Vitamin A modulates many different aspects of immune function, both nonspecific (innate) immunity (i.e., maintenance of mucosal surfaces, natural killer (NK) cell activity, and phagocytosis) and specific (adaptive) immunity (i.e., generation of antibody responses). Some aspects of immunity are not affected by vitamin A deficiency. Much of our knowledge of vitamin A and immune function is based on experimental animal studies involving mice, rats, and chickens, and from in vitro studies involving modulation of specific cell lines with retinoids. The effects of vitamin A deficiency on immune function are summarized in Table 4.
The mucosal surfaces of the body include the respiratory, gastrointestinal, and genitourinary tracts as well as the cornea and conjunctiva. There are at least seven known mechanisms by which vitamin A deficiency impairs mucosal immunity: (1) loss of cilia in the respiratory tract, (2) loss of microvilli in the gastointestinal tract, (3) loss of mucin and goblet cells in the respiratory, gastrointestinal, and genitourinary tracts, (4) squamous metaplasia with abnormal keratinization in the respiratory tract, (5) alterations in antigen-specific secretory immunoglobulin (Ig)A concentrations, (6) impairment of alveolar monocyte/macrophage function, and (7) decreased integrity of the gut. In early studies of vitamin A deficiency in autopsy studies of humans and experimental animals, the findings included widespread pathological alterations in the respiratory, gastrointestinal, and genitourinary tracts (87,368,369). During vitamin A deficiency, there is loss of mucin and goblet cells from the conjunctiva and squamous metaplasia of the conjunctiva and cornea (285,370) and impaired wound healing (298). Vitamin A is involved in the expression of both mucins (248,371) and keratins (249,372,373). Lactoferrin, an iron-binding glycoprotein involved in immunity to bacteria, viruses, and fungi, appears to be modulated in the tear film of children by vitamin A supplementation (374). Loss of mucin and alterations in keratins in vitamin A deficiency may increase susceptibility to experimental ocular infection with pathogens such as Herpes simplex virus (375) and Pseudomonas (299,300). Other corneal alterations in experimental vitamin A deficiency include structural abnormalities of the epithelial basement membrane complex (376).
In the respiratory tract, pathogens are constantly trapped and removed by the muco-ciliary elevator in the normal tracheobronchial tree. Vitamin A-deficient animals show loss of ciliated epithelial cells and mucus and replacement by stratified, keratinized epithelium (377-379). The terminal differentiation of keratins is modulated by vitamin A (380,381) and mucin gene expression is regulated by all-irans retinoic acid (382,383). Such broad pathological changes in the tracheobronchial tree may be reflected in the observation that vitamin A-deficient mice are more susceptible to ozone-induced lung inflammation (384).
Vitamin A deficiency is associated with morphological and function alterations in the gut that may predispose individuals to more severe diarrheal disease. Vitamin A deficiency in rats is associated with a large reduction in goblet cells in duodenal crypts (385) and impaired biliary secretion of total secretory IgA (386). Reduced villus height was observed in the jejunum of vitamin A-deficient rats that were not challenged with any gastrointestinal pathogens (387). Vitamin A-deficient mice were more susceptible to the destruction of duodenal villi following experimental challenge with rotavirus (388). The genitourinary tract is also adversely affected by vitamin A deficiency, with replacement of normal transitional epithelium with stratified squamous epithelium and expression of distinct types of keratins (389). Changes in the genitourinary epithelia may contribute to increased urinary tract infections in vitamin A-deficient children (390).
