What Activates Vitamin D

What Activates Vitamin D

Understanding Vitamin D Metabolism & Function

Vitamin D is a steroid hormone involved in the intestinal absorption of calcium and the regulation of calcium homeostasis, bone differentiation and immune response. The term "vitamin D" refers to several different forms of this vitamin.

There are two major types of vitamin D:

1. Vitamin D2 (ergocalciferol) – which is synthesized by plants and is not produced by the human body.
2. Vitamin D3 (cholecalciferol) – which is made in large quantities in the skin when sunlight strikes bare skin. It can also be ingested from animal sources.

 Video produced by Animated Technologies for Abbott Labs

The storage type of vitamin D, namely 25- hydroxy vitamin D, is formed in the liver. The hormone 1,25-dihydroxy vitamin D (D hormone) is formed in a second hydroxylation step in the kidney. The responsible enzyme, the kidney 1 α-hydroxylase, is subjected to a rigid control through hormones (especially parathyroid hormone) and its activity is influenced by the serum concentrations of calcium and phosphate.

Forms of Vitamin D

25 Hydroxy

25-OH Vitamin D plays a key role in the maintenance of mineral balance and skeletal integrity. Long associated only with its role in bone formation; Vitamin D is actually active throughout the human body, influencing immune system responses and cell defenses.

25-Hydroxyvitamin D (25OHD) is the major circulating form of vitamin D and the precursor of the active form (1,25-dihydroxyvitamin D). Because of its long half-life, 25OHD measurements are useful for assessing vitamin D status.Vitamin D occurs in 2 forms: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Most current methods do not differentiate between the 2 forms: only total 25OHD concentrations are reported.

The reference range for total 25OHD (20-100 ng/mL) is based on 25OHD correlation with physiological parameters that include parathyroid hormone concentration and calcium absorption.^4-8 The range is not based on the distribution of levels in an apparently healthy population. 25OHD2– and 25OHD3– specific reference ranges are not available.

Total Vitamin D (25-hydroxy) Interpretation Ranges¹

These reference ranges represent clinical decision values that apply to males and females of all ages, rather than population-based reference values.

* Could be associated with osteomalacia or rickets
** May be associated with increased risk of osteoporosis or secondary hyperparathyroidism
*** Optimum levels in the normal population
**** 80 ng/mL is the lowest reported level associated with toxicity in patients without primary hyperparathyroidism who have normal renal function.

1,25 Dihydroxy

Of all the steroid hormones, 1,25(OH)2D represented the most difficult challenge to the analytical biochemist with respect to quantitation. 1,25(OH)2D circulates at pmol concentrations (too low for direct UV or MS quantitation), is highly lipophilic and its precursor, 25(OH)D, circulates at nmol levels.²

1,25-Dihydroxy vitamin D (aka Calcitiol) is the most potent vitamin D metabolite. It stimulates calcium absorption in the intestine and its production is tightly regulated through concentrations of serum calcium, phosphorus, and parathyroid hormone. Calcitriol is produced in the cells of the proximal tubule of the nephron in the kidneys by the action of 25-hydroxyvitamin D3 1-alpha-hydroxylase, a mitochondrial oxygenase and an enzyme which catalyzes the hydroxylation of 25-hydroxycholecalciferol (calcifediol). The activity of the enzyme is stimulated by PTH. The reaction is an important control point in Ca2+ homeostasis.³

Calcitriol increases blood calcium levels ( [Ca2+] ) by promoting absorption of dietary calcium from the gastrointestinal tract and increasing renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine. Calcitriol also stimulates release of calcium from bone by its action on the specific type of bone cells referred to as osteoblasts, causing them to release RANKL, which in turn activates osteoclasts.⁴

Calcitriol acts in concert with parathyroid hormone (PTH) in all three of these roles. For instance, PTH also stimulates osteoclasts. However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion of Ca2+. The resulting decrease in serum phosphate causes Ca5(PO4)3OH to dissolve out of bone thus increasing serum calcium. PTH also stimulates the production of calcitriol.³

Various research has shown 1,25 levels as an indication for:

