Vitamin D and The Immune System
Although vitamin D is best known for its ability to maintain bone health and ensure normal circulating calcium levels, it is also now well recognized for its ability to regulate the immune system. Many cells of the immune system, which are termed leukocytes, including dendritic cells and macrophages, express the various cytochrome P450 enzymes and the vitamin D receptor (VDR), which are essential to metabolize, activate and respond to vitamin D appropriately.
Vitamin D deficiency is prevalent among many populations worldwide and is associated with increased susceptibility to diseases. Studies have been conducted to assess if increasing 25-hydroxyvitamin D levels via supplementation can prevent or reduce the severity of inflammatory diseases. The literature supports the immune-modulating role of vitamin D in supporting host defence against infectious diseases while, at the same time, being able to avert excess inflammation associated with certain autoimmune disorders. Infectious diseases reported in the literature to benefit from vitamin D include but are not limited to influenza, pulmonary tuberculosis and COVID-19. Various autoimmune disorders such as rheumatoid arthritis (RA), type 1 diabetes (T1D) and psoriasis have also been reported to benefit from vitamin D supplementation [Murdaca et al. 2019].
The role of vitamin D in protecting against the flu has been well studied. Vitamin D is in part able to upregulate an important defence molecule called defensin β2, which has a direct antiviral effect on influenza viruses by blocking the fusion of viral hemagglutinin to hose cell membranes, which is required for the invasion of host cells [Urashima et al. 2010]. Vitamin D also can decrease levels of various inflammatory cytokines such as TNF-𝛼, IFN-β and downregulates IL-8, IL-6 induced by influenza A infection [Gruber-Bzura 2018].
Tuberculosis (TB) is a bacterial disease caused by Mycobacterium tuberculosis that remains a leading cause of morbidity and mortality in many countries [Zaman 2010]. Vitamin D deficiency is associated with an increased risk of developing TB, and increased susceptibility of progression from latent to active disease [Cao et al. 2022]. A cohort human study (n=95) for example, observed an inverse association between active TB and vitamin D status, with 86% of active TB patients having serum 25(OH)D concentrations < 30 ng/mL [49]. Since the 18th century, patients with TB have been given a daily regimen of sunshine.
Over the past few years, many studies have observed an association between low vitamin D levels and severe COVID-19 [D’Avolio et al. 2020]. A retrospective study conducted in Israel assessed 25(OH)D levels in 1176 patients before testing positive for COVID-19 and found that low vitamin D status (25(OH)D < 20 ng/mL) was associated with severe disease [Dror et al. 2022]. Two studies also reported that individuals who had 25(OH)D > 30 ng/mL had a lower risk of COVID-19 infection, lower risk of severe COVID-19, lower risk of mortality and improved clinical outcomes, including a decreased inflammatory marker of C-reactive protein (CRP) [Oristrell et al. 2022, Maghbooli Z et al. 2020]. One mechanism to explain this is that 1,25(OH)2D binding to the VDR has been shown to downregulate the expression of ACE2 thereby preventing the SARS-CoV 2 spike protein from binding to host cells [Maghbooli et al. 2020]. A pilot study was also conducted to assess the effect of vitamin D on the rate of COVID-19 patients entering the ICU [Castillo et al. 2020]. Individuals in the vitamin D-supplemented group had a significant reduction of risk of requiring ICU treatment compared to the control group.
Several Randomized Control Trials (RCT) have also been conducted to assess the role of vitamin D in preventing and reducing COVID-19 disease severity. For example, a study conducted in Saudi Arabia assessed the clinical outcomes and recovery time of COVID-19 patients. Participants were allocated to either the 5000 IU/day of vitamin D3 or to 1000 IU/day of vitamin D3 for two weeks. A significant decrease in recovery time for cough and loss of taste was seen in the higher vitamin D treatment group, which also had a significant increase in serum 25(OH)D3 [Sabico et al. 2021].
