Vitamin A deficiency exacerbates extrinsic atopic dermatitis development by potentiating type 2 helper T cell-type inflammation and mast cell activation.

BACKGROUND: Vitamin A deficiency (VAD) has been hypothesized to play a role in the pathophysiology of atopic dermatitis (AD). OBJECTIVE: We sought to verify whether VAD can exacerbate AD development, and explore the possible pathophysiologic mechanism. METHODS: We detected serum vitamin A (VA) concentration in different phenotypes of AD infants (intrinsic AD, iAD and extrinsic AD, eAD), and established ovalbumin (OVA) percutaneous sensitized AD model and passive cutaneous anaphylaxis (PCA) model on VAD and vitamin A supplementation (VAS) model in wild-type mice (C57BL/6) and established AD model on both normal VA (VAN) and VAD feeding mast cell deficiency mice (ckitw-sh/w-sh ). RESULTS: The average serum VA concentration of eAD was significantly lower than that of iAD, as well as healthy controls. In OVA-induced C57BL/6 mouse AD model, compared with VAN group, VAD mice manifested significantly more mast cells accumulation in the skin lesions, more severe Th2-mediated inflammation, including higher serum IgG1 and IgE levels, more IL-4, IL-13 mRNA expression in OVA-sensitized skin, and lower Th1 immune response, including lower serum IgG2a and IFN-γ mRNA expression in the skin. But there was no significant difference in the expression of IL-17 mRNA between OVA-treated skin of VAN and VAD mice. However, in OVA-induced ckitw-sh/w-sh mouse AD model, we did not find any significant differences in the above measurements between VAD and VAN group. In PCA model, VAD mice showed remarkable more blue dye leakage than that in VAN mice. Compared with VAD group, the above-mentioned inflammatory measurements in VAS group and VAN group were similar in OVA-induced AD model mice. CONCLUSIONS AND CLINICAL RELEVANCE: VAD can exacerbate extrinsic AD by augmenting Th2-mediated inflammation and mast cell activation. Therapeutic VAS can rescue VAD-aggravated eAD. It may provide a new strategy for future prevention or treatment of atopic dermatitis.

An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice.

Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration.

Alpha-tocopherol transfer protein gene inhibition enhances the acquired immune response during malaria infection in mice.

Immune response to malaria infection is complex and seems to be regulated by innate and adaptive immune response as well as environmental factors such as host genetics and nutritional status. Previously, we have reported that α-tocopherol transfer protein knockout (α-ttp(Δ)) mice, showing low concentrations of α-tocopherol in circulation, infected with Plasmodium berghei NK65 survived significantly longer as compared with the wild-type mice. In addition, Plasmodium yoelii XL-17, a lethal strain, showed non-lethal virulence in α-ttp(Δ) mice. Thus, we hypothesized that the ability of the α-ttp(Δ) mice to control P. yoelli XL-17 proliferation may allow them to build an efficient immune response against murine malaria infection. On 15 days after infection with P. yoelli XL-17, α-ttp(Δ) mice were challenged to infection with P. berghei NK65. Results indicated that α-ttp(Δ) mice infected with P. yoelli XL-17 built a protective immunity against P. berghei NK65 associated to extremely low levels of parasitemia, a controlled inflammatory response, and a robust antibody response. Moreover, the importance of α-tocopherol for parasite proliferation was remarkable. The results suggest that inhibition of α-tocopherol transfer protein activity is effective for the enhancement of acquired immunity in murine malaria infection.

Vitamin E deficiency in developing countries.

In addition to its role as a potent antioxidant, vitamin E is involved in a wide range of physiological processes, ranging from immune function and control of inflammation to regulation of gene expression and cognitive performance. Results from multiple studies suggest that poor nutritional status and higher prevalence of other oxidative stressors such as malaria and HIV infection predispose populations in developing countries for vitamin E deficiency. Although direct comparison between study outcomes is complicated by varied definitions of vitamin E deficiency, data trends indicate that children and the elderly are more vulnerable age groups and that men may be at higher risk for deficiency than women. Public health initiatives aimed at improving the vitamin E status of high-risk populations in developing countries would be prudent to counteract oxidative stress, improve immune function, and protect against neurologic and cognitive deficits. Additional research is needed to establish dose-response relationships of various interventions and to develop cost-effective, culturally-appropriate, and targeted programs.

