Keratomalacia

Introduction

Vitamin A and related retinoids play an important role in the regulation of immune function. Vitamin A deficiency compromises immunity, resulting in major morbidity and mortality. The link between clinical vitamin A deficiency (nightblindness and xerophthalmia) and infectious disease morbidity and mortality has been known for hundreds of years. Experimental observations and clinical trials in the 1920s and 30s led to the reputation of vitamin A as the "anti-infective" vitamin (Green and Mellanby 1928). By the 1960s, it was noted that among the micronutrients, "no nutritional deficiency is more consistently synergistic with infectious disease than that of vitamin A" (Scrimshaw et al. 1968). More recent community- and hospital-based clinical trials show that vitamin A supplementation reduces child mortality by 20-30% (Beaton et al. 1993). Vitamin A capsule distribution is recognized as one of the most cost-effective interventions to improve health (World Bank 1993) and ranks among vaccination and oral rehydration therapy in importance as a public health measure.

The underlying basis for the use of vitamin A supplementation to reduce infectious disease morbidity and mortality is its role in enhancing immunity. Vitamin A and related retinoids have therapeutic potential as immune modulators, and some of these uses are also beginning to be realized in the fields of dermatology and oncology. Over the last several decades, major progress has been made in elucidating the role of vitamin A and related retinoids in immune function. The discovery of retinoic acid receptors has greatly facilitated our understanding of how vitamin A may influence immune function at the genetic level. Improvements in analytical methods have led to the discovery of new natural metabolites of vitamin A and retinoic acid, which suggests immense complexity in the regulation of biologic responses by retinoids. The purpose of this review is to provide an overview of the different effects that vitamin A and related retinoids play in immune function, with an emphasis on developments in the last decade ITable 1). Comprehensive coverage of the earlier literature can be found in previous reviews (Nauss 1986, Ross 1992, Semba 1994a).

Retinoids and Nuclear Receptors

The widespread immunologic effects of vitamin A appear to be mediated primarily through its acid derivatives, which include all-trans retinoic acid and 9-cis retinoic acid (Chytil and Haq 1990, Pfahl and Chytil 1996, Napoli 1996). There are numerous other natural isomers of retinoic acid that have been identified and may help explain the pleiotropic effects of retinoids (Pfahl and Chytil 1996). Two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), consist of three isotypes (alpha, beta, gamma) and control gene expression by retinoid signals (Chambon 1996). The expression of RAR and RXR isotypes varies in different tissues, and vitamin A deficiency may selectively alter the expression of certain isotypes in various tissues (Haq et al. 1991). All-trans retinoic acid is a ligand for RARs, whereas 9-cis retinoic acid is a ligand for both RARs and RXRs.

RARs and RXRs form RXR/RAR heterodimers and bind to retinoic acid response elements (RAREs) of target genes. Most RAREs have been identified in the regulatory region of a variety of genes. RXR may also form heterodimers with the thyroid hormone receptor, vitamin D^sub 3^ receptor, peroxisome proliferator activator receptors, and a number of newly described "orphan receptors." In the presence of 9-cis retinoic acid, RXR/RXR homodimers may form and recognize a subset of RXREs or inhibit the formation of certain heterodimers (Pfahl and Chytil 1996). Orphan receptors such as chicken ovalbumin up-stream promoter transcription factor (COUP-TF) (Tran et al.1992), ARP-1, TAKI (Hirose et al.1995), RVR (Retnakaran et al. 1994), RZR (Carlberg et al.1994), and thymus orphan receptor (TOR) (Ortiz et al.1995) may repress or modulate the induction of genes by retinoic acid. Thus, RARs and RXRs may interact with multiple transcriptional mediators and/or corepressors, adding an enormous level of complexity to regulation of retinoic acid responses. Experiments with RAR-deficient, or "knock-out," mice suggest that there may be a great deal of functional redundancy involved in signaling (Kastner et al.1995). Other vitamin A metabolites in the retroretinoid family may support biologic functions via a pathway that is distinct from the retinoic acid pathway.14-Hydroxy-4,14-retro retinol supports, whereas anhydroretinol inhibits, cell growth (Buck et al. 1991, Buck et al. 1993, Eppinger et al. 1993). In addition, the oxoretinoids may play a role as retinoic acid receptor ligands (Blumberg et al. 1996).

Mucosal Immunity

Vitamin A deficiency compromises mucosal immunity by altering the integrity of mucosal epithelia, including those of the eye as well as the respiratory, gastrointestinal, and genitourinary tracts. In addition, secretory IgA (sIgA) responses to various pathogens may be impaired by vitamin A deficiency (Wiedermann et al. 1993a, Stephensen et al. 1996, Gangopadhyay et al. 1996). Ocular changes related to vitamin A deficiency include squamous metaplasia of the conjunctiva and cornea, loss of goblet cells, abnormal keratinization, and keratomalacia (Tseng et al. 1984, Sommer and West 1986). Lactoferrin, an iron-binding glycoprotein involved in immunity to bacteria, viruses, and fungi, is found in mucosal secretions, and its expression appears to be modulated by vitamin A. Tear lactoferrin levels are increased by vitamin A supplementation in children (Van Agtmaal 1989). Pathologic changes in the ocular surface may result in increased susceptibility to infection, for example, as shown in animal models of Pseudomonas keratitis (Twining et al. 1996a).

The normal tracheobronchial tree consists of ciliated columnar respiratory epithelium with mucus and goblet cells. The mucociliary escalator continuously traps and removes inhaled microorganisms and carcinogens and is an important first line of immune defense for the tracheobronchial tree. Vitamin A deficiency in rats and hamsters leads to loss of ciliated epithelial cells and mucus in the tracheobronchial tree and replacement by stratified, keratinized epithelium (Wilhelm 1954, Wong and Buck 1971, McDowell et al. 1984). Extensive squamous metaplasia of the respiratory tract was described in autopsy studies of vitamin A-deficient children (Blackfan and Wolbach 1933, Sweet and K'ang 1935). These pathologic alterations of the respiratory epithelium may partially explain the epidemiologic observation that children with mild vitamin A deficiency have an increased risk of subsequently developing respiratory disease (Sommer et al.1984).

Vitamin A regulates the terminal differentiation of human keratinocytes (Fuchs and Green 1981) and promotes the synthesis of some keratins while suppressing the synthesis of others (Eckert and Green 1984). In vitamin A-deficient rats, immunohistochemical alterations in cytokeratin expression were observed in the bladder, ureter, kidney, salivary glands, uterus, and conjunctiva before histologic changes could be observed (Gijbels et al. 1992). The expression of keratins is regulated by RAR and thyroid hormone receptors (Tomic-Canic et al.1996). Mucin gene expression appears to be regulated by all-trans retinoic acid (Manna et al. 1994, Manna et al. 1995), although regulation of the different mucin genes by retinoid receptors has not yet been elucidated. Thus, vitamin A, through its metabolites, may regulate keratinization and mucin production on the transcriptional level.

