Vitamin D: Focus on Immune Modulation
Abstract
Vitamin D supplementation is not strictly for healthy bone metabolism. There is a significant expression of vitamin D receptors (VDRs) in specific target cells and tissues. Vitamin D deficiency is very common around the world, being affected by latitude/winter season, melanin production, pharmaceutical side effects, obesity, and fat malabsorption disorders. Deficient serum vitamin D levels modulate VDR expression which influences expression of downstream genes and induces protein cascades in different tissues to elicit disease symptoms. The common theme in all of the studies reviewed is the role vitamin D plays in the immune response. Vitamin D deficiency has been implicated in not only immune related conditions, but chronic medical conditions as well. While the mechanism of action of vitamin D in these conditions has not been fully elucidated, significant associations have been documented. This suggests vitamin D may provide effective, non-invasive, and non-pharmaceutical interventions for treatment and prevention of many diseases. The present review will summarize key findings from various literature reviews and meta-analyses of in vitro studies, in vivo studies, as well as human clinical trials, to provide evidence for the role of vitamin D in immune modulation.
Introduction
Vitamin D has a well established role in calcium and phosphorus homeostasis, vital to optimal mineralization of bones and teeth. It is not surprising that individuals with a vitamin D deficiency present with conditions such as osteomalacia, osteoporosis, and periodontitis. However, due to vitamin D’s various target tissues and cells, a deficiency can cause patients to present with symptoms that are not related to bone health.
In order to understand the physiological activity of vitamin D, identification of its receptor in specific cells and tissues is crucial. Vitamin D receptor (VDR) are abundant in small intestinal epithelium, large intestine, pancreatic beta islet cells, distal renal tubular epithelial cells, bronchial epithelial cells, epidermal epithelial cells, osteoblasts, T-lymphocytes, monocytes/macrophages, and parathyroid epithelial cells (Wang et al 2012). VDR expression is lower, yet significant, in the center of efferent ducts in testes, prostate gland, and in lobule and ductal epithelial cells in mammary glands (Wang et al 2012). VDR was undetectable in hepatocytes, brain tissue, skeletal, smooth and cardiac muscle, thyroid, and adrenal gland. However, the antibodies used in the immunoassays were not one hundred percent VDR specific (Wang et al 2012). Optimal functioning of these target tissues and cells depends on adequate serum vitamin D levels.
Vitamin D has two main forms: 25-hydroxyvitmain D (25(OH)D), which is produced in the liver, and 1,25-dihydroxyvitamin D (1,25(OH)D), which is the active form of vitamin D, that is produced in the kidneys. In order to determine an individual’s vitamin D status, serum 25(OH)D levels are measured (Holick et al 2011). Vitamin D deficiency is defined as a serum level of 25(OH)D below 50nmol/L, while insufficiency is a serum level of 52.5-72.5nmol/L (Holick et al 2011). In order to consistently raise serum levels above 75nmol/L, at least 1000IU per day of vitamin D is required in all age groups; however, various dosages above 1000IU are required to correct the deficiency depending on age, pregnancy, and use of certain medications (anticonvulsants, glucocorticoids, and antifungals) (Charoenngam and Holick 2020, Holick et al 2011). The main cause for deficiency is the lack of exposure to sunlight due to sunscreen use, dark skin pigmentation, and the winter season (Charoenngam and Holick 2020). Other significant factors that are associated with vitamin D deficiency are body mass index greater than 30, fat malabsorption disorders (such as celiac disease, bile insufficiency, irritable bowel disease, and cystic fibrosis), liver and kidney failure, medications such as anticonvulsants, drugs used to treat HIV/AIDS, corticosteroids, rifampicin, and primary hyperparathyroidism (Charoenngam and Holick 2020, Holick et al 2011). One of the main target cells that are greatly affected by inadequate serum vitamin D levels are those of the immune system.
Vitamin D and the Immune System
Over the last decade the immunological role of vitamin D has become more evident. More recently, a deficiency of vitamin D has been associated with immune related conditions and diseases such as cancer, viral respiratory infections, and SARS-CoV-2 infection (Carlberg and Velleuer 2021, Charoenngam and Holick 2020, Davari et al 2021 Ghasemian et al 2021, Herr et al 2011). Vitamin D deficiency has also been implicated in many chronic medical conditions such as uterine fibroids, metabolic syndrome, cardiovascular disease, and polycystic ovarian syndrome (PCOS), all of which have some inflammatory component to disease progression (Cai et al 2021, Ciebiera et al 2018, Gokosmanoglu et al 2020, Theik et al 2021). Awareness of the role that Vitamin D has in both the innate and adaptive immune responses can help to understand how and why vitamin D deficiency is associated with the aforementioned conditions.