Vitamin E and immunity.

Vitamin E is the most important chain-breaking, lipid-soluble antioxidant present in body tissues of all cells and is considered the first line of defense against lipid peroxidation and it is important for normal function of the immune cells. However, vitamin E deficiency is rare in well-nourished healthy subjects and is not a problem, even among people living on relatively poor diets, both T- and B-cell functions are impaired by vitamin E deficiency. While immune cells are particularly enriched in vitamin E because of their high polyunsaturated fatty acid content, this point puts them at especially high risk for oxidative damage. Besides its immunomodulatory effects, vitamin E also plays an important role in carcinogenesis with its antioxidant properties against cancer, and ischemic heart disease with limiting the progression of atherosclerosis. Supplementation of vitamin E significantly enhances both cell mediated and humoral immune functions in humans, especially in the elderly and animals.

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.

The effect of alpha-tocopherol transfer protein gene disruption on Trypanosoma congolense infection in mice.

At present 15 to 20 million people are estimated to be infected with pathogenic trypanosome parasites worldwide, mainly in developing countries. There are a number of factors that affect the severity of trypanosomiasis, including the nutritional status of the host. However, the relationship between micronutrient levels and trypanosomiasis outcome has yet to be reported in detail. Here, we demonstrate that the inhibition of alpha-tocopherol transfer protein, a determinant of the vitamin E concentration in host circulation, confers resistance to Trypanosoma congolense infection, evidently owing to oxidative damage to parasite DNA. These results suggest that transient inhibition of alpha-tocopherol transfer gene activity could possibly be exploited as a strategy for both the prevention and the treatment of trypanosomiasis.

The dendritic and T cell responses to herpes simplex virus-1 are modulated by dietary vitamin E.

Previous studies from our laboratory have shown that dietary alpha-tocopherol (vitamin E, or VE) is essential for regulating the cytokine and chemokine response in the brain to herpes simplex virus-1 (HSV-1) infection. The timing of T cell infiltration is critical to the resolution of central nervous system HSV-1 infections. Specifically, the appearance of "neuroprotective" CD8(+)IFN-gamma(+) T cells is crucial. During CNS infection, CD8(+) T cell priming and expansion in the draining lymph node, followed by recruitment and expansion, occurs in the spleen with subsequent accumulation in the brain. Weanling male BALB/cByJ mice were placed on VE-deficient (Def) or -adequate diets for 4 weeks followed by intranasal infection with HSV-1. VE-Def mice had fewer CD8(+)IFN-gamma(+) T cells trafficking to the brain despite increased CD8(+)IFN-gamma(+) T cells and activated dendritic cells in the periphery. VE-Def mice had increased T regulatory cells (Tregs) in the periphery and brain, and the increase in Tregs decreased CD8(+) T cell numbers in the brain. Our results demonstrate that adequate levels of VE are important for trafficking antigen-specific T cells to the brain, and dietary VE levels modulate T regulatory and dendritic cells in the periphery.

Vitamin E deficiency enhances pulmonary inflammatory response and oxidative stress induced by single-walled carbon nanotubes in C57BL/6 mice.

Exposure of mice to single-walled carbon nanotubes (SWCNTs) induces an unusually robust pulmonary inflammatory response with an early onset of fibrosis, which is accompanied by oxidative stress and antioxidant depletion. The role of specific components of the antioxidant protective system, specifically vitamin E, the major lipid-soluble antioxidant, in the SWCNT-induced reactions has not been characterized. We used C57BL/6 mice, maintained on vitamin E-sufficient or vitamin E-deficient diets, to explore and compare the pulmonary inflammatory reactions to aspired SWCNTs. The vitamin E-deficient diet caused a 90-fold depletion of alpha-tocopherol in the lung tissue and resulted in a significant decline of other antioxidants (GSH, ascorbate) as well as accumulation of lipid peroxidation products. A greater decrease of pulmonary antioxidants was detected in SWCNT-treated vitamin E-deficient mice as compared to controls. Lowered levels of antioxidants in vitamin E-deficient mice were associated with a higher sensitivity to SWCNT-induced acute inflammation (total number of inflammatory cells, number of polymorphonuclear leukocytes, released LDH, total protein content and levels of pro-inflammatory cytokines, TNF-alpha and IL-6) and enhanced profibrotic responses (elevation of TGF-beta and collagen deposition). Exposure to SWCNTs markedly shifted the ratio of cleaved to full-length extracellular superoxide dismutase (EC-SOD). Given that pulmonary levels of vitamin E can be manipulated through diet, its effects on SWCNT-induced inflammation may be of practical importance in optimizing protective strategies.