Vitamin A deficiency also causes loss of microvilli, goblet cells, and mucin in the small intestine (DeLuca et al. 1969, Rojanapo et al. 1980). Mucins are large glycoconjugates found on cell surfaces and which are secreted into the lumens of the gastrointestinal, respiratory, and genitourinary tracts. Gastrointestinal mucin is a first line of defense for cells lining the gut. The vitamin Arelated pathologic alterations in the gastrointestinal tract may contribute to the increased severity of diarrheal disease in vitamin A-deficient children (Sommer et al.1984, Barreto et al.1994).

The genitourinary tract is also affected by vitamin A deficiency. Extensive replacement of normal transitional epithelium with stratified squamous epithelium and the accompanying appearance of distinct types of keratins in the urinary tract have been described in vitamin A-deficient mice (Molloy and Laskin 1988). These mucosal changes might predispose children with vitamin A deficiency to increased urinary tract infections as previously observed (Brown et al. 1979). Vitamin A deficiency also results in altered expression of keratins and metaplastic changes in the endocervix (Darwiche et al. 1993). Whether vitamin A-related alterations in the genital tract increases the risk of sexually transmitted diseases, such as human immunodeficiency virus (HIV) infection, is unknown.

Skin

Skin barrier function is provided by keratinocytes in the epidermis. Vitamin A deficiency induces changes in epidermal keratins (Molloy and Laskin 1985) of which detailed clinical descriptions have been made (Frazier and Hu 1936). Increased skin infections have been described in children with vitamin A deficiency (Spence 1931). An increased susceptibility to skin infections could be caused by changes in keratinization, antigen presentation or other immunologic alterations in skin that may occur during vitamin A deficiency. The relationship between vitamin A status and the pathogenesis of skin infections in humans remains a major gap in current knowledge.

Hematopoiesis

Vitamin A and related retinoids play a central role in the development and differentiation of neutrophils, monocytes, erythrocytes, eosinophils, basophils, megakaryocytes, and lymphocytes (Gottgens and Green 1995) and can modulate T lymphocyte subpopulations in lymphoid tissues and peripheral blood (Semba et al. 1993a). Decreased numbers of circulating lymphocytes and anemia are common during vitamin A deficiency, and vitamin A deficiency is associated with decreased circulating CD4+ lymphocytes in children (Semba et al. 1993a) and adults (Semba et al.1993b). Supplementation with vitamin A has been shown to increase circulating CD4+ lymphocytes in vitamin A-deficient children (Semba et al. 1993a) and in children with acquired immunodeficiency syndrome (AIDS) (Hussey et al.1996). The underlying mechanisms by which retinoids influence hematopoietic stem cells and myeloid precursors appears to involve regulation by retinoid receptors (Gottgens and Green 1995).

Apoptosis

Retinoids are potent regulators of cell growth, differentiation, and apoptosis (programmed cell death). Regulation of apoptosis by retinoids may have implications for immune effector cells, virus-infected cells, and tumor cells. All-trans retinoic acid and 9-cis retinoic acid inhibit activation-driven T lymphocyte and thymocyte apoptosis, suggesting that RXRs may play a role in regulating the negative selection of T lymphocytes in the thymus (Iwata et al. 1992, Yang et al. 1993). In P 19 embryonal carcinomal cells, all-trans retinoic acid was effective in inducing apoptosis (Horn et al. 1996). Synthetic retinoids selective for RAR induced apoptosis in P19 cells, whereas synthetic retinoids selective for RXR had no effect, and a combination of RAR and RXR ligands resulted in a synergistic increase in apoptosis. This study suggests that both RAR and RXR play a role in apoptosis. Induction of apoptosis in HL-60 cells, a human myeloid leukemia cell line, requires ligand activation of RXR (Nagy et al. 1995). HIV-infected adults who were given daily oral retinoic acid had reduced apoptosis of T lymphocytes, suggesting that retinoid therapy could possibly reduce the decline of CD4+ lymphocytes during HIV infection (Yang et al. 1995). Although these studies suggest a strong role for retinoids in apoptosis, the potential effects of retinoids on apoptosis of immune effector cells still needs further elucidation.

Neutrophils

Neutrophils plays an important role as a first line of defense against infections because they phagocytize and kill bacteria, viruses, parasites, virus-infected cells, and tumor cells (Twining et al. 1997). However, a reduction in circulating neutrophils, or neutropenia, does not appear to be a feature of clinical vitamin A deficiency. During vitamin A deficiency, neutrophils appear to have impaired function, which could result in initial exposure to a greater number of pathogenic organisms. In vitamin A-deficient rats, the total number of circulating neutrophils was normal; however, a higher proportion of neutrophils were hypersegmented. Functional studies showed defects in chemotaxis, adhesion, phagocytosis, and ability to generate active oxidant molecules in neutrophils from vitamin A-deficient animals compared with controls (Twining et al. 1997). A decrease in neutrophil cathepsin G, which is involved in degradation of phagocytosed material, was found in neutrophils from vitamin A-deficient animals (Twining et al. 1996b).

Natural Killer Cells

Natural killer (NK, or CD 1 6/CD56) cells are found in blood, liver, and spleen and are responsible for "natural cytotoxicity," i.e., antiviral and antitumor immunity that is not MHC-restricted. Vitamin A deficiency reduces the numbers of NK cells and impairs their cytolytic activity (Zhao et al. 1994a, Zhao and Ross 1995). In rats, retinoic acid repletion increased NK cells in peripheral circulation and also increased NK cell cytotoxicity (Zhao and Ross 1995). A recent clinical trial showed that high-dose vitamin A supplementation was associated with a large increase in circulating NK cells in children with AIDS (Hussey et al. 1996). A synthetic retinoid, N-(4-hydroxyphenyl)retinamide, increased cytolytic activity of NK cells in rats (Zhao et al. 1994b).

Monocytes/Macrophages

Cells of the monocyte/macrophage lineage play a central role in immunity as antigen-presenting cells and as generators of oxygen and nitrogen radicals (Guzman et al. 1991). Monocytes circulate in the blood and then are distributed to different tissues where they contribute to the macrophage population. Macrophages rapidly take up bacteria and viruses, process them, and present antigen to CD4+ lymphocytes in an MHC II-restricted manner. Vitamin A and related retinoids influence monocyte differentiation and function; most of these effects have been studied in leukemic myelomonocytic cell lines such as HL60, U-937, and THP- 1 (Breitman et al.1989, Oberg et al. 1993, Hemmi and Breitman 1985). In the differentiation of U-937 cells, retinoic acid increased the expression of CD23, a receptor for IgE that plays a role in the regulation of B lymphocyte growth, and decreased the expression of CD 14, a receptor for monocyte adhesion during inflammation (Oberg et al.1993). Vitamin D3 had the inverse effect, suggesting that there is a functional antagonism between vitamin D^sub 3^ and retinoic acid in the regulation of immune responses by monocytes. Tumor necrosis factor-alpha (TNFalpha), a major inflammatory mediator, is produced in high amounts by activated monocytes/macrophages and has a wide range of effects, including induction of B and T lyme phocyte proliferation and stimulation of cell adhesion molecules on endothelial cells. The in vitro release of TNFalpha appears to be dependent on all-trans retinoic acid (Turpin et al.1990).

