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FOR IMMEDIATE RELEASE
It's Official: Vitamin D Reduces the Incidence of Autoimmunity
by Michael Passwater
OMNS (Feb. 17, 2022) The Harvard led Vitamin D and Omega 3 trial (VITAL), recently published findings showing a meaningful (22%) and statistically significant (p = 0.05, Hazard ratio = 0.78 95% CI = 0.61 - 0.99) reduction in the incidence of autoimmune disease in older adults taking 2000 IU (50 mcg) per day for 5 years.  This was a large nationwide study involving 12,786 men 50 years or older and 13,085 women 55 years or older. It was a randomized double blind, placebo-controlled trial. The British Medical Journal notes, "The clinical importance of this trial is high because these are well tolerated, non-toxic supplements, and other effective treatments to reduce the incidence of autoimmune diseases are lacking". In 2017, the National Institutes of Health (NIH) estimated that 23.5 million Americans, >7% of the population, suffered from an autoimmune disease. The NIH noted that the prevalence appeared to be rising. 
Illustrating the high prevalence of vitamin D deficiency and insufficiency in the USA, 13% of participants in the VITAL trial had vitamin D levels < 20 ng/mL (50 nmol/L) at the start of the trial, and 45% had levels < 30 ng/mL (75 nmol/L). A subgroup of participants (1,644 people) had vitamin D levels tested one year into the study. In aggregate, participants taking 2000 IU vitamin D had an increase of 40% in vitamin D levels to 41.8 ng/mL (104.5 nmol/L), while participants in the soybean oil placebo group remained similar to baseline (30.7 ng/mL, 77.1 nmol/L). Strengths of this study include its size and diversity; its design as a prospective, placebo controlled, randomized trial -- the "gold standard" for medical drug studies; its baseline measurement of blood levels of vitamin D and follow-up testing of a sample of participants, rather than relying on intake estimates; the use of a meaningful, safe dose more than double the US RDA for vitamin D, and its duration with a median follow-up time of 5.3 years.
"P values" are an expression of the degree of probability that the results of an experiment testing a hypothesis are due to chance. Generally speaking, the lower the P value, the higher the reliability of the data.
But nutrient studies require different approaches than drug studies. [3,4,5] A weakness of the VITAL trial was the absence of evaluation of synergistic nutrients. Additionally, with appreciation for Roger Williams' principle of biochemical individuality,  it would have been interesting and helpful to compare the outcomes for each range of vitamin D levels achieved after the fixed dose intervention (e.g. stratifying participants by vitamin D levels achieved < 20, 20 - 29, 30-39, 40-49, 50-59). However, this would have required more measurements, thus increasing the expense of the trial.
The 3 Ds for vitamin D (and any nutrient) assessments:
Dose - how much of the nutrient reached the blood/tissue; whether the individual achieved and maintained sufficient or therapeutic levels.
Duration - how long sufficient or therapeutic levels were maintained. Vitamin D has extensive epigenetic effects, impacting over 3,000 genes. It has been estimated that as much as 3-4% of the genome may be influenced by vitamin D. These genetic influences may be especially important during fetal development.  The half-life of the active form of vitamin D is about 4 hours, and the half-life of the pre-hormone form of vitamin D is 2-3 weeks. However, it may take even longer for the effects of proteins from genes upregulated and downregulated by vitamin D to make their biological impact. Bruce Ames' concept of "longevity proteins" applies.  With saturation of a full set of nutrients, cell metabolism is able to expand from production of only survival proteins to producing additional proteins he called "longevity proteins". For these reasons, it is important to maintain vitamin D in the healthy range on an ongoing basis rather than waiting until illness occurs. When rescue therapy is needed, calcifediol (25OHD) increases active vitamin D levels more rapidly than cholecalciferol (D3). [10-12] (see http://www.orthomolecular.org/resources/omns/v17n17.shtml and http://www.orthomolecular.org/resources/omns/v16n55.shtml for discussions of nutritional support in critical illness).
