhSEBP) was cloned by homology cloning and rapid amplification of cDNA ends (RACE) technique. The full length of HdhSEBP cDNA was 2071 bp, consisting of a 5' untranslated region (UTR) of 55 bp, a 3' UTR of 522 bp, and an open reading frame (ORF) of 1494 bp. The deduced protein has 497 amino acid residues with a calculated molecular mass of 55.6 kDa and a predicted isoelectric point of 5.47. BLAST analysis reveals that HdhSEBP shares high identities with other known SEBPs from mammal, bird, fish and mollusk, etc. The mRNA expression patterns of HdhSEBP in hepatopancreas and haemocytes were measured by real-time PCR in abalone fed with nine different diets containing graded levels of selenium (0, 1 and 50 mg kg(-1)), iron (0, 65 and 1300 mg kg(-1)) and zinc (0, 35 and 700 mg kg(-1)) for 20 weeks, respectively. The results showed that the expression of the HdhSEBP mRNA increased and reached the maximum at optimal dietary selenium (1 mg kg(-1)), iron (65 mg kg(-1)) and zinc (35 mg kg(-1)), respectively. Deficient or excessive level of dietary selenium, iron or zinc, respectively, leaded to significant depression of HdhSEBP mRNA. It is concluded that the expression levels of HdhSEBP are affected by dietary selenium, iron or zinc.

Modulatory effects of selenium and zinc on the immune system.

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, and both insufficient and excessive intakes can have negative consequences on the immune status and susceptibility to a variety of pathogens. We summarize the evidence for the importance of two micronutrients, selenium and zinc, and describe the mechanisms through which they affect the immune status and other physiological functions. As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes and some other immune mechanisms. Elevated selenium intake may be associated with reduced cancer risk and may alleviate other pathological conditions including oxidative stress and inflammation. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases. Zinc is required as a catalytic, structural and regulatory ion for enzymes, proteins and transcription factors, and is thus a key trace element in many homeostatic mechanisms of the body, including immune responses. Low zinc ion bioavailability results in limited immunoresistance to infection in aging. Physiological supplementation of zinc for 1-2 months restores immune responses, reduces the incidence of infections and prolongs survival. However, in every single individual zinc supplementation of food should be adjusted to the particular zinc status in views of the great variability in habitat conditions, health status and dietary requirements.

The importance of selenium to human health.

The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.

Effect of dietary vitamin E and selenium deficiency on chicken splenocyte proliferation and cell surface marker expression.

Beginning at hatching, chicks were fed a Basal diet, without vitamin E or selenium (Se) or the same diet supplemented with vitamin E (100 IU/kg) and Se (0.2 ppm). The effect of these treatments on the expression of cell surface markers (CT-1a, CD3, CD4, CD8, sIgs, and Ia) defining specific thymocyte and peripheral blood leukocyte (PBL) subpopulations were examined using flow cytometric analyses. In parallel studies the effect of the dietary deficiencies on splenocyte proliferative responses to ConA or PHA stimulation was examined. The mean expression of CD3 and CT-1a per cell was increased while CD8 and CD4 expression was decreased on thymocytes from chicks fed the Basal diet. The proportion of double negative (CD4-, CD8-) thymocytes and single positive CD8+ thymocytes was significantly decreased while single positive CD4+ and double positive (CD4+, CD8+) thymocytes were significantly increased by the dietary vitamin E and Se deficiencies. The dietary deficiencies resulted in a decreased proportion of peripheral T cells and specifically decreased the number of CD4+ PBL. The proliferative response to both ConA and PHA was impaired by the vitamin E and Se dietary deficiencies. The proliferative response could be fully reconstituted but only after vitamin E and Se supplementation for periods longer than 1 week. Plasma SeGSHpx and alpha-tocopherol levels paralleled the mitogen responsiveness observed. These results support the conclusion that vitamin E and Se deficiencies may affect both the maturation of specific lymphocyte subpopulations and the functional and proliferative capabilities of the peripheral lymphocytes.

In vitro OKT3-induced mitogenesis in selenium-deficient patients on a diet for phenylketonuria.

Patients with phenylketonuria (PKU) are frequently deficient in the essential trace element selenium (Se), because of their very low protein diet. Using two approaches to investigate T-cell response to proliferative signaling, viz, mitogenesis caused by the monoclonal antibody OKT3 and the plant lectin phytohaemagglutinin (PHA), we demonstrated significantly reduced responses to optimal concentrations of OKT3 in a group of PKU patients with reduced serum Se compared with a normal group (p = 0.0005) and with a group of PKU patients whose serum Se was normal (p = 0.0023). The response of the Se-deficient group to optimal levels of PHA did not differ from that of the normal controls or from that of Se-normal PKU patients. A dose-dependent relationship between serum Se levels and mitogenic response was evident for OKT3 (r = 0.34, p = 0.0154), but not for PHA (r = -0.02, p = 0.9086). We suggest that the reduced response to OKT3 mitogenesis in Se-deficient PKU patients is possibly the consequence of impaired Se-dependent metabolic activity, which affects mitogenic signaling via the T cell antigen receptor (TCR/CD3) complex.