Deficiencies in selenium and/or vitamin E lower the resistance of mice to Heligmosomoides polygyrus infections.

Previous studies have shown that deficiencies in selenium (Se) and/or vitamin E (VE) can exacerbate the infectivity and pathogenesis of coxsackievirus B3 and influenza. Both Se and VE play a role in immune function and antioxidant defense. To determine whether these deficiencies would affect the normal course of infection with a metazoan parasite, mice were made deficient in Se and/or VE and inoculated with the gastrointestinal nematode parasite Heligmosomoides polygyrus. Both primary and secondary infections were assessed. Although the course of a primary infection with H. polygyrus was unaffected by diet, diets deficient in Se, VE, and both Se and VE (Se/VE double-deficiency) all caused delayed adult worm expulsion and increased fecundity during a secondary infection; suggesting an impaired intestinal response. H. polygyrus-induced IL-4 levels were diet-independent; but Se/VE double-deficiency blocked the H. polygyrus-induced IL-4 receptor-associated decrease in sodium-dependent glucose absorption in the jejunum that contributes to worm expulsion. In contrast, Se/VE double-deficiency had no effect on the infection-induced, IL-4R-associated increase in epithelial cell permeability that accompanies the infection. These results suggest that both Se and VE are required for specific IL-4-related changes in intestinal physiology that promote host protection against H. polygyrus.

Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency.

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae.

Immunological dysregulation of lung cells in response to vitamin E deficiency.

Vitamin E supplementation exhibits anti-inflammatory properties. In the lung, the beneficial effects of vitamin E supplementation on inflammation and infections are well documented, but potential consequences of alimentary vitamin E deficiency to the immunological status of lung cells are not known. It is unclear if temporary vitamin E deficiency exhibits deleterious consequences or can be compensated for by other cellular antioxidants. To address this question, the alimentary vitamin E supply to rats was modified. We then investigated the effects on major histocompatibility molecule (MHC) class II, cell adhesion molecules, interleukin (IL)10, tumor necrosis factor (TNF)alpha in various lung cells. The constitutive expression of MHC class II, intercellular adhesion molecule (ICAM)-1, L-selectin, alpha5-integrin, and CD 166, was demonstrated by flow cytometry on type II pneumocytes, alveolar macrophages, and on co-isolated lymphocytes. Vitamin E depletion increased ICAM-1 and CD166 on type II cells and macrophages, whereas the expression of L-selectin increased only on macrophages. Furthermore, the vitamin E depletion increased the cellular content and secretion of IL10 in type II cells, but decreased the content and secretion of TNFalpha. Vitamin E depletion decreased the cellular vitamin E content, but did not change the activity of antioxidant enzymes (catalase, superoxide dismutase) and the glutathion (GSH)/oxidized glutathion (GSSG) ratio in alveolar type II cells. The shift of protein kinase C (PKC) from the cytosol to membranes indicates that a PKC-dependent signaling pathway may be involved in the change of the immunological status of type II cells. All these effects were reversed by vitamin E repletion. In summary, these results are clearly compatible with the view that a temporary vitamin E deficiency induces a reversible immunological dysregulation in alveolar type II cells and lung macrophages. This deficiency might predispose the lung to develop acute or chronic inflammation.

Dietary vitamin E and rainbow trout (Oncorhynchus mykiss) phagocyte functions: effect on gut and on head kidney leucocytes.