Dynamic interactions - were sufficient levels of synergistic cofactors maintained? Magnesium is necessary in eight steps of vitamin D metabolism. [13,14] Intracellular selenocysteine can also be a rate limiting factor in vitamin D production and function. Increasing glutathione and cysteine can increase production of vitamin D even without vitamin D intake or sunlight exposure. In turn, vitamin D increases production of several selenoproteins. [15-17] Vitamin C and zinc also assist actions of vitamin D, and it is important to balance vitamin D with vitamin K2 to ensure mobilized calcium gets where it is needed rather than being deposited in arteries. 100 mcg K2 for every 5000 IU D3 is a good ratio for wellness. [18,19]
In research, controls matter too. This same VITAL study also looked at the effects of supplementing 1000 mg/day of omega-3 vs. placebo. A 15% reduction in the incidence of autoimmune disease was seen compared to the control group. However, this did not reach statistical significance. Interestingly, olive oil, which is known to be anti-inflammatory and a source of vitamin K, was used as the placebo for comparison. It is possible that the choice of a non-inert placebo blunted the signal of true benefit from the omega-3 intervention.
Vitamin D: influence on the immune system
The VITAL study adds important support on the benefits of vitamin D for the immune system. Vitamin D regulates calcium and phosphate homeostasis in the body. Calcium is important for much more than strong bones. [20-23] Mobilized ionized calcium is essential for muscle contractions, nerve impulses, cell signalling, blood clotting, immune function, and catalyzing hundreds of enzymatic reactions throughout the body. Nearly all cells in the body have vitamin D receptors (VDRs). Intestine, bone, kidney, parathyroid glands, and immune cells (T cells, B cells, Dendritic Cells, Macrophages) have high levels of VDRs. The CYP27B1 enzyme which produces the active form of vitamin D and the ligand for VDR is also widely expressed in many cells throughout the body. The liver and kidney produce much of the active vitamin D in the body, however activated immune cells will also produce 1,25(OD)2D when the 25OHD substrate is present for conversion into the active hormone. Parathyroid Hormone (PTH) regulates the production of the active form of vitamin D in non-immune cells. Active vitamin D production in immune cells is not influenced by PTH, but is instead regulated by cytokines and the availability of the prehormone 25OHD in the local cellular environment.
Vitamin D has important influences on many phases in the innate branch of the immune system (cellular, complement, antimicrobial peptides, lectins, non-antibody producing aspects of immunity), and also in the adaptive branch of the immune system (antibody-producing aspects of immunity). The adaptive branch of the immune system has two major phases. The effector phase involves antibody production while the regulatory phase involves removal of B cells producing antibodies that cross-react with self-cells. The antibody-antigen lock and key fit isn't always exact. Even healthy people have self-reactive B cell clones.  Similarity between a "foreign" antigen and a host cell membrane element may exist or an antibody may overlap the membrane portion of a neoantigen-membrane complex. When B cells with these self-reacting or self-cross-reacting antibodies are stimulated to mass divide and produce their antibodies, they must be destroyed by the regulatory immune cells (Tregs) to minimize self-injury. Imbalance or dysfunction in the regulatory phase of the adaptive immune response is the major mechanism of autoimmune diseases in humans.  Interestingly, several sensitive areas of the body, the brain, anterior chamber of the eyes, and testes, are devoid of adaptive immune responses. The risk of collateral damage from antibody production in these areas is too great.
The active form of vitamin D: [26,27]
The overall effect is a stronger innate immune response, and a safer adaptive immune response.
A short history of clinical observations about vitamin D
Vitamin D is important for a wide range of functions in human biology from conception onward. We now have more evidence pointing towards the importance of maintaining a vitamin D level in the 40-60 ng/mL range, along with maintaining adequate levels of synergistic nutrients to fight infections, sustain helpful immunity, and also to prevent harmful autoimmune reactions.
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2. NIH Autoimmune Diseases Coordinating Committee: Autoimmune Diseases Research Plan, March 2005. https://www.niaid.nih.gov/sites/default/files/adccfinal.pdf
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7. Over 200 Scientists, Doctors, & Leading Authorities Call For Increased Vitamin D Use To Combat COVID-19 Scientific evidence indicates vitamin D reduces infections & deaths. Open Letter #VitaminDforAll, October 2020. https://vitamind4all.org/letter.html
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