The cells of the innate and adaptive immune system have the ability to convert 25(OH)D to its active form, 1,25(OH)D. They also express VDR, which is a nuclear receptor that can influence gene expression, so that the 1,25(OH)D can induce antimicrobial responses in those cells (Baeke et al 2010). During an infection, 1,25(OH)D is produced within monocytes and macrophages, which stimulates antimicrobial activities of these immune cells through an autocrine signaling cascade initiated by VDR binding and gene expression of cytokines, chemokines, pattern recognition receptors, and antimicrobial peptides (Baeke et al 2010, Biriken et al 2021, Charoengam and Holick 2020). It also influences the immune response of neighbouring lymphocytes by upregulating TH2 and Treg cells and downregulating B, TH1, and TH17 cells, effectively suppressing the proinflammatory state (Cantorna et al 2015, Charoengam and Holick 2020, Holick 2007). Vitamin D downregulates B lymphocyte antibody production (Charoengam and Holick 2020). The lack of vitamin D in target cells and tissues can help to explain the presence of disease symptoms and why supplementation may be used as an adjunct therapy for symptom relief and suppression of disease progression. Vitamin D and its effects can be clearly seen when studying viral infections.
Viral Respiratory Infections: Special Focus on COVID-19
The course of a respiratory tract infection depends on the innate and adaptive immune response. Since vitamin D has demonstrated a strong influence on immune cell function (Charoengam and Holick 2020), it is probable that vitamin D levels can affect incidence and severity of a viral infection. At optimal levels, vitamin D causes enhancement of the lung epithelial cell barrier, stimulates maturation of type 2 pneumocytes, promotes surfactant production, and increases the innate immune response within the airways (Costagliola et al 2021B). Recent studies have shown that vitamin D deficient status is associated with increased incidence and severity of viral respiratory infections (Lai et al 2017, Martineau et al 2017). This association is stronger in patients with lung disease, such as asthma, COPD (Ginde et al 2009) and COVID-19 (Kazemi et al 2021).
A key theme that has emerged from observing and treating patients with SARS-COV-2 infection is immune hyperinflammation, making immunomodulation a possible treatment strategy (Tan et al 2020). The cytokine storm that is created during this infection leads to acute respiratory syndrome, organ failure and, in many cases, death (Musavi et al 2020). In a systematic review and meta-analysis of 15 recent studies, Kazemi et alrevealed that there is an association between vitamin D deficient status and severity of COVID-19 disease (Kazemi et al 2021). In other words, patients who are vitamin D deficient suffer from a more severe SARS-COV-2 infection (Alsafar et al 2021, Lau et al 2020). The greater the cytokine storm, the more severe the infection is (Alsafar et al 2021, Mustavi et al 2020). The role of vitamin D as a therapeutic agent comes into play here by inducing an anti-inflammatory response and suppressing the production of proinflammatory cytokines (Charoengam and Holick 2020). A recent RCT studying patients with mild to moderate COVD-19 symptoms demonstrated that supplementing patients with 5000IU of vitamin D orally per day for two weeks significantly reduced the symptoms of cough and ageusia (Sabico et al 2021).
It has been posited that, in an effort to control SARS-COV-2 viral replication, vitamin D induces numerous antimicrobial pathways, which reduce serum vitamin D levels quicker than the body can replenish them back to sufficiency. The antimicrobial response is then muted once vitamin D insufficiency is present (Lau et al 2020). However, this effect does not last as the body is capable of recovering from the acute inflammatory response allowing vitamin D levels to rise again (Smolders et al 2021). Unfortunately, this reaction was demonstrated in only nine healthy male volunteers. While these volunteers had insufficient vitamin D levels, patients with severe COVID-19 disease had marked vitamin D deficiency (Karonova et al 2021), which could make recovery from the acute inflammatory response more difficult.
Current investigations have demonstrated the role of vitamin D in inducing an antiviral response and negatively regulating the renin-angiotensin-aldosterone system (RAS). (Costagliola et al 2021A). The RAS consists of two protein axes, which are ACE/Ang II/ATR and ACE2/Ang 1-7/MasR (Musavi et al 2020). SARS-COV-2 infection disrupts this balance and causes lung damage, whereas vitamin D upregulates ACE2 receptor expression providing a protective effect on lung tissue (Musavi et al 2020). It is also through this mechanism that vitamin D protects against hypertension and inflammation by inhibiting RAS activity and suppressing renin synthesis (Musavi et al 2020). While much remains unknown regarding SARS-COV-2 infection and more large-scale studies are required, vitamin D may be a possible adjunct treatment and prevention strategy for severe COVID-19 disease.