Retinoids have been shown to influence both the number and in vitro activity of macrophages (Katz et al. 1987a). An approximate two-fold increase in phagocytosis was caused by all-trans retinoic acid in murine macrophages (Dillehay et al.1988). All-trans retinoic acid increased the production of transforming growth factor-beta (TGF-1) by human peripheral blood monocytes and human myelomonocytic cells (Szabo et al.1994). TGF-betahas many effects but is primarily involved in the promotion of wound healing. Increased TGF-beta immunoreactivity has also been described in human skin biopsies from individuals using topical retinoic acid (Fisher et al. 1992). Antiinflammatory activity of retinoids are also suggested by in vitro studies which showed that various retinoids could inhibit phospholipase A^sub 2^ and arachidonic acid release from rat peritoneal macrophages (Hope et al.1990).

All-trans retinoic acid has been shown to increase interleukin 1 (IL- ) production by human peripheral blood mononuclear cells, murine macrophage cell lines, and murine macrophages (Trechsel et al.1985, Dillehay et al.1988). In human monocytes and in a human myeloid leukemia cell line, all-trans retinoic acid appeared to enhance IL-1 beta expression at the transcriptional level (Matikainen et al. 1991). IL- 1 is an important mediator of inflammation that has many effects similar to TNF- alpha , including stimulation of proliferation by T and B lymphocytes. IL- 1 is also produced by keratinocytes and may be modulated by all-trans retinoic acid and 13-cis retinoic acid (Tokura et al. 1992, Gruaz et al.1990). The potential influence of retinoids on expression of other cytokines by macrophage/monocytes such as IL-10, IL-12, macrophage inflammatory protein (MIP-1), and MIP-2 is unknown.

Langerhans Cells

Langerhans cells are an important component of the immune defense in the skin, where they function as antigenpresenting cells. Dietary vitamin A increases contact sensitivity to a variety of chemical agents in the murine model, probably due to the increased numbers or function of Langerhans cells (Maisey and Miller 1986, Katz et al. 1987b, Sailstad et al. 1995). In vivo retinoic acid treatment increases the ability of human Langerhans cells to present alloantigen to T lymphocytes and is associated with increases in surface expression of HLA-DR and CD 11 c, two molecules involved in antigen presentation (Meunier et al. 1994). Topical retinoic acid appears to upregulate cutaneous antigen-presenting function without inducing autoimmunity. This may have therapeutic implications for improving cutaneous immune responsiveness to vaccines, tumor antigens, and skin infections.

T Lymphocytes

T lymphocytes are major regulatory cells of the immune system and include T helper (CD4+) and T cytotoxic (CD8+) lymphocytes. CD4+ lymphocytes recognize antigen in the presence of MHC class II complexes, and CD8+ lymphocytes recognize cells bearing MHC class I complexes. Human lymphocytes contain both retinol and retinoic acid (Sklan et al. 1995). Activation of T cells appears to require retinol (Garbe et al. 1992). In murine T lymphocytes, alltrans retinoic acid stimulated expression of RAR-alpha and increased antigen-specific T lymphocyte proliferation (Friedman et al. 1993). In human T lymphoblasts, retinoic acid increased expression of IL-2 receptors (Sidell et al. 1993). The role of CD4+ lymphocytes in helping B cells develop into antibody-producing cells is discussed below.

CD8+ lymphocytes are involved in the lysis of cells, such as virus-infected cells, expressing antigens in the presence of MHC class I molecules. Vitamin A deficiency was shown to impair cytotoxic T lymphocyte activity in chickens infected with Newcastle disease virus (Sijtsma et al. 1990). Both CD4 and CD8+ lymphocytes are involved in allograft rejection, and a standard murine diet supplemented with retinyl acetate (0.5 g/kg) has been shown to increase allograft reaction in mice (Malkovsky et al. 1983a). Cytotoxic lymphocyte function during vitamin A deficiency in humans has not been studied. A recent clinical trial showed that oral vitamin A supplementation could increase delayed-type hypersensitivity reactions in infants whose serum vitamin A levels increased to greater than 0.70 [mol/L after supplementation (Rahman et al. 1997). This observation may reflect, in part, vitamin A-related upregulation of lymphocyte and/or Langerhans cell function.

Retinoids are involved in the expression of glycoproteins, including some adhesion molecules involved in lymphocyte function. ICAM-1 (CD54) is cell surface glycoprotein and a member of the immunoglobulin gene superfamily. It is expressed on a wide variety of cells and serves as a ligand for the beta-2 integrin molecules leukocyte-function associated antigen- 1, LFA- I (CD 11 a/CD 18) and MacI (CD1 lb/CD 8). The adhesion system plays a key role in lymphocyte circulation, T lymphocyte cytotoxicity, antigen presentation, leukocyte adhesion to endothelial cells, fibroblasts, and hematopoietic cells. The ICAM-1 gene appears to contain a RARE, which is regulated by retinoic acid through RAR- beta and RXR- alpha (Aoudjit et al. 1994, Aoudjit et al. 1995). Retinoic acid can increase expression of ICAM-I on various tumor cell lines (Bassi et al. 1995,

Wang et al. 1992, Bouillon et al. 1991, Darley et al. 1993), suggesting that retinoic acid could mediate the interaction of the immune system, such as cytotoxic T lymphocytes and NK cells, with recognition of some types of cancer cells.

B Lymphocytes and Antibody Responses

B lymphocytes are involved in the production of immunoglobulin, and the growth and activation of B lymphocytes requires retinol (Buck et al.1990, Blomhoff et al.1992). B lymphocytes may also use a metabolite of retinol,14-hydroxy-4,14-retro-retinol, instead of retinoic acid, as a mediator for growth (Buck et al.1991). The effects of retinol and all-trans retinoic acid on immunoglobulin synthesis by B lymphocytes has been studied in human cord blood and adult peripheral mononuclear cells (Israel et al.1991, Wang et al.1993a, Wang and Ballow 1993b, Ballow et al. 1996). A T cell-dependent antigen, formalinized Cowan I strain Staphylococcus aureus, was used in a model system to induce differentiation of B lymphocytes into immunoglobulin-secreting cells. The addition of all-trans retinoic acid augmented the production of immunoglobulin M (IgM) synthesis by cord blood mononuclear cells and the production of immunoglobulin G (IgG) by adult peripheral blood mononuclear cells. Highly purified T lymphocytes incubated with retinoic acid enhanced IgM synthesis by cord blood B lymphocytes, providing evidence that retinoic acid modulates T cell help through cytokine production (Ballow et al.1996). In the murine model, alltrans retinoic acid was more active than retinyl acetate, retinaldehyde, or retinol in restoring IgG responses (Chun et al.1992).