Not all RCTs, however, have shown benefits. For example, an effect of 200 000 IU dose of vitamin D on the length of hospital stay of COVID-19 patients was not observed [Murai et al. 2021], and inflammatory markers were unaffected by this single dose of vitamin D treatment.
Overall, meta-analyses support the use of vitamin D.
Although many studies show the benefits of vitamin D supplementation, there remain conflicting data on the ideal dose of vitamin D in managing inflammatory diseases. Generally, a serum level between 50-80 ng/ml is within the optimal range. Nonetheless, there is still much to learn regarding the multifaceted role of vitamin D on health and well-being.
Factors Influencing Vitamin D Levels
Various environmental factors influence vitamin D status. People living further away from the equator have less exposure to direct sunlight, which reduces their potential for vitamin D production. Individuals living in colder climates also commonly cover most of their skin with warm dark clothing leaving little skin exposed to sunlight, and widespread use of sunscreens containing high SPF (sun protection factor) during the summer months contributes to vitamin D insufficiency [Tsiaras et al. 2011]. Skin temperature also affects an individual’s ability to synthesize vitamin D.
Ethnicity plays a key role in vitamin D production. Individuals with dark skin pigment are better adapted to living in high UV radiation environments because they have higher levels of melanin production than fair skin individuals; however, this comes at the expense of lower vitamin D production efficiency, which in lower UV radiation latitudes contributes to vitamin D deficiency.
Genetics also contributes to an individual’s potential to produce vitamin D. The nucleotide sequences of genes encoding the proteins and enzymes that function in the vitamin D metabolic pathway can vary among individuals and affect levels of bioactive vitamin D. For example, a single nucleotide change (rs10877011) was discovered in the CYP27B1 gene, which codes for a key enzyme involved in vitamin D bioactivation, and one version of this variant was associated with decreased levels of serum vitamin D 25(OH)
Malabsorption disorders such as cystic fibrosis and Crohn’s disease, along with kidney and liver diseases, can also increase one’s risk of vitamin D deficiency, as insufficiencies in these organs can inhibit the proper functioning of the vitamin D pathway.
Pregnant women are also at higher risk of vitamin D deficiency. A small prospective study involving 40 pregnant women who were supplemented with prenatal vitamins containing 600 IU of vitamin D daily throughout their pregnancy concluded that 76% of mothers and 81% of newborns were vitamin D deficient [Lee et al. 2007]. Deficiency during pregnancy can increase the risk of preeclampsia, wheezing disorders and tooth decay in offspring [Holick et al. 2017b].
Age is another risk factor for vitamin D deficiency. A Swedish study involving 333 participants over 65 years old living in a nursing home reported the mean concentration of 25(OH)D was ~16.08 ng/mL (40.2 nmol/l), and 80 participants had serum levels < 20 ng/mL (50 nmol/l). Serum levels measured in this study peaked during the summer months, highlighting the importance of sunlight therapy on the vitamin D status of the elderly [Samefors et al. 2014].
Vitamin D Toxicity
Vitamin D toxicity has rarely been reported but can occur and is characterized by severe hypercalcemia. Vitamin D production from sunlight exposure or through the consumption of food is not likely to lead to toxicity. Toxic levels of serum 25(OH)D will vary between individuals; however, levels reaching 150 ng/ml (375 nmol/l) have been observed during vitamin D overdose [Marcinowska-Suchowierska et al. 2018]. It is typically recommended to increase vitamin K2 intake if supplementing with high doses of vitamin D to reduce any chance of toxicity. In addition, since magnesium is a cofactor for vitamin D metabolism [Tan et al. 2020], large doses of vitamin D can lead to magnesium depletion. Individuals who increase their vitamin D intake must therefore ensure adequate magnesium intake. Nevertheless, many studies have safely used supplement doses of 5000-10,000 IU per day without any adverse effects.
All references may be found on our Research and Resources page.