Anti-Tumor Activity
Vitamin D not only affects the immune system in response to a microbial infection, but also its response to malignant cells. The human body is capable of searching for and destroying cancerous cells. Malignant tumor cell survival relies on genes and immune pathways, some of which are regulated by vitamin D (Carlberg and Velleuer 2021). In addition, in vitro studies using human colon cancer cell lines have shown that vitamin D has direct effects on differentiation, proliferation, and apoptosis of neoplastic cells by altering specific gene expression (Carlberg and Velleuer 2021, Palmer et al 2003, Wood et al 2004). Vitamin D also has indirect effects on tumor cell survival by regulating immune cells (Carlberg and Velleuer 2021). Vitamin D induces autophagy of cancerous cells by genomic and non-genomic pathways to regulate cell proliferation and differentiation (Bhutia 2021). Animal models as well as human and cancer cell lines have shown that vitamin D has antiproliferative effects by influencing specific genes involved in cancer cell growth (Banerjee and Chatterjee 2003).
Many in vitro studies have shown that vitamin D demonstrated anti-tumor activity when it was used to treat several cancer cells lines. Recent work confirms the presence of VDR in glioma cells since stimulating glioma cells lines with vitamin D increased VDR expression and subsequent anti-tumor effects (Lo et al 2021). Cell cycle arrest is the most well documented mechanism of how vitamin D exerts its anti-cancer effects in numerous glioblastoma cell lines (Lo et al 2021). Vitamin D works synergistically with temozolomide to significantly increase apoptosis in the C6 rat glioblastoma cell line (Bak et al 2016). Treating breast cancer cells with vitamin D and its analog, EB1089, also induces apoptosis through a VDR-mediated signaling cascade that suppresses the anti-apoptotic protein Beclin-2, which is normally overexpressed in tumors (Hoyer-Hansen et al 2005). Downregulation of Beclin-2 was also demonstrated in prostate cancer cell lines (Guzey et al 2002). Vitamin D and its analogs have also been shown to have anti-invasive effects in glioma cell lines (Lo et al 2021). An interesting new find is that VDR polymorphisms may be a genetic risk factor for several cancers; however, more large-scale association studies are required to confirm this in each individual cancer type (Lo et al 2021). Human trials using vitamin D supplementation in patients with cancer, both invasive and in situ types, revealed that supplementation did not prevent cancer, reduce its risk, or affect cancer incidence (Avenell et al 2012, Scragg et al 2018). It is suggested that humans may respond to vitamin D differently leading to the insignificant response in its supplementation (Carlberg and Velleuer 2021). There are numerous factors that affect cancer progression in humans, so if vitamin D is demonstrating anti-proliferative effects in vitro, there may still be a therapeutic role for it in treatment strategies.
Uterine Fibroids
Vitamin D has anti-tumor effects not only in cancerous cells, but also in benign tumor cells. One example is uterine fibroids or uterine leiomyomas. The uterine fibroid, derived from the myometrium of the uterus, is the most common benign tumor in women of reproductive age (Vergara et al 2021). Many studies have demonstrated the association of vitamin D deficiency and increased risk of developing uterine fibroids (Baird et al 2013, Li et al 2020, Mitro and Zota 2015, Paffoni et al 2013, Singh et al 2019). In vitro studies demonstrated an anti-proliferative effect of vitamin D on human leiomyoma cells, in a concentration and time-dependent manner (Sharan et al 2011). Proteins involved in tumor proliferation, such as cyclin-dependant kinase 1 {CDK-1}, proliferating cell nuclear antigen {PCNA}, catechol-O-methyltransferase {COMT}, and proliferation marker protein KI-67 {MKI-67} were significantly reduced in the presence of vitamin D (Sharan et al 2011). In addition, transforming growth factor beta {TGF-β}, which is responsible for extracellular matrix regulation, was significantly inhibited by vitamin D, leading to decreased fibroid volume (Halder et al 2011). It is well known that uterine fibroids are hormonally regulated. Increased extracellular vitamin D regulates the expression of nuclear estrogen and progesterone receptors in a dose dependent manner (Al-hendy et al 2015). In recent clinical trials, treating women with uterine fibroids who had a vitamin D deficiency demonstrated tumor growth inhibition (Arjeh et al 2020, Ciavattini et al 2016, Suneja et al 2021) as well as reduction in tumor volume (Hajhashemi et al 2019). It has been suggested that uterine fibroids could be the result, in part, of a chronic pro-inflammatory immune response that is governed predominantly by TH17 cytokines (Wegienka 2012). Vitamin D can regulate the expression of TH17 cytokines through activation of its receptor and downstream genes (Charoengam and Holick 2020). This simple treatment may have beneficial implications in female health standards of care for dysmenorrhea and fertility.