Antibody molecules, or immunoglobulins, play a central role in immune function by attaching to pathogens and recruiting immune effector cells to destroy the pathogens. A hallmark of vitamin A deficiency is the impaired ability to mount an antibody response against T cell-dependent antigens (Smith and Hayes 1987, Semba et al. 1992, Semba et al.1994b, Wiedermann et al.1993b) and T cell-independent type 2 antigens, such as pneumoccocal polysaccharide (Pasatiempo et al. 1989). Many of the earlier studies have been summarized elsewhere (Nauss 1996, Ross 1992, Semba 1994a).

Vitamin A deficiency has been hypothesized to influence the balance between T-helper type 2-like and T-helper type 1-like immune responses. Trichinella spiralis infection in mice normally stimulates a strong T helper type 2like response with high levels of parasite-specific IgG and a cytokine profile characterized by IL-4, IL-5, and IL-IO production. In contrast, vitamin A-deficient mice infected with T. spiralis produced T helper type 1-like responses that were characterized by low production of parasite-specific IgG and a cytokine profile characterized by interferongamma (IFN- gamma ) and IL-12 production(Carman et al. 1992, Cantorna et al. 1994, Cantorna et al. 1995). In vitamin Adeficient rats immunized with w beta -lactoglobulin, serum IgG, IgM, and IgE, and bile IgA responses against beta -lactoglobulin were impaired as compared with pair-fed control animals (Wiedermann et al. 1993b). In vitro lymphocyte stimulation to concanavalin A or beta -lactoglobulin was higher in vitamin A-deficient rats, with higher production of IL-2 and IFN- gamma in lymphocyte supernatants, providing additional evidence that vitamin A deficiency increased Thelper type 1-like responses (Wiedermann et al. 1993b). Hymenolepis nana, the dwarf tapeworm, is known to elicit a strong T-helper type 1-like response in normal mice. In vitamin A-deficient mice infected with H. nana, mesenteric lymph node cells in the presence of soluble egg antigen secreted more IFN- gamma but less IL-2 than the same cells from normal mice (Ikeda et al. 1994).

All-trans retinoic acid has been shown to decrease IFN production by murine L-929 cells infected with Newcastle disease virus (Blalock and Gifford 1976, Blalock and Gifford 1977). In cloned Thl cells, physiologic concentrations of all-trans retinoic acid downregulated IFN- gamma synthesis through the CD28 costimulatory pathway (Cantorna et al. 1996). Downregulation of IL-2 by all-trans retinoic acid in a regulatory pathway involving RAR has also been shown in Jurkat T cells (Felli et al. 1991). Modulation of the balance between T-helper type 1 and type 2 responses by retinoids may be influenced by the type of infection. In mice infected with Mycobacterium bovis, a standard murine diet supplemented with retinyl acetate, 0.5 g/kg, increased IL-2 production by PPD-stimulated spleen cells and augmented delayed type hypersensitivity (Colizzi and Malkovsky 1985). Pathologic studies revealed that there was a more vigorous inflammatory response in the footpads in vitamin A-supplemented mice 14 days after inoculation with M. bovis antigens in the footpad.

Other studies in rats support the idea that certain cytokine signals for B cell activation, proliferation, and production of immunoglobulin are missing during vitamin A deficiency. Vitamin A-deficient rats usually have impaired IgG responses to tetanus toxoid and pneumococcal polysaccharide, however, when these respective antigens were given concomitantly with bacterial lipopolysaccharide, a potent adjuvant (Arora and Ross 1994, Pasatiempo et al. 1994), vitamin A-deficient rats were able to produce a strong antibody response.

Mice with severe combined immunodeficiency (SCID) have been used to study the effects of vitamin A on human antibody responses to tetanus toxoid (Molrine et al. 1995). Peripheral blood lymphocytes from humans previously immunized with tetanus toxoid were used to reconstitute vitamin A-deficient and nondeficient SCID mice. After challenge with tetanus toxoid, vitamin A-deficient SCID mice had a 2.9-fold increase in human anti-tetanus toxoid antibody compared with a 74-fold increase in SCID mice with normal vitamin A status. These data are consistent with the observation that vitamin A supplementation enhances secondary antibody responses to tetanus toxoid in preschool children (Semba et al. 1992).

Cancer Immunity

Vitamin A deficiency has been associated with a higher incidence of cancer and increased susceptibility to carcinogens (Lotan 1996). Vitamin A and related retinoids may increase immunity to tumors by several mechanisms, including enhancement of T cytotoxic lymphocyte activity, NK cell activity, macrophage activity, and apoptosis (Tachibana et al. 1984, Malkovsky et al. 1983b). Alveolar macrophages isolated from vitamin A-supplemented rats had enhanced phagocytosis and tumoricidal activity compared with alveolar macrophages from control rats (Tachibana et al. 1984). Upregulation of HLA-DR expression by all-trans retinoic acid has also been described in human breast cancer cells, which also suggests the potential of retinoic acid to induce tumor immunity (Gardner and Walker 1993). All-trans retinoic acid has been shown to be beneficial as therapy for acute promyelocytic leukemia (Warrell et al. 1991).

Immunity to Infections

Vitamin A deficiency in children is associated with increased morbidity and mortality (Sommer and West 1986), and these epidemiologic observations are consistent with a large and comprehensive literature describing increased susceptibility to experimental infection in vitamin A-deficient animals (Nauss 1986, Ross 1992, Semba 1994a). As mentioned previously, vitamin A supplementation is widely carried out in many developing countries to improve child survival (Sommer and West 1986). High-dose vitamin A supplementation reduces morbidity and mortality in acute measles (Hussey and Klein 1990) and has become recommended therapy for measles in both developing countries (World Health Organization 1987) and in the United States (Committee on Infectious Diseases 1993).

The encouraging results from community-based clinical trials and hospital-based trials of measles have led to investigations regarding the use of vitamin A supplementation for specific infections. Given the wide range of immune responses to different types of pathogens, it is doubtful that vitamin A will show benefit as disease-targeted therapy for all types of infections. Clinical trials of vitamin A supplementation for respiratory syncytial virus infection have had equivocal results (Bresee et al.1996, Dowell et al.1996). Meta-analyses from the recent series of large clinical trials show that vitamin A supplementation reduces the severity of diarrheal disease but has little impact on childhood pneumonia (The Vitamin A and Pneumonia Working Group 1995). High-dose vitamin A supplementation targeted specifically to children with acute diarrhea in India reduced persistent diarrhea and also reduced the severity of diarrhea among nonbreastfed children (Bhandari et al.1997). Although vitamin A supplementation was incidentally shown to have little impact on malaria morbidity in Ghana (Binka et al.1995), clinical trials that are specifically designed to address this issue are needed (Shankar 1996). A recent clinical trial from Papua New Guinea shows that periodic high-dose vitamin A supplementation in preschool children reduces malarial morbidity by one third (Shankar et al. 1997), and a large clinical trial shows that vitamin A supplementation reduces malarial morbidity in pregnant women in Nepal by about 30% (West et al., unpublished data).

