Vitamin D and the immune system

VITAMIN D AND THE IMMUNE SYSTEM

Vitamin D is a steroid hormone commonly known for its contribution to the maintenance of calcium and phosphorus homeostasis. But this is not its only function. In recent decades clinical, epidemiological and experimental studies have shown that increasing the serum level of vitamin D can reduce the risk of various autoimmune diseases such as systemic lupus erythematosus (SLE), type 1 diabetes mellitus (DM1), multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as other chronic diseases such as hypertension, cardiovascular diseases, pulmonary diseases and various types of cancer.(1,2)

Its effects are mediated through binding to its specific nuclear receptor (VDR, Vitamin D Receptor) with which it forms a complex that acts as a transcription factor affecting the expression of certain genes, regulating an increase or decrease in their expression. It is estimated that about 3% of the human genome is regulated by vitamin D in its active form. The VDR receptor is present in the cells of practically all tissues, including cells of the immune system (dendritic cells, macrophages and T lymphocytes). It is thus actively involved in modulating the immune response by contributing to self-tolerance and enhancing the innate immune response against microorganisms by increasing the phagocytosis capacity of activated macrophages. From the point of view of adaptive immunity it has been observed that vitamin D produces a decrease in the transcription of genes encoding cytokines such as IL-2 and IL-12, interferon γ and tumour necrosis factor α α producing an imbalance between Th 1 and Th 2 helper T lymphocytes and interfering in the antigen presenting capacity of T lymphocytes. (3) For all these reasons, the immunomodulatory activity of vitamin D could be used as a therapeutic strategy in the development of autoimmunity phenomena by increasing the level of tolerance in grafts or transplants. In addition, vitamin D could be an effective tool for infection control . (4,5)

VITAMIN D SYNTHESIS

Vitamin D3, better known as “the sunshine vitamin” is obtained endogenously from its precursor 7-dehydrocholesterol when the sun’s rays come into contact with the skin. Cholecalciferol (vitamin D3) is an inactive prohormone that needs to undergo a series of hydroxylations to be activated and fulfil its function. The first hydroxylation takes place in the liver becoming 25-hydroxycholecalciferol (25-OH-D3), which is the circulating form, which is converted in the kidney by the action of the enzyme 1α-hydroxylase to the active form 1,25-dihydroxycholecalciferol (1,25-(OH)2 D3), also called calcitriol. Activated vitamin D acts directly in the intestinal cells increasing the absorption of calcium and phosphorus in the blood. It acts by mobilizing calcium from bone and inhibits the secretion of parathyroid hormone (PTH), which indirectly stimulates osteoclasts, and facilitates bone mineralization that allows our bones to be healthy and strong. (6)

The serum concentration of vitamin D may depend on several factors: exposure to sunlight (a process influenced in turn by genetic factors and place of residence), age (as we age our ability to synthesize the active metabolite is less), ethnicity (dark skins synthesize less vitamin D), cultural aspects (customs of dressing more covered with clothing), body mass index (the greater the weight the lower the endogenous synthesis) and the use of some drugs (steroids and immunosuppressants) mean that our blood levels of vitamin D may be insufficient. (7)

EXOGENOUS SOURCES OF VITAMIN D

Vitamin D3 can also be supplied through the diet (oily fish, eggs and fortified dairy products) or through food supplements. It should be noted that there are two main sources of vitamin D: cholecalciferol (vitamin D3), of animal origin, and ergocalciferol (vitamin D2) of plant origin, which is produced by the action of ultraviolet radiation on the ergosterol of the membrane of some fungi and yeasts.

The question that the scientific community has been trying to clarify for a long time is whether vitamin D2 and vitamin D3 have the same capacity to generate the active metabolite (vitamin D). In recent years several studies have shown that vitamin D3 seems to be more effective in this regard. In 2015, B. Oliveri et al. indicated that the greater efficacy of D3 in increasing serum vitamin D levels lies in the different half-life of the two vitamins, being 82 days for 25(OH)D3 and only 33 days for 25(OH)D2. (8) Years later, L. Tripkovic et al. conducted a double-blind study, randomly selecting European and Asian women who were given 12-week doses of 15 µg of vitamin D2 and D3. (9) The results indicated that 100% of the European women supplemented with D3 achieved acceptable serum vitamin D levels (>50 nmol/L) versus 90% who received equivalent doses of vitamin D2. The same trend was observed in the group of Asian women: 70% (supplemented with D3) versus 50% (supplemented with D2). This result also reflects the worse genetic predisposition of Asians to synthesize the active vitamin D metabolite compared to Europeans. The authors suggest that the differences could be due to a higher affinity of the VDR receptor for vitamin D3 than for D2, as well as a higher response of hydroxylation enzymes.

RECOMMENDED VITAMIN D LEVELS

Measurement of serum 25-hydroxyvitamin D (25(OH)D) levels is the universal marker indicating the necessary amount of the metabolite in the blood to preserve optimal health of our bones and the body in general. (10) The diversity of opinions on what are the adequate levels of this hormone and the appropriate dose to achieve these levels has been and continues to be a source of controversy among researchers and scientific societies. (11)

Below is a table with the different values proposed by the Endocrine Society of America (ES) and the Institute of Medicine (IOM):

The nutritional recommendations of the FAO and WHO have been modified over the years based on published scientific studies that establish the needs of the organism in situations of health and disease. Specifically for vitamin D, the regulation of the 2008/100/EC directive, which established recommended daily allowances (RDA) of 5 µg, was revised upwards in the EFSA opinion 2013-2016 increasing the adequate intake to 15 µg of vitamin D under conditions of minimal skin synthesis in healthy individuals. (12)

Regarding the tolerable upper limit (UL), the EFSA in 2012 ruled the following values based on age, sex and individual situation: (13)

The Endocrine Society published in 2011 a Clinical Practice Guideline on the appropriate dose of vitamin D supplementation to treat vitamin D deficiency or insufficiency. (14) In this statement the Endocrine Society recommends daily doses of at least 1500-2000 international units (IU) to achieve vitamin D levels above 30 ng/ml. In people with a high body mass index or taking steroid or immunosuppressive drugs, they recommend increasing the intake to values of (3000-6000 IU/day). On the other hand, if the aim is to correct severe deficiencies, they recommend reaching the TML which should be 2000 IU/day for children under 12 months, 4000 IU/day for children and adolescents up to 18 years of age, and 10000 IU/day in adults over 18 years of age.

Vitamin D toxicity, also known as hypervitaminosis D, is a condition that can cause serious health problems, but fortunately it is not very frequent. It is usually caused by excessive and/or long-term ingestion of vitamin D or by an abnormal functioning of vitamin D metabolism. It occurs when serum levels of 25(OH)D are higher than 100-150 ng/ml, the main consequence being an excessive accumulation of calcium in the blood (hypercalcemia). The most frequent symptoms are: nausea, recurrent vomiting, abdominal pain, apathy, weakness and frequent urination. Excessive blood calcium levels (severe hypercalcemia) can weaken bones, form kidney stones and interfere with normal brain and heart function. (15)

BIBLIOGRAPHIC REFERENCES:

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