Metabolic Syndrome
Chronic infection and systemic inflammation are major contributors to metabolic syndrome (MeS) and insulin resistance. Vitamin D has the ability to modulate the adaptive and innate immune system, hence, it is not surprising that a vitamin D deficiency has been associated with increased incidence of type 2 diabetes, increased risk for MeS, increased triglycerides, decreased high density lipoprotein levels, obesity, and non-alcoholic fatty liver disease (NAFLD) (Barchetta et al 2011, Bea et al 2015, Ceglia et al 2017, Chon et al 2014, Zheng et al 2019).
An inflammatory terrain is associated with the health of the gastrointestinal tract. The small intestine is a major vitamin D targeting tissue, where VDR levels are abundantly expressed (Wang et al 2012, Zeng et al 2020). VDR expression is greater in the distal small intestine, more specifically within Paneth cells, which are also more abundant than in proximal regions (Zeng et al 2020). These intestinal cells are responsible for secreting antimicrobial agents, known as α-defensins, within the lumen of the small intestine modulating bacterial growth. In a narrative literature review of animal and human studies, vitamin D supplementation given to vitamin D-deficient subjects led to an increase in beneficial bacteria, including Ruminococcaceae, Akkermansia, Faecalibacterium, Lactococcus, and Coprococcus, and a decrease in Firmicutes (Tangestani et al 2021). Therefore, vitamin D signaling is crucial to maintaining the gut microbiome and a deficiency leads to dysbiosis and inflammation (Su et al 2016). Conversely, a sufficient amount of vitamin D can significantly suppress metabolic disorders by improving insulin resistance, reducing plasma triglycerides, and decreasing progression of hepatic steatosis (Su et al 2016). Targeting treatment plans to optimize gut health can have beneficial implications for many conditions characterized by inflammation.
Polycystic Ovarian Syndrome (PCOS)
PCOS is characterized by a polycystic ovarian morphology, hyperandrogenism, and ovulatory impairment, with insulin resistance as the main pathophysiological finding. As with uterine fibroids, there is an association of vitamin D deficiency with the development of PCOS in women of reproductive age (Gokosmanoglu et al 2020). Furthermore, higher androgen levels were associated with vitamin D deficiency in women with PCOS (Gokosmanoglu et al 2020). Supplementing women with vitamin D demonstrated a significant reduction in androgen levels and significant increase in insulin sensitivity post treatment (Karadag et al 2018). While the pathophysiology of PCOS cannot be fully explained, vitamin D deficiency and its associations with androgen excess and insulin sensitivity sheds light on possible mechanisms. As suggested with uterine fibroids, vitamin D may modulate androgen production through activation of its receptor in ovarian cells.
Conclusion
A key element in all of the conditions and diseases discussed within this review is inflammation. Whether it is acute or chronic, inflammation paves the way for disease progression. Fortunately, vitamin D can influence the inflammatory response in each of the mentioned diagnoses. How do we alleviate vitamin D deficiency? Current standards for treating vitamin D deficiency suggest testing only at-risk individuals. It makes sense that a patient who is likely to develop osteoporosis, based on age, diet, lifestyle and family history, is tested to confirm vitamin D status. However, patients with recurrent infections, cancer, metabolic syndrome, uterine fibroids, or PCOS may not show typical signs of vitamin D deficiency. Overall, recent scientific investigations have demonstrated that vitamin D has a strong impact in treating symptoms and preventing disease progression. It is time to change standards of care. Just as a complete blood count is run as a routine check, perhaps vitamin D levels should be included. Many more clinical trials are necessary to determine a therapeutic vitamin D dose that provides beneficial biological effects in each disease and condition. Having a non-invasive, non- pharmaceutical, and non-surgical treatment strategy can have a positive impact on today’s health care system and in people’s lives.
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