Another area in which vitamin A or related retinoids may have therapeutic potential are as therapy for HIV infection. Vitamin A deficiency has been linked with increased mortality (Semba et al.1993b), higher mother-tochild transmission of HIV (Semba et al.1994c, Greenberg et al.1997), increased infant mortality (Semba et al.1995), child growth failure (Semba et al.1997a), and higher HIV load in breastmilk (Nduati et al.1995) and the vagina (Johns et al.1997, Mostad et al.1997). Four clinical trials involving over 3000 HIV-infected pregnant women are currently in progress to determine whether antenatal vitamin A supplementation and other micronutrients can reduce mother-to-child transmission of HIV and improve other health outcomes in mothers and infants (Semba 1997b). It is unclear whether vitamin A supplementation will have any value as disease-targeted therapy for HIV infection.

Conclusions

In the last decade, major progress has been made in elucidating the role of vitamin A and related retinoids in immune function. Vitamin A acts via all-trans or 9-cis retinoic acid or other metabolites and nuclear retinoic acid receptors (RAR, RXR) to regulate gene transcription or may utilize a pathway involving 14-hydroxy-4,14-retro retinol. Retinoids influence many aspects of immunity, including mucin and keratin expression, hematopoiesis, apoptosis, the growth, differentiation and function of neutrophils, natural killer cells, monocytes/macrophages, Langerhans cells, T and B lymphocytes, balance between T helper type 1-like and T helper type 2-like immune responses, immunoglobulin production, and expression of cytokines (TGF-, beta , TNF- alpha , IFN- gamma , IL-1, IL-2, IL-3, IL-4, IL-6, IL- 10) and adhesion molecules such as ICAM-1. The results of many of the studies using vitamin A and related retinoids in vitro depend upon cell line, culture conditions, stage of cell differentiation, retinoid concentration, and mode of delivery of the retinoids. Extrapolation to in vivo conditions must be made with caution. However, these observations provide important data to guide future experimental and clinical investigations. The impact of vitamin A deficiency on immunity is more well-established in some immune compartments, including impairment of mucosal immunity by alterations in keratins and mucins, compromised function of accessory cells such as neutrophils, macrophages, and NK cells, alterations in cytokine networks which influence immune responses, and altered antibody responses to T-cell dependent and T-cell independent type 2 antigens. Although great progress has been made in the last decade, regulation by vitamin A and related metabolites on the molecular level of hematopoiesis, apoptosis, generation of specific reactive oxygen species, antigen processing and presentation, CD8 lymphocyte function, cytokine expression, and other aspects of immune function await further clarification.

Acknowledgments. Supported in part by grants from the National Institutes of Health (HD30042, HD32247), the Fogarty International Center, the Thrasher Research Fund, the World Health Organization Expanded Programme on Immunisation, and the United States Agency for International Development (Cooperative Agreement DAN-0045A-5094-00). The author wishes to thank Anu Shankar and Alan Scott for helpful comments on the manuscript.

Aoudjit F, Bosse J M, Stratowa C, et al (1994) Regulation of intercellular adhesion molecule-1 expression by retinoic acid: analysis of the 5' regulatory region of the gene. Int J Cancer 58:543-9

Aoudjit F, Brochu N, Morin N, et al (1995) Heterodimeric retinoic acid receptor-s and retinoid X receptor-a complexes stimulate expression of the intercellular adhesion molecule-1 gene. Cell Growth Diff 6:51521

Arora D, Ross AC (1994) Antibody response against tetanus toxoid is enhanced by lipopolysaccharide or tumor necrosis factor-alpha in vitamin A-sufficient and deficient rats. Am J Clin Nutr 59:922-8

Ballow M, Wang W, Xiang S (1996) Modulation of B-cell immunoglobulin synthesis by retinoic acid. Clin Immunol Immunopath 80:S73-81

Barreto ML, Santos LMP, Assis AMO, et al (1994) Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet 344:228-31

Bassi V, Vitale M, Feliciello A, et al (1995) Retinoic acid induces intercellular adhesion molecule-1 hyperexpression in human thyroid carcinoma cell lines. J Clin Endocrinol Metab 80:1129-35

Beaton GH, Martorell R, Aronson K, et al (1993) Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. State-of-the-Art Nutrition Policy Discussion Paper No 13. Geneva: ACC/SCN

Bhandari N, Bahl R, Sazawal S, et al (1997) Breast-feeding status alters the effect of vitamin A treatment during acute diarrhea in children. J Nutr 127:59-63

Binka FN, Ross DA, Morris SS, et al (1995) Vitamin A supplementation and childhood malaria in northern Ghana. Am J Clin Nutr 61:853-9

Blackfan KD, Wolbach SB (1933) Vitamin A deficiency in infants: a clinical and pathological study. J Pediatr 3:679-706

Blalock JE, Gifford G (1976) Suppression of interferon production by vitamin A. J Gen Virol 32:143-7

Blalock JE, Gifford GE (1977) Retinoic acid (vitamin A acid) induced transcriptional control of interferon production. Proc Natl Acad Sci USA 74:5382-6

Blomhoff HK, Smeland EB, Erikstein B, et al (1992) Vitamin A is a key regulator for cell growth, cytokine production, and differentiation in normal B cells. J Biol Chem 267:23988-92

Blumberg B, Bolado J Jr, Derguini F, et al (1996) Novel retinoic acid receptor ligands in Xenopus embryos. Proc Natl Acad Sci USA 93:4873-8

Bouillon M, Tessier P, Boulianne R, et al (1991) Regulation by retinoic acid of ICAM-1 expression on human tumor cell lines. Biochim Biophys Acta 1097:95-102

Breitman TR, Selonick SE, Collins SJ (1980) Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA 77:2936-40

Bresee JS, Fischer M, Dowell SF, et al (1996) Vitamin A therapy for children with respiratory syncytial virus infection: a multicenter trial in the United States. Pediatr Infect Dis J 15:777-82

Brown KH, Gaffar A, Alamgir SM (1979) Xerophthalmia, protein-calorie malnutrition, and infections in children. J Pediatr 95:651-6

Buck J, Ritter G, Dannecker L, et al (1990) Retinol is essential for growth of activated human B cells. J Exp Med 171:1613-24

Buck J, Derguini F, Levi E, et al (1991) Intracellular signaling by 14-hydroxy-4,14-retro retinol. Science 254:1654-5

Buck J, Grun F, Kimura S, et al (1993) Anhydroretinol: a naturally occurring inhibitor of lymphocyte physiology. J Exp Med 1993;178:675

Cantorna MT, Nashold FE, Hayes CE (1994) In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J Immunol 152:1515-22

Cantorna MT, Nashold FE, Hayes CE (1995) Vitamin A deficiency results in a priming environment conducive for Th1 cell development. Eur J Immunol 25:1673-9

Cantorna MT, Nashold FE, Chun TY, et al (1996) Vitamin A down-regulation of IFN- gamma synthesis in cloned mouse Th1 lymphocytes depends on the CD28 costimulatory pathway. J Immunol 1996;156:26749

