“A vitamin is a substance that makes you ill if you don’t eat it.” (Albert Szent-Gyorgyi, Nobel Prize in Physiology or Medicine, 1937).
Vitamins are natural components of foods and are organic compounds distinct from fat, carbohydrates and proteins. Vitamin A is the generic descriptor for compounds with the qualitative biological activity of retinol. Unlike beta-carotene, vitamin A is not an antioxidant and its benefit is related to its intimate relationship with immune reactions.
The effect of vitamin A on immune function is wide-reaching and its deficiency appears to affect immunity in several ways. Both the innate and adaptive immune responses are affected by lack of vitamin A.
Retinoids seem to act on differentiation of lymphocytes, antibody production, phagocytosis of macrophages, NK, Treg, and T helper cell activity. In addition, in humans, signs of a vitamin A deficiency also include the dysregulation of cytokine/chemokine generation and release. However, excess of vitamin A has been demonstrated to have toxic effects in most species studied.
Some more clarification
Vitamin A is obtained from plant- or animal-derived food. Whilst overt vitamin A deficiency is rare in the Western world but common in resource-poor regions, with night blindness an early sign of its deficiency, sub clinical vitamin A deficiency due to poor diet and conversion SNPs in northern Europeans is becoming recognised as a clinically relevant finding.[1]
Plant food based approaches have a real potential on prevention of vitamin A deficiency in a sustainable way. Carotenoids are important as precursors of vitamin A as well as for prevention of cancers, coronary heart diseases, age-related macular degeneration, cataract etc. Bioaccessibility and bioefficacy of carotenoids are known to be influenced by numerous factors including dietary factors such as fat, fibre, dosage of carotenoid, location of carotenoid in the plant tissue, heat treatment, particle size of food, carotenoid species, interactions among carotenoids, isomeric form and molecular linkage and genes.
Plants provide us with a non-biological active form of vitamin A known as provitamin A carotenoid or β-carotene, which is water soluble and consequently not stored in the body. It must pass through some conversion steps that require oxidation by members of the alcohol dehydrogenase (ADH) membrane bound enzyme family or retinol dehydrogenase (RDH) family to be converted into retinal, which is reversibly reduced to retinol, enabling uptake by cells.
Subsequently, retinal dehydrogenase (RALDH), expressed in epithelial cells and dendritic cells (DCs) generates all-trans-retinoic acid and 9-cis-retinoic acid. Using these pathways, the human body can make all the required vitamin A from plant-derived carotenoids subject to availability and utilisation factors being optimised.
In contrast, animal-derived vitamin A is directly bioavailable from fat stores as retinal, retinol and retinoic acid and can become toxic when built up in the body[2]. Retinoic acids are small, lipophilic, rapidly diffusing molecules that can be generated by epithelial cells and intestinal dendritic cells. Some DCs located in the intestine express alchohol dehydrogenase (ADH) isoforms constitutively, as well as retinoid X receptor (RXR) and other nuclear receptor isoforms according to their intestinal location.[3] Those located in the Peyer’s patches (the numerous areas of lymphoid tissue in the wall of the small intestine which are involved in the development of immunity to antigens present there) express ALDH1A1, whereas DCs sourced from mesenteric lymph nodes (Mesenteric lymph nodes are the 100 to 150 lymph nodes that lie within the mesentery, a double-layered section of peritoneum, the membrane that lines the abdominal cavity.) express ALDH1A2, which is important for directing B and T lymphocytes to the correct tissues.[4]
Vitamin A directs responses by binding to the Retinoic Acid Receptor) RAR nuclear receptors, of which at least three isoforms exist, and to retinoid X RXRs. Upon retinoid binding, these receptors form RAR/RXR heterodimers, each with specificity to particular DNA sequences.[5] In addition, RXR homodimers can be formed.
This complexity is further enhanced by RXR’s ability to dimerize with additional lipid mediator–sensing nuclear receptors, including the vitamin D receptor (VDR). The implication being that excess or insufficient availability of these vitamins may impose some receptor challenges on their opposite nuclear receptor, and for clinical consideration, the increased intake of Vitamin D without periodic measurements and consideration of vitamin A status may increase immune responsiveness to challenges in the mucosal tissues and lead to inappropriate inflammation.
Therefore, it is possible that, given their common RXR nuclear binding partners, some ligands, such as 1,25(OH)2VD3 and retinoic acid, might antagonize each other’s effects.[6] Keep this in mind when asking if someone is supplementing in large doses of vitamin D.
References
[1] Borel P, Desmarchelier C, Nowicki M, Bott R. A Combination of Single-Nucleotide Polymorphisms Is Associated with Interindividual Variability in Dietary β-Carotene Bioavailability in Healthy Men. J Nutr. 2015 Jun 10. pii: jn212837. View Abstract
[2] de Francisco A, Chakraborty J, Chowdhury HR, Yunus M, Baqui AH, Siddique AK, Sack RB. Acute toxicity of vitamin A given with vaccines in infancy. Lancet. 1993 Aug 28;342(8870):526-7. View Abstract
[3] Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004 Oct;21(4):527-38. View Full Paper
[4] Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature. 2003 Jul 3;424 (6944):88-93. View Abstract
[5] Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008 Sep;8(9):685-98 View Full Paper
[6] Bastie JN, Balitrand N, Guidez F, Guillemot I, Larghero J, Calabresse C, Chomienne C, Delva L. 1 alpha,25-dihydroxyvitamin D3 transrepresses retinoic acid transcriptional activity via vitamin D receptor in myeloid cells. Mol Endocrinol. 2004 Nov;18(11):2685-99. View Abstract
