Vitamin A: The Key to A Tolerant Immune System?
Originally published at ClinicalEducation.org
Vitamin D and Vitamin A are essential co-partners in immunological and bone health., I’m particularly excited about vitamin A because of its profound effects on the gut mucosal immune system—a specialty of mine. Just as vitamin D has attracted attention for its ability to increase antimicrobial peptides and help us defeat pathogens, it’s fascinating to me that vitamin A is also essential for the very tissues that protect us from the same pathogens.
The availability of vitamin A in our food is a key factor in a tolerant, highly functional immune system. To quote from the title of a brilliant commentary in the March 2008 issue of Nature’s Mucosal Immunology, “Vitamin A rewrites the ABCs of oral tolerance.”
Vitamin A is crucial to a very sophisticated bi-directional mechanism that takes place in the digestive system and leads to immune tolerance across the entire gut lining. Immune tolerance is the essence of good health. An intolerant immune system will lead to a wide range of illnesses, and the gut is where many people first lose immune tolerance. Vitamin A (retinoic acid) is key to our ability to consume a wide range of antigens (food) and yet not react adversely, and it’s quite fascinating.
When we speak of vitamin A, we are usually speaking of three essential fat-soluble molecules, retinol, retinal and retinoic acid. Retinol is the form in which vitamin A is stored. Retinal is crucial for vision. And retinoic acid actually functions like a hormone, binding to two receptors (RAR and RXR) and impacting over 500 different genes. Vitamin A is required for innate and adaptive immunity and is an immune enhancer that potentiates the antibody response, maintains and restores the integrity and function of all mucosal surfaces.
Vitamin A is also of fundamental importance for energy homeostasis. New research finds that retinol is essential for the metabolic fitness of mitochondria. When cells are deprived of retinol, respiration and ATP synthesis fall. They recover energy output as soon as retinol is restored to physiological concentration. This may answer the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action. Most important of all, the forgotten genius of vitamin A is its amazing ability to direct immune tolerance in the body through the cooperative interactions of gut-associated lymphoid tissues, Secretory IgA, bacterial communities and dendritic cells.
Immunity Starts in the Mucosa—with Vitamin A
Vitamin A cannot be synthesised by the human body; it must be absorbed by the intestine from the diet. In the presence of innate danger signals Vitamin A effects can diminish or synergise with innate responses to promote or enhance protective immunity, ensuring suitable plasticity.
The cells along the vast mucosal surfaces of your body are constantly in contact with foods, microbes and toxins. They make innumerable immunological decisions every day—so many that a single day’s encounters exceed that of the rest of your immune system over a lifetime. As the gut makes its decisions, it then relays information from the innate to the adaptive, systemic immune system. Mucosal tolerance is a necessity for us to survive; without it we would not survive a single day.
The gut is where health begins, and is also home to a huge microbiome made of innumerable species of bacteria. Vitamin A is the key to the gut making the right decisions. When you are deficient in vitamin A, you veer towards a type of effector T cell called TH17 and its production of IL-17—inflammation pro-inflammatory cytokine, with propensity to causing autoimmune disease. In contrast, when your stores of vitamin A are sufficient, you’ll have enough peripheral naïve T cells converted to T regulatory cells (Tregs) to help maintain tolerance across the immune system, and quench ‘inappropriate inflammation’ derived from the effector T Cells: TH17, TH1 and TH2. 
The discovery of T cells that secrete IL-17 and other inflammatory cytokines-is profoundly important. The TH17 subset is centrally involved in autoimmune disease and is important in host defense at mucosal surfaces. 
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