Carlberg C, van Huijsduijnen RH, Staple JK, et al (1994) RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol Endocrinol 8:757-70

Carman JA, Pond L, Nashold F, et al (1992) Immunity to Trichinella spiralis infection vitamin A-deficient mice. J Exp Med 175:111-20

Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10:940-54

Chun TY, Carman JA, Hayes CE (1992) Retinoid repletion of vitamin A-deficient mice restores IgG responses. J Nutr 122:1062-9

Chytil F, Haq RU (1990) Vitamin A mediated gene expression. Crit Rev Eukary Gene Exp 1:61-73

Colizzi V, Malkovsky M (1985)Augmentation of interleukin2 production and delayed hypersensitivity in mice infected with Mycobacterium bovis and fed a diet

supplemented with vitamin A acetate. Infect Immun 48:581-3

Committee on Infectious Diseases (1993) Vitamin A treatment of measles. Pediatrics 91:1014-5 Darley R, Morris A, Passas J, et al (1993) Interactions between interferon gamma and retinoic acid with transforming growth factor beta in the induction of immune recognition molecules. Cancer Immunol Immunother 37:112-8

Darwiche N, Celli G, Sly L, et al (1993) Retinoid status controls the appearance of reserve cells and keratin expression in mouse cervical epithelium. Cancer Res 53:2287-99

De Luca L, Little EP, Wolf G (1969) Vitamin A and protein synthesis by rat intestinal mucosa. J Biol Chem 244:701-8

Dillehay DL, Walia AS, Lamon EW (1988) Effects of retinoids on macrophage function and IL-1 activity. J Leuk Biol 44:353-60

Dowell SF, Papic Z, Bresee JS, et al (1996) Treatment of respiratory syncytial virus infection with vitamin A: a randomized, placebo-controlled trial in Santiago, Chile. Pediatr Infect Dis J 15:782-6 Eckert RL, Green H (1984) Cloning of cDNAs specifying vitamin A-responsive human keratins. Proc Natl Acad Sci USA 81:4321-5

Eppinger TM, Buck J, Hammerling U (1993) Growth control or terminal differentiation: endogenous production and differential activities of vitamin A metabolites in HL-60 cells. J Exp Med 178:1995-2005 Felli MP, Vacca A, Meco D, et al (1991) Retinoic acidinduced down-regulation of the interleukin-2 promotor via cis-regulatory sequences containing an octamer motif. Mol Cell Biol 11:4771-8 Fisher GJ, Tavakkol A, Griffiths CEM, et al (1992) Differential modulation of transforming growth factor-p1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin. J Invest Dermatol 98:102-8

Frazier CN, Hu CK (1936) Nature and distribution according to age of cutaneous manifestations of vitamin A deficiency: a study of two hundred and seven cases. Arch Derm Syph 33:825-52

Friedman A, Halevy O, Schrift M, et al (1993) Retinoic acid promotes proliferation and induces expression of retinoic acid receptor- alpha gene in murine T lymphocytes. Cell Immunol 152:240-8

Fuchs E, Green H (1981) Regulation of terminal differentiation of cultured human keratinocytes by vitamin A. Cell 25:617-25

Gangopadhyay NN, Moldoveanu Z, Stephensen CB (1996) Vitamin A deficiency has different effects on immunoglobulin A production and transport during influenza A infection in BALB/c mice. J Nutr 126:29607

Garbe A, Buck J, Hammerling U (1992) Retinoids are important cofactors in T cell activation. J Exp Med 176:109-17

Gardner FJE, Walker RA (1993) Modulation of cell surface components of human breast cancer cells by retinoic acid: enhanced HLA-DR expression. J Pathol 170:23-9

Gijbels MJJ, van der Ham F, van Bennekum AM, et al (1992) Alterations in cytokeratin expression precede histological changes in epithelia of vitamin A-defi

cient rats. Cell Tissue Res 268:197-203 Gottgens B, Green AR (1995) Retinoic acid and the differentiation of lymphohaemapoietic stem cells. BioEssays 17:187-9

Green HN, Mellanby E (1928) Vitamin A as an anti-infec

tive agent. BMJ 2:691-6

Greenberg BL, Semba RD, Vink PE, et al (1997) Vitamin A deficiency and maternal-infant transmission of HIV in two metropolitan areas in the United States. AIDS 11:325-32

Gruaz DC, Didierjean L, Gumowski-Sunek D, et al (1990) Effect of topical retinoic acid on the interleukin 1 alpha and P immunoreactive pool in normal human epidermis. Brit J Dermatol 123:283-9 Guzman JJ, Marks JF, Caren LD (1991) In vivo and in vitro studies on the effects of vitamin A on the chemiluminescent response of murine peritoneal exudate cells. Toxicol Lett 57:125-137

Haq RU, Pfahl M, Chytil F (1991) Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol-deficient rats. Proc Natl Acad Sci 88:8272-6

Hemmi H, Breitman TR (1985) Induction of functional differentiation of a human monocytic leukemia cell line (THP-1) by retinoic acid and cholera toxin. Jpn J Canc Res 76:345-51

Hirose T, Apfel R, Pfahl M, et al (1995) The orphan receptor TAK1 acts as a repressor of RAR-, RXR- and T^sub 3^R-mediated signaling pathways. Biochem Biophys Res Comm 211:83-91

Hope WC, Patel BJ, Fiedler-Nagy C, et al (1990) Retinoids inhibit phospholipase A^sub 2^ in human synovial fluid and arachidonic acid release from rat peritoneal macrophages. Inflammation 14:543-59

Horn V, Minucci S, Ogryzko W, et al (1996) RAR and RXR selective ligands cooperatively induce apoptosis and neuronal differentiation in P19 embryonal carcinoma cells. FASEB J 10:1071-7

Hussey GD, Klein M (1990) A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 323:160-4

Hussey G, Hughes J, Potgieter S, et al (1996) Vitamin A status and supplementation and its effects on immunity in children with AIDS. Abstracts of the XVII International Vitamin A Consultative Group Meeting, Guatemala City. Washington, DC: International Life Sciences Institute, p 6

Ikeda K, Matsuo S, Asano K, et al (1994) Modulation of cytokine secretion by mesenteric lymph node cells from vitamin A-deficient mice during Hymenolepis nana infection. In Vivo 8:1015-8 Israel H, Odziemiec C, Ballow M (1991) The effects of retinoic acid on immunoglobulin synthesis by human cord blood mononuclear cells. Clin Immunol Immunopath 59:417-25

Iwata M, Mukai M, Nakai Y, et al (1992) Retinoic acids inhibit activation-driven apoptosis in T cell hybridomas and thymocytes. J Immunol 149:3302-8 Johns GC, Nduati RW, Mbori-Ngacha D, et al (1997) Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deficiency, J Infect Dis 175:57-62

Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear

receptors: what are genetic studies telling us about their role in real life? Cell 83:859-69 Katz DR, Drzymala M, Turton JA, et al (1987a) Regulation of accessory cell function by retinoids in murine immune responses. Brit J Exp Path 68:343-50 Katz DR, Mukherjee S, Maisey J, et al (1987b) Vitamin A acetate as a regulator of accessory cell function in delayed-type hypersensitivity responses. Int Archs Allergy Appl Immun 82:53-6