Vitamin A deficiency may affect both the concentrations of secretory IgA on mucosal surfaces and specific IgA responses in the gut. In vitamin A-deficient chickens, the concentrations of total IgA were lower in the gut than in control animals (391). Vitamin A-deficient BALB/c mice that were challenged with influenza A had a lower influenza-specific IgA response than control mice (392). Vitamin A-deficient mice had significantly lower serum antibody responses against epizootic diarrhea of infant mice (EDIM) rotavirus infection compared with pair-fed control mice (393). An impaired ability to respond with IgA antibodies to oral cholera vaccine was demonstrated in vitamin A-deficient rats (394). Vitamin A treatment prevented the decline in IgA in the intestinal mucosa of protein-malnourished mice (395). Recent studies in IL-5 receptor-knockout mice suggest that IL-5 may play an important role in vitamin A-induced modulation of mucosal IgA (396). In vitro studies with HT-29 cells, a human intestinal epithelial cell line, indicate that vitamin A may be involved in the regulation of polymeric immunoglobulin receptor by IL-4 and interferon-y (397). These data suggest that vitamin A is involved in regulation of IgA transport in response to mucosal infections. Human and animal studies suggest that vitamin A status may also influence gut integrity and healing. Using the urinary lac-tulose/mannitol excretion test, increased gut permeability was found in infants, and the gut integrity improved following vitamin A supplementation (398). Vitamin A-deficient rats had impaired healing of surgically-induced anastamoses of the colon compared with control rats (399).
NK cells play a role in antiviral and antitumor immunity that is not major histocompatibility complex (MHC)-restricted, and NK cells are involved in the regulation of immune responses. Vitamin A deficiency appears to reduce both the number and activity of NK cells. In experimental animal models, vitamin A deficiency reduced the number of NK cells in the spleen (400,401) and peripheral blood (402). The cytolytic activity of NK cells is reduced by vitamin A deficiency (401,402). In aging Lewis rats, marginal vitamin A status reduced the number of NK cells in peripheral blood and the cytolytic activity of NK cells (403). There have been few studies of vitamin A status and NK cells in humans. Children with AIDS who received two doses of oral vitamin A, 60 mg retinol equivalents (200,000 IU), had large increases in circulating NK cells compared with children who received placebo (404).
Neutrophils play an important role in nonspecific immunity because they phagocytize and kill bacteria, parasites, virus-infected cells, and tumor cells. The function of neutrophils appears to be impaired during vitamin A deficiency. Retinoic acid plays an important role in the normal maturation of neutrophils (405). Experimental animal studies show widespread defects in neutrophil function, including impaired chemotaxis, adhesion, phagocytosis, and ability to generate active oxidant molecules during vitamin A deficiency (406,407). In rats challenged with Staphylococcus aureus, impaired phagocytosis and decreased complement lysis activity were found in vitamin A-deficient rats compared with controls rats (408). Vitamin A treatment was shown to increase superoxide production by neutrophils from Holstein calves (409). During vitamin A deficiency, an increase in circulating neutrophils has been observed in some experimental animal studies (410), and this has been attributed in part to impaired apoptosis of myeloid cells (411). Vitamin A inhibited neutrophilic infiltration in rats undergoing induced lung granuloma formation, and histological evidence suggested that vitamin A suppressed the expression of nuclear factor-KB (412).
Vitamin A deficiency appears to impair hematopoiesis of some lineages, such as CD4+ lymphocytes, NK cells, and erythrocytes. In humans, clinical vitamin A deficiency has been characterized by lower total lymphocyte counts and decreased CD4+ lymphocytes in peripheral blood, and CD4+ lymphocyte counts or percentage increased after vitamin A supplementation (404,413). Vitamin A supplementation does not appear to have any long term effect on CD4+ or CD8+ lymphocyte subsets among infants without clinical vitamin A deficiency (414). In the vitamin A-deficient rat, lower NK cell, B-cell, and CD4+ lymphocyte counts were found in peripheral blood, and these counts responded to retinoic acid supplementation (411). Retinoids have been implicated in the maturation of pluripotent stem cells to cell lineages that produce different hematopoietic cell lines such as lymphocytes, granulocytes, and megakaryocytes. Retinoids also appear to play a role in the maturation of differentiation of pluripotent stem cells into multipotent (colony-forming unit granulocyte erythroid macrophage mixed [CFU-GEMM]) cells, and differentiation and commitment of CFU-GEMM into erythroid burst-forming units (BFU-E) and then into erythroid colony-forming units (CFU-E) (415-417).
