“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).

This statement by the Hungarian biochemist Albert Szent-Gyorgyi, highlights the impact of vitamins on the body’s vital organs, including the immune system. Vitamins (vital amines) are organic compounds that are required in trace amounts in the diet because they cannot be synthesized in sufficient quantities by the human body. Vitamins and their metabolites are essential for a large number of physiological processes, fulfilling diverse functions as hormones and antioxidants, as regulators of tissue growth and differentiation, in embryonic development and in calcium metabolism, among many others ⁽¹⁾.

The essential roles vitamins contribute to the immune system extend to both innate and adaptive immune responses. Although some vitamins, such as vitamins C and E and members of the B complex, can act in a relatively general manner in the immune system (for example, as antioxidants), other vitamins, such as vitamins A and D, influence the immune response in highly specific ways. ⁽²⁾

This blog post will focus on vitamins A and D as they have recently received particular attention regarding their multi-faceted roles in enabling effective immune capacity. Vitamins A and D are notably distinct from other vitamins in that their respective bioactive metabolites, retinoic acid and 1,25-dihydroxyvitamin D3, have hormone-like properties. Both of these active vitamin forms are synthesized from their vitamin precursors by different tissues and cells in the body and exert their effects on target cells by binding to cellular receptors. This is to say that these two fat soluble vitamins not only play a nutritional role, but also act as active immune signaling agents.

Vitamin D and Immune Activity

Vitamin D is created de novo in the human body when the skin is exposed to sunlight. Lack of adequate sun exposure or utilization of sun block can prevent this interaction from occurring. This dynamic explains why people in nursing homes may have lower levels of circulating active vitamin D (25-dihydroxyvitamin D, as they are often confined indoors. Diet is another source of the “sunshine vitamin” (3). Good dietary sources include eggs, dairy products, mushrooms, and fatty fish. Widespread use of cod liver oil, a time-tested source of vitamin D, in Northern Europe may explain why active vitamin D levels are often robust in these darker climates and why Northern European countries experienced lower levels of mortality in the recent covid-19 pandemic(4).

In order to protect us from outside invaders such as bacteria or viruses, and to not damage our bodies by excessive activity, our immune systems must function in a balanced manner. Like Goldilocks proverbial porridge, we don’t want our complex immune systems to run cold or too hot, it needs to be “just right”. This is where vitamin D comes in. Vitamin D plays a role in both the innate (what we are born with), and the adaptive (what we develop) immune systems. Active vitamin D is required for the function of nearly every type of immune cell, including T killer cells which destroy pathogens and Beta cells tasked with making antibodies that target active intruders and can circulate for years in vigilance of a pathogens return.

One of the breakthrough discoveries of the last couple of decades is the role 25-dihydroxyvitamin D₃ plays in controlling immune activity. Active vitamin D is used as a signaling agent whereby the immune system “calls off the attack” so to speak (5). When active vitamin D is released by immune cells, white blood cell activity is reduced and pro-inflammatory signaling factors such as various cytokines (protein based immune communication compounds) and C reactive protein levels drop. This action by vitamin D not only promotes the tissue healing process, but also works against autoimmune conditions characterized by ongoing, or chronic inflammation do to elevated immune activity. Autoimmunity is marked by immune dysregulation that results in our powerful immune system attacking our own bodies.

Vitamin A and Immune Activity

Active vitamin A, or retinoic acid, generally acts to support and enhance innate immune activity. For example, retinoic acid enhances various T cells’ ability to move freely and swiftly through out the body and increases their ability to destroy pathogens. Active vitamin A also has been shown to inhibit Beta cell apoptosis or “cell death” thereby potentially increasing their resilience (6).

A key component of the general immune system are barrier tissues, such as the skin, mucus membranes, and the gastrointestinal track (GI). Healthy barrier tissues help to keep pathogens from entering our bodies in the first place. Further, many barrier tissues, such as those in our gastrointestinal tracks (small and large intestines) contain a vast array of immune cells. For example, up to 40% of the lymphatic cells in the human body reside in the gastrointestinal track. This, or course, makes a great deal of sense as the GI track is one of the two primary areas where the external world can enter our internal environment (the other being the lungs). Vitamin A is essential for healthy mucosal tissues and supports the effective and balanced activity of immune cells imbedded in these critical barrier tissues.

Vitamins A and D Intimate Partners in Health

Scientists have known since as far back as the1930s that vitamins A and D work together in a synergistic fashion. In 1964 doctors Clark and Smith determined that vitamins A and D mutually protect against the possible toxicity of each other (7). These vitamins exert physiological immune activity by interacting with the same set of cellular receptors, therefore they share the same route towards influencing gene expression and protein synthesis.

The immune supportive, fat soluble vitamins A and D are both multifacetedly essential for healthy immune activity. They both play a variety of critical roles and functions that could literally fill an entire book of immune biology. And the effective action of one, depends upon the presence of the other. These vital amines A true one, two punch for promoting balanced immune activity.

1. Rosenberg IH. Challenges and opportunities in the translation of the science of vitamins.  J. Clin. Nutr. 2007;85:325S–327S.
2. Llesuy S, et al. Effect of vitamins A and E on ischemia-reperfusion damage in rabbit heart.  Cell. Biochem. 1995;145:45–51. 
3. Holick MF. Vitamin D deficiency.  Engl. J. Med. 2007;357:266–281.
4. Lancet May, 20 2020 org/10.1016/S2213-8587(20)30183-2
5. van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D₃: basic concepts.  Steroid. Biochem. Mol. Biol. 2005;97:93–101
6. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function.  Neurobiol. 2006;66:606–630
7. Clark and Smith (1964). Effects of Hypervitaminosis A and D on Skeletal Metabolism. The journal of Biological Chemistry, 239 1266