Lotan R (1996) Retinoids in cancer chemoprevention. FASEB J 10:1031-9

Maisey J, Miller K (1986) Assessment of the ability of mice fed on vitamin A supplemented diet to respond to a variety of potential contact sensitizers. Contact Dermatitis 15:17-23

Malkovsky M, Edwards AJ, Hunt R, et al (1983a) T-cellmediated enhancement of host-versus-graft reactivity in mice fed a diet enriched in vitamin A acetate. Nature 302:338-40

Malkovsky M, Dore J C, Hunt R, et al (1983b) Enhancement of specific antitumor immunity in mice fed a diet enriched in vitamin A acetate. Proc Natl Acad Sci USA 80:6322-6

Manna B, Lund M, Ashbaugh P, et al (1994) Effect of retinoic acid on mucin gene expression in rat airways in vitro. Biochem J 297:309-13 Manna B, Ashbaugh P, Bhattacharyya SN (1995) Retinoicacid regulated cellular differentiation and mucin gene expression in isolated rabbit tracheal epithelial cells in culture. Inflammation 19:489-502 Matikainen S, Serkkola E, Hurme M (1991) Retinoic acid enhances IL-1 beta expression in myeloid leukemia cells and in human monocytes. J Immunol 147:1627

McDowell EM, Keenan KP, Huang M (1984) Effects of vitamin A-deprivation on hamster tracheal epithelium: a quantitative morphologic study. Virchows Arch B 45:197-219

Meunier L, Bohjanen K, Voorhees JJ, et al (1994) Retinoic acid upregulates human Langerhans cell antigen presentation and surface expression of HLA-DR and CD11c, a beta 2 integrin critically involved in T-cell activation. J Invest Dermatol 103:775-9 Molloy CJ, Laskin JD (1985) Alterations in mouse epidermal keratin production induced by dietary vitamin A deficiency. Ann N Y Acad Sci 455:739-40 Molloy CL, Laskin JD (1988) Effect of retinoid deficiency on keratin expression in mouse bladder. Exp Mol Pathol 49:128-40

Molrine DC, Polk DB, Ciamarra A, et al (1995) Impaired human responses to tetanus toxoid in vitamin Adeficient SCID mice reconstituted with human peripheral blood lymphocytes. Infect Immun 63:286772

Mostad SB, Overbaugh J, DeVange DM, et al (1997) Hormonal contraception, vitamin A deficiency, and other risk factors of shedding of HIV-1 infected cells from the cervix and vagina. Lancet 350:922-7 Nagy L, Thomazy VA, Shipley GL, et al (1995) Activation of retinoid X receptors induces apoptosis in HL-60 cell lines. Mol Cell Biol 15:3540-51 Napoli JL (1996) Retinoic acid biosynthesis and me

tabolism. FASEB J 10:993-1001

Nauss KM (1986) Influence of vitamin A status on the immune system. In: Bauernfeind JC (ed), Vitamin A

deficiency and its control. Orlando, FL: Academic Press, pp 207-43

Nduati RW, John GC, Richardson BA, et al (1995) Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency. J Infect Dis 172:1461-8 Oberg F, Botling J, Nilsson K (1993) Functional antagonism between vitamin D^sub 3^ and retinoic acid in the regulation of CD14 and CD23 expression during monocytic differentiation of U-937 cells. J Immunol 150:3487-95

Ortiz MA, Piedrafita FJ, Pfahl M, et al (1995) TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. Mol Endocrinol 9:1679-91

Pasatiempo AMG, Bowman TA, Taylor CE, et al (1989) Vitamin A depletion and repletion: effects on antibody response to the capsular polysaccharide of Streptococcus pneumoniae, type Ill. Am J Clin Nutr 49:501-10

Pasatiempo AMG, Kinoshita M, Foulke DT, et al (1994) The antibody response of vitamin A-deficient rats to pneumococcal polysaccharide is enhanced through coimmunization with lipopolysaccharide. J Infect Dis 169:441-4

Pfahl M, Chytil F (1996) Regulation of metabolism by retinoic acid and its nuclear receptors. Annu Rev Nutr 16:257-83

Rahman MM, Mahalanabis D, Alvarez JO, et al (1997) Effect of early vitamin A supplementation on cellmediated immunity in infants younger than 6 mo. Am J Clin Nutr 65:144-8

Retnakaran R, Flock G, Giguere V (1994) Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator. Mol Endocrinol 8:1234-44

Rojanapo W, Lamb AJ, Olson JA (1980) The prevalence, metabolism and migration of goblet cells in rat intestine following the induction of rapid, synchronous vitamin A deficiency. J Nutr 110:178-88 Ross AC (1992) Vitamin A status: relationship to immunity and the antibody response. Proc Soc Exp Biol Med 200:303-20

Sailstad DM, Krishnan SD, Tepper JS, et al (1995) Dietary vitamin A enhances sensitivity of the local lymph node assay. Toxicology 96:157-63 Scrimshaw NS, Taylor CE, Gordon JE (1968) Interactions of nutrition and infection. Geneva: World Health Organization

Semba RD, Muhilal, Scott AL, et al (1992) Depressed immune response to tetanus in children with vitamin A deficiency. J Nutr 122:101-7 Semba RD, Muhilal, Ward BJ, et al (1993a) Abnormal Tcell subset proportions in vitamin A-deficient children. Lancet 341:5-8

Semba RD, Graham NMH, Caiaffa WT, et al (1993b) Increased mortality associated with vitamin A deficiency during human immunodeficiency virus type 1 infection. Arch Intern Med 153:2149-54 Semba RD (1994a) Vitamin A, immunity, and infection.

Clin Infect Dis 19:489-99

Semba RD, Muhilal, Scott AL, et al (1994b) Effect of vitamin A supplementation on IgG subclass responses to tetanus toxoid in children. Clin Diag Lab Immunol 1:172-5

Semba RD, Miotti PG, Chiphangwi JD, et al (1994c) Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet 343:1593-7 Semba RD, Miotti PG, Chiphangwi JD, et al (1995) Infant mortality and maternal vitamin A deficiency during HIV infection. Clin Infect Dis 21:966-72 Semba RD, Miotti PG, Chiphangwi JD, et al (1997a) Maternal vitamin A deficiency and child growth failure during human immunodeficiency virus infection. J Acquired Immun Defic Syndr 14:219-22 Semba RD (1997b) Vitamin A and human immunodefi

ciency virus infection. Proc Nutr Soc 56:1-11 Shankar AH (1996) Vitamin A and malaria [letter]. Am J Clin Nutr 62:842