Macrophages are involved in the inflammatory response and in the phagocytosis of viruses, bacteria, protozoa, fungi, and tumor cells. Macrophages secrete a wide variety of cytokines, including tumor necrosis factor (TNF)-a, IL-1 P, IL-6, and IL-12. The effect of retinoids on monocyte differentiation has been studied in leukemic myelomonocytic cell lines such as HL-60, U-937, and THP-1 (418-420). Retinoids appear to influence both the number and activity of macrophages (421,422). Vitamin A-deficient animals may have increased numbers of macrophages in lymphoid tissues (423). In vitro studies suggest that all-trans retinoic acid decreases TNF-a production in a murine macrophage cell line (424) and regulates IL-1P expression by human monocytes (425) and human alveolar macrophages (425). All-trans retinoic acid inhibited IL-12 production in activated murine macrophages (427) and caused a twofold increase in phagocytosis in murine macrophages (428). Expression of IL-1 may be modified by retinoids in murine macrophages (428,429). In the rat model, vitamin A deficiency was associated with reduced phagocytic function of macrophages (408). In experimental Salmonella infection in the rat, vitamin A supplementation improved phagocytosis by macrophages (430).
Langerhan cells serve as antigen-presenting cells in the skin. Dietary vitamin A increases contact sensitivity to a variety of chemical agents in the murine model, and this observation may be related to vitamin A-related modulation of the numbers and function of Langerhans cells (431,432). Retinoic acid treatment in vivo increases the ability of human Langerhans cells to present alloantigens to T-lymphocytes and is associated with increases in surface expression of HLA-DR and CD11c, two molecules involved in antigen presentation (433).
Vitamin A deficiency may influence T-lymphocyte-related immunocompetence through such mechanisms as a decrease in numbers or distribution, changes in pheno-type, alterations in cytokine production, or decreased expression or function of cell surface molecules involved in T-cell signaling (434). There is some evidence that each of these mechanisms may play a role in the immunosuppression associated with vitamin A deficiency. The effects of vitamin A deficiency on lymphopoiesis were discussed previously in "Hematopoiesis." In preschool children with clinical and subclinical vitamin A deficiency in Indonesia, high-dose vitamin A supplementation was associated with an increase in the proportion of circulating CD4+CD45RA+, or "naive" CD4+ lymphocytes, suggesting that vitamin A influences lymphopoiesis (413). Activation of T-lymphocytes requires retinol (435). In human peripheral mononuclear cells, retinol is a cofactor in CD3-induced T-lymphocyte activation (436). All-trans retinoic acid has been shown to increase antigen-specific T-lymphocyte proliferation (437) and expression of IL-2 receptors (438). In a trial in Bangladesh, vitamin A supplementation improved responses to delayed type hypersensitivity skin testing among infants who were supplemented to higher vitamin A levels (439).
Vitamin A appears to modulate the balance between T-helper type 1-like responses and T-helper type 2-like responses in experimental animal studies, and this has been the prevailing paradigm for the last decade, as reviewed in detail elsewhere (440). According to this model, vitamin A deficiency causes a shift toward T-helper 1-like responses, whereas vitamin A supplementation causes a shift toward T-helper 2-like responses. There is little evidence to support this model for human vitamin A deficiency, and in fact, clinical observations are not consistent with this model. Vitamin A supplementation enhances immunity to a wide variety of infections such as tuberculosis, measles, malaria, HIV infection, and diarrheal diseases, in which the specific immune-protective immune responses have been characterized as either T-helper 1-like or T-helper 2-like responses.