The effects of vitamin E (deficiency or supplementation) on the non-specific immune system in rainbow trout, Oncorhynchus mykiss, were evaluated. Rainbow trout were fed daily a semi-purified diet supplemented with vitamin E at 0, 28 and 295 mg x kg(-1) of diet. After 80 days of experimental feeding, the phagocytic function (respiratory burst evaluated by the CL response, phagocytosis) from gut leucocytes and head kidney enriched macrophages was measured; head kidney cell pinocytosis and serum lysozyme activity were also analysed. The results showed that some phagocyte functions were influenced by dietary vitamin E. When fish were fed the high dietary dose of vitamin E an enhancement of phagocytosis was found, but only significantly for the leucocytes isolated from the gut of rainbow trout; moreover, an impaired response was also observed in the fish fed no vitamin E for 80 days. However, no significant differences were noticed on the oxidative burst (CL) response of both gut and head kidney cells according to the dietary dose of vitamin E. Pinocytosis evaluated on head kidney cells was not influenced by dietary vitamin E. Fish fed vitamin E at 295 mg x kg(-1) had a lower serum lysozyme activity than those fed with vitamin E at 28 mg x kg(-1) and the fish fed no vitamin E for 80 days had an impaired activity. Thus, the present results demonstrate that altered dietary levels of vitamin E modulates the phagocytic functions of gut leucocytes in rainbow trout; moreover, the vitamin E diet effect seems to be greater on the local intestinal response as compared to systemic (head kidney). Taken together, this study confirms the crucial role of gut phagocytes in mucosal non-lymphoid defences in fish.

Vitamin E and immunity.

Vitamin E is a potent antioxidant and has an ability to modulate host immune functions. This chapter consists of five parts: (1) vitamin E deficiency and immunity, (2) vitamin E supplementation and immunity, (3) vitamin E and the decreased cellular immunity with aging, (4) vitamin E and T-cell differentiation in the thymus, and (5) vitamin E and acquired immune deficiency syndrome (AIDS). In vitamin E deficiency most of the immune parameters show a downward trend, which is associated with increased infectious diseases and the incidence of tumors. In contrast, vitamin E supplementation has various beneficial effects on the host immune system. The decreased cellular immunity with aging or during the development of AIDS is markedly improved by the intake of a high vitamin E diet. In addition, vitamin E plays an important role in the differentiation of immature T cells in thymus. Vitamin E deficiency induces the decreased differentiation of immature T cells, which results in the early decrease of cellular immunity with aging in spontaneously hypertensive rats. Conversely, vitamin E supplementation induces a higher differentiation of immature T cells via increased positive selection by thymic epithelial cells, which results in the improvement of decreased cellular immunity in the aged. Furthermore, vitamin E supplementation induces the early recovery of thymic atrophy following X-ray irradiation. Taken together, these results suggest that vitamin E is an important nutrient for maintaining the immune system, especially in the aged.

Vitamin E-deficient diets enriched with fish oil suppress lethal Plasmodium yoelii infections in athymic and scid/bg mice.

Mice fed vitamin E-deficient diets containing omega-3 fatty acids survive infection with lethal Plasmodium yoelii. The current study sought to determine if antimalarial T- and B-cell responses were required for such dietary-mediated protection. In the first set of experiments, nu/nu mice (which lack alphabeta T-cell-receptor-positive T cells and do not produce antimalarial antibody) and nu/+ mice were fed casein-based diets containing 4% menhaden oil, with or without vitamin E supplementation, for 4 weeks prior to infection with lethal P. yoelii. All mice fed diets containing vitamin E developed fulminating parasitemias and quickly died, whereas both nu/nu and nu/+ mice fed diets deficient in vitamin E controlled their parasitemias for the first 18 days of infection. Thereafter, the nu/nu mice became anemic and died, whereas the nu/+ mice produced antimalarial antibodies and survived. In the second set of experiments, scid/scid.bg/bg mice (which lack B cells and alphabeta and gammadelta T cells and have reduced NK-cell activity) were fed the experimental diet for 6 weeks and then infected with the less virulent 17XNL strain of P. yoelii. Mice fed vitamin E-containing diets quickly died, whereas those fed the vitamin E-deficient diet survived without developing detectable parasitemias. Results from these experiments show that under prooxidant dietary conditions, mice were able to control and even survive malaria in the absence of malaria-primed T cells and antimalarial antibody. These results emphasize the importance of cellular oxidative processes in parasite elimination.

Vitamin E status and immune function.

Evidence from animal and human studies indicates that vitamin E plays an important role in the maintenance of the immune system. Even a marginal vitamin E deficiency impairs the immune response, while supplementation with higher than recommended dietary levels of vitamin E enhances humoral and cell-mediated immunity. The current RDA level of vitamin E prevents clinical deficiency syndrome but in some situations, especially in older subjects or in a disease state, fails to maintain optimal host defense. The immunological parameters reviewed are all sensitive to changes in the availability of vitamin E and, therefore, may reflect the vitamin E status of a given individual more accurately than conventional methods.