Shankar AH, Genton B, Semba RD, et al (1997) Vitamin A supplementation as a nutrient-based intervention to reduce malarial morbidity. Abstracts of the XVIII International Vitamin A Consultative Group Meeting, Cairo, Egypt, September 22-26, 1997, p 31 Sidell N, Chang B, Bhatti L (1993) Upregulation by retinoic acid of interleukin-2-receptor mRNA in human T lymphocytes. Cell Immunol 146:28-37 Sijtsma SR, Rombout JHWM, West CE, et al (1990) Vitamin A deficiency impairs cytotoxic T lymphocyte acitivity in Newcastle disease virus-infected chickens. Vet Immunol Immunopath 26:191-201 Sklan D, Trifon S, Kedar O, et al (1995) Retinoid metabolism in human leukocytes. Brit J Nutr 73:889-95 Smith SM, Hayes CE (1987) Contrasting impairments in IgM and IgG responses of vitamin A-deficient mice. Proc Natl Acad Sci USA 84:5878-82 Sommer A, Katz J, Tarwotjo I (1984) Increased risk of respiratory disease and diarrhea in children with preexisting mild vitamin A deficiency. Am J Clin Nutr 40:1090-5

Sommer A, West KP Jr (1986) Vitamin A deficiency: health, survival, and vision. New York: Oxford University Press

Spence JC (1931) A clinical study of nutritional xerophthalmia and night-blindness. Arch Dis Child 6:17-26

Stephensen CB, Moldoveanu Z, Gangopadhyay NN (1996) Vitamin A deficiency diminishes the salivary IgA response and enhances the serum IgG response to influenza A virus infection in BALB/c mice. J Nutr 126:94-102

Sweet KL, K'ang HJ (1935) Clinical and anatomic study of avitaminosis A among the Chinese. Am J Dis Child 50:699-734

Szabo S, Puppolo M, Verma B, et al (1994) Regulatory potential of ethanol and retinoic acid on human monocyte functions. Alcohol Clin Exp Res 18:54854

Tachibana K, Sone S, Tsubura E, et al (1984) Stimulatory effect of vitamin A on tumoricidal activity of rat alveolar macrophages. Brit J Cancer 49:343-8 Tokura Y, Edelson RL, Gasparro FP (1992) Retinoid augmentation of bioactive interleukin-1 production by murine keratinocytes. Brit J Dermatol 126:485-95 Tomic-Canic M, Day D, Samuels HH, et al (1996) Novel regulation of keratin gene expression by thyroid hormone and retinoid receptors. J Biol Chem 271:141623

Tran P, Zhang XK, Salbert G, et al (1992) COUP orphan receptors are negative regulators of retinoic acid

response pathways. Mol Cell Biol 12:4666-76 Trechsel U, Evequoz V, Fleisch H (1985) Stimulation of interleukin 1 and 3 production by retinoic acid in vitro. Biochem J 230:339-44

Tseng SCG, Hatchell D, Tierney N, et al (1984) Expression of specific keratin markers by rabbit corneal, conjunctival, and esophageal epithelia during vitamin A deficiency. J Cell Biol 99:2279-86 Turpin J, Mehta K, Blick M, et al (1990) Effect of retinoids on the release and gene expression of tumor necrosis factor-a in human peripheral blood monocytes. J Leuk Biol 48:444-50

Twining SS, Zhou X, Schulte DP, et al (1996a) Effect of vitamin A deficiency on the early response to experimental Pseudomonas keratitis. Invest Ophthalmol Vis Sci 37:511-22

Twining SS, Schulte DP, Wilson PM, et al (1996b) Neutrophil cathepsin G is specifically decreased under vitamin A deficiency. Biochim Biophys Acta 1317:112-8

Twining SS, Schulte DP, Wilson PM, et al (1997) Vitamin A deficiency alters rat neutrophil function. J Nutr 127:558-65

Van Agtmaal EJ (1989) Vitamin A and protein in tear fluid: a nutritional field survey on preschool children in northeast Thailand. (Thesis) Amsterdam: University of Amsterdam

The Vitamin A and Pneumonia Working Group (1995) Potential interventions for the prevention of childhood pneumonia in developing countries: a metaanalysis of data from field trials to assess the impact of vitamin A supplementation on pneumonia morbidity and mortality. Bull WHO 73:609-19 Wang Z, Cao Y, D'Urso CM, et al (1992) Differential susceptibility of cultured human melanoma cell lines to enhancement by retinoic acid of intercellular adhesion molecule 1 expression. Cancer Res 52:476672

Wang W, Napoli JL, Ballow M (1993a) The effects of retinol on in vitro immunoglobulin synthesis by cord blood and adult peripheral blood mononuclear cells. Clin Exp Immunol 92:164-8

Wang W, Ballow M (1993b) The effects of retinoic acid on in vitro immunoglobulin synthesis by cord blood and

adult peripheral blood mononuclear cells. Cell Immunol 148:291-300

Warrell RP Jr, Frankel SR, Miller WH Jr, et al (1991) Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med 324:1385-93

Wiedermann U, Hanson LA, Holmgren J, et al (1993a) Impaired mucosal antibody response to cholera toxin in vitamin A-deficient rats immunized with oral cholera vaccine. Infect Immun 61:3952-7 Wiedermann U, Hanson LC, Kahu H, et al (1993b) Aberrant T-cell function in vitro and impaired T-cell dependent antibody response in vivo in vitamin A-deficient rats. Immunology 80:581-6 Wilhelm DL (1954) Regeneration of the tracheal epithelium in the vitamin-A-deficient rat. J Pathol Bact 67:361-5

Wong YC, Buck RC (1971) An electron microscopic study of metaplasia of the rat tracheal epithelium in vitamin A deficiency. Lab Invest 24:55-66 World Bank (1993) World Bank Reports 1993: Investing in health. New York: Oxford University Press World Health Organization (1987) Joint WHO/UNICEF statement on vitamin A for measles. WHO Wkly Epidemiol Rec 62:133-4

Yang Y, Vacchio MS, Ashwell JD (1993) 9-cis-retinoic acid inhibits activation-driven T-cell apoptosis: implications for retinoid X receptor involvement in thymocyte development. Proc Natl Acad Sci USA 90:6170-4 Yang Y, Bailey J, Vacchio MS, et al (1995) Retinoic acid inhibition of ex vivo human immunodeficiency virus-associated apoptosis of peripheral blood cells. Proc Natl Acad Sci USA 92:3051-5 Zhao Z, Murasko DM, Ross AC (1994a) The role of vitamin A in natural killer cell cytotoxicity, number and activation in the rat. Nat Immun 13:29-41 Zhao Z, Matsuura T, Popoff K, et al (1994b) Effects of N(4-hydroxyphenyl)-retinamide on the number and cytotoxicity of natural killer cells in vitamin-A-sufficient and -deficient rats. Nat Immun 13:280-8 Zhao Z, Ross AC (1995) Retinoic acid repletion restores the number of leukocytes and their subsets and stimulates natural cytotoxicity in vitamin A-deficient rats. J Nutr 125:2064-73

Richard D. Semba

Johns Hopkins University School of Medicine

Copyright International Life Sciences Institute and Nutrition Foundation Jan 1998
Provided by ProQuest Information and Learning Company. All rights Reserved