In mice, Trichinella spiralis infection usually stimulates a strong T-helper type 2-like responses, characterized by strong parasite-specific IgG responses and a cytokine profile dominated by IL-4, IL-5, and IL-10 production. However, in vitamin A-deficient mice, infection by T. spiralis results in low production of parasite-specific IgG and a cytokine profile dominated by interferon (IFN)-y and IL-12 production (441-443). Lymphocyte stimulation to concanavalin A or P-lactoglobulin was higher and production of IL-2 and IFN-y was higher in lymphocyte supernatants from vitamin A-deficient rats compared with control rats, suggesting that vitamin A deficiency modulates a shift toward T-helper type 1-like responses in rats (444). Vitamin A appears to inhibit IFN-y, IL-2, and granulocyte/macrophage colony-stimulating factor (GM-CSF) by type 1 lymphocytes in vitro (445). The effect of high-level dietary vitamin A on the shift to T-helper type 2-like responses in BALB/c mice has been used to explain the apparent lack of benefit of vitamin A supplementation for acute lower respiratory infections in humans (446). The enhancement of T-helper type 2-like responses by vitamin A may be modulated via 9-cis retinoic acid and RXRs (447). Vitamin A-deficient mice show overproduction of IFN-y (448) and both retinol and retinoic acid appear to downregulate expression and transcription of IFN-Y (449,450). In a mouse model, vitamin A deficiency at the time of antigen exposure was associated with diminished development of T-helper 1 memory cells and increased development of IL-10-producing T-helper 2 cells (451).
Vitamin A deficiency impairs the growth, activation, and function of B-lymphocytes. Activated B-lymphocytes depend on retinol but not retinoic acid (452-454). B-lymphocytes have been shown to utilize a metabolite of retinol, 14-hydroxy-4,14-retro-retinol, instead of retinoic acid, as mediator for growth (241). The effects of retinol and all-trans retinoic acid on immunoglobulin synthesis B-lymphocytes has been examined in human cord blood and adult peripheral mononuclear cells (455-458). A T-cell-dependent antigen was used to induce differentiation of human B-lymphocytes into immunoglobulin-secreting cells, and all-trans retinoic acid increased the synthesis of IgM and IgG by these cells. Highly purified T-lymphocytes incubated with retinoic acid enhanced IgM synthesis by cord blood B-lymphocytes, suggesting that retinoic acid modulates T-cell help through cytokine production (458). Apoptosis in B-lymphocytes appears to be mediated via RAR (459). In common variable immunodeficiency, a B-cell deficiency syndrome characterized by defective antibody production, T-cell and monocyte dysfunction, and recurrent infections, vitamin A supplementation was associated with enhanced anti-CD40-stimulated IgG production, serum IgA concentrations, and lymphocyte proliferation to phytohemagglutinin (460).
The hallmark of vitamin A deficiency is an impaired capacity to generate an antibody response to T-cell-dependent antigens (444,461), including tetanus toxoid (462,463) and diphtheria antigens in humans (464), tetanus toxoid and other antigens in animal models (465-467), and T-cell-independent type 2 antigens such as pneumococcal polysaccharide (468). Antibody responses are involved in protective immunity to many types of infections and are the main basis for immunological protection for many vaccines. Depressed antibody responses to tetanus toxoid have been observed in vitamin A-deficient children (462) and in vitamin A-deficient animals (469,470). Vitamin A deficiency appears to impair the generation of primary antibody responses to tetanus toxoid, but if animals are repleted with vitamin A prior to a second immunization, the secondary antibody responses to tetanus toxoid are comparable to control animals (466). These findings suggest that formation of immunological memory and class switching are intact during vitamin A deficiency, despite an impaired IgM and IgG response to primary immunization. Human peripheral blood lymphocytes from subjects previously immunized against tetanus toxoid were used to reconstitute control and vitamin A-deficient mice with severe combined immunodeficiency. After challenge with tetanus toxoid, vitamin A-deficient severe combined immunodeficient (SCID) mice had a 2.9-fold increase in human anti-tetanus toxoid antibody compared with a 74-fold increase in control SCID mice (471). In healthy children without vitamin A deficiency, vitamin A supplementation did not enhance antibody responses to tetanus toxoid (472). These findings suggest that vitamin A supplementation is unlikely to enhance antibody responses in subjects who are not vitamin A-deficient. Other evidence that vitamin A is needed for the generation of antibody responses has been noted in retinol-binding protein knockout mice, where serum vitamin A concentrations are extremely low and associated with circulating Ig concentrations (473).
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