Cell Morphology and Differentiation

Soon after the discovery of vitamin A, a light microscopic investigation of the tissues of vitamin A-deficient rats revealed marked abnormalities in many epithelial tissues. It is now recognized that essentially all organ systems require retinoids. Some epithelial tissues (skin, respiratory tract, the immune system, the reproductive organs, etc.) are especially sensitive to a lack, as well as an excess, of vitamin A. The systemic effects of vitamin A deficiency include dryness of the skin (follicular hyperkarotosis), loss of mucus-secreting goblet cells in the trachea and respiratory tract, and a generalized flattening of epithelia (squamous metaplasia, sometimes with keratinization) throughout the body. The hemato-poietic system is also affected, as are reproductive organs. In the testes, spermatogenesis is inhibited by vitamin A deficiency. Although a lack or an excess of retinoids is recognized to affect many organ systems, the developing embryo and the functions of the immune system have been studied most intensively. Essentially all of the functions of vitamin A other than those involving the retina are mediated by its active metabolite, RA, in conjunction with nuclear retinoid receptors.

Nuclear Retinoid Receptors

The nuclear retinoid receptor proteins are synthesized in the cytoplasm but reside in the nucleus where they form dimers capable of binding to specific sequences of DNA in target genes (retinoid response elements, RAREs). The family consists of six retinoid receptors (RARa, fi and □, and RXR&& and □) that belong to the superfamily of steroid hormone receptors. The RAR and RXR function as ligand-activated transcription factors to either activate or repress the transcription of hormone-responsive genes. Two isomers of retinoic acid, all-ira«s-retinoic acid and 9-czs-retinoic acid, function as the major ligands for the RAR and RXR subfamilies, respectively. The binding of all-trans-retinoic acid to the RAR induces a conformational change in the receptor dimer pair, bound to its response elements (RARE) in the regulatory region of the DNA of target genes. This conformational change, in turn, promotes the interaction of the retinoid receptor dimer with other transcriptional regulators. Ligand binding may promote the dissociation of corepressor molecules and the binding of coactivator molecules, leading to gene activation when the basal transcriptional complex is recruited. This multiprotein complex then functions enzymati-cally to transcribe the DNA template into messenger RNA. Additionally, some receptor functions appear to be ligand independent. Similarly to all-trans-reti-noic acid, 9-cis-retinoic acid has been shown to bind to nuclear receptors of the RXR family. However, the physiological role of 9-cis-retinoic acid in vivo is currently unclear and, moreover, other ligands besides 9-cis-RA (such as polyunsaturated fatty acids) may also activate the RXR. Besides forming dimers with the RAR, the RXR bind in a similar manner with the nuclear receptors for vitamin D, thyroid hormone, and several other lipophilic hormones and xenobiotic agents.

Embryonic Development

Vitamin A is essential in appropriate amounts for normal embryogenesis. Retinoids are required from the early, postgastrulation stage of embryonic development. The requirement for retinoids has been deduced from molecular developmental studies in mice, and other species. These studies have consistently shown a highly regulated pattern of expression of the genes for nuclear retinoid receptors, retinoid-binding proteins, and enzymes of retinoid production and catabolism. It is likely, based on the expression of retinoid biosynthetic enzymes, that maternally derived retinol is metabolized by the embryo to produce retinoic acid at specific times in specific cells, and that retinoic acid is also catabolized in a highly regulated, tissue-specific manner. Retinoic acid has been proposed to be an essential morphogen whose concentration, or concentration gradient, is a key determinant of the expression of one or more families of genes, particularly the Hox gene family. This gene family is crucial in determining the formation of the anterior-posterior body axis. Some of these key genes contain a RARE.

In animals, both vitamin A deficiency and an excess of dietary vitamin A or retinoid analogs, at specific critical periods of development, can result in severe developmental defects, and may be lethal to the embryo. The differentiation of cells in the neural crest and the development of the head and sensory organs, nervous system, heart, limbs, and skeleto-muscular system are often affected. Birth defects of a similar nature have occurred in women exposed to excessive dietary vitamin A, or to pharmacologic retinoids for treatment of skin diseases, in early pregnancy.

Immunity

Impaired immunity was one of the earliest effects described for vitamin A deficiency. Numerous abnormalities have been described. A dysregulation of T cell functions has been implicated in many abnormal immune responses, as vitamin A-deficient animals often have reduced T cell counts and an altered pattern of differentiation markers on T cell subsets. The response of T cells to antigens and mitogens tends to be low. Similarly, the functional capacity of cytotoxic cells, such as cytotoxic T cells and natural killer cells, and macrophages is often low. Numerous alterations have been documented in the production of cytokines that regulate T cell immunity and antibody production by B cells. Because the immune response elicited by pathogens, vaccines, or other experimental treatments can differ significantly depending on the type of stimuli, it is not surprising that the effect of vitamin A status has also varied depending on the type of natural infection or experimental challenge. Consistently, however, the administration of vitamin A, or therapeutic doses of retinoic acid, has restored a more normal pattern of T cell-dependent immune responses, often quite rapidly, to previously vitamin A-deficient hosts.

In children at risk of vitamin A deficiency, vitamin A supplementation, given prophylactically or as therapy during illness, has significantly reduced the severity of measles and measles-related mortality (see 'Hypervitaminosis A and Vitamin A Toxicity').

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