• Disturbances of kidney functions:
  • Chronic kidney failure
  • Haemodialysis following kidney transplants
• Renal osteopathy
• Osteomalacia from various types of vitamin D metabolism disturbances
• Monitoring of therapy with active vitamin D metabolites
• Idiopathic hypercalciuria
• Hypercalcaemia

References

1. http://cclnprod.cc.nih.gov/dlm/testguide.nsf/Index/353F860EA5F1704585256BA700666862?OpenDocument/
2. Bruce W. Hollis, Bruce and Horsta, Ronald K. (2007). J Steroid Biochem Mol Biol. March; 103(3-5): 473–476.
3. Voet, Donald; Voet, Judith G. (2004). Biochemistry. Volume one. Biomolecules, mechanisms of enzyme action, and metabolism, 3rd edition, pp. 663–664. New York: John Wiley & Sons. ISBN 0-471-25090-2.
4. Bringhurst, F. R; Demay, Marie B.; Krane, Stephen M.; Kronenberg, Henry M. "Bone and Mineral Metabolism in Health and Disease", chapter 233 in Fauci, Anthony S.; Braunwald, E.; Kasper, D. L.; Hauser, S. L.; Longo D. L.; Jameson, J. L.; Loscalzo, J. (2008). Harrison's Principles of Internal Medicine, 17th edition. New York: McGraw-Hill. ISBN 978-0-07-159991-7

Chao Yuan, Justin Kosewick, Xiang He, Marta Kozak and Sihe Wang (2011). Sensitive measurement of serum 1α,25‐dihydroxyvitamin D by
liquid chromatography/tandem mass spectrometry after removing interference with immunoaffinity extraction. Rapid Commun. Mass Spectrom.
2011, 25, 1241–1249

What Activates Vitamin D

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Vitamin D 50 000 Units Side Effects

Vitamin D 50 000 Units Side Effects

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Hypercalcemia and kidney damage are possible side effects of vitamin D supplementation.

Doctors tend to consider vitamin D levels to be adequate if there are at least 20 nanograms (ng) of the vitamin per milliliter (mL) of blood. If levels rise above 50 ng/mL, a person may experience adverse side effects.

However, most research indicates that the toxicity threshold for vitamin D is fairly high, around 200–240 ng/mL.

A person with levels of vitamin D in this range usually consumes between 10,000 and 40,000 international units (IUs) of the vitamin per day.

Below are some of the most serious side effects associated with overexposure to vitamin D.

1. Hypercalcemia

Most of the significant side effects associated with vitamin D toxicity are related to hypercalcemia.

Hypercalcemia is an excess of calcium in the blood. This occurs when there are more than 10,4000 ng/mL of calcium in the blood.

Researchers often cite this threshold as 10.4 milligrams (mg) of calcium per deciliter of blood or as 0.104 mg/mL.

There is a strong relationship between vitamin D and calcium. When there are high levels of vitamin D metabolites in the blood, this increases the amount of calcium that the intestines absorb.

High levels of vitamin D metabolites can also promote the release of calcium from the bones into the bloodstream.

Having too much calcium in the blood can lead to a wide range of complications and symptoms. Some of the most serious include:

• a loss of appetite
• diarrhea and constipation
• confusion, disorientation, or trouble thinking
• nausea and vomiting
• joint and muscle pain
• continuous headaches
• irritability and anxiety
• unexplained exhaustion
• muscle weakness
• increased thirst and more frequent urination
• an irregular heartbeat
• reduced reflexes
• a metallic taste in the mouth
• high blood pressure

2. Kidney damage

Excess calcium in the bloodstream can bind with phosphate and form crystals that deposit in soft body tissues.

These crystals can cause tissue damage and eventually organ damage, depending on their location, number, and size.

The kidney is especially vulnerable to calcium deposits because of its role as a filter and its many small passageways.

When calcium deposits get stuck in kidney tissues, nephrocalcinosis can occur. If this condition is severe, it can cause permanent kidney damage and, eventually, kidney failure.

Symptoms of nephrocalcinosis include:

• nausea and vomiting
• fever and chills
• severe pain in the stomach, the sides of the back, or the groin area, including the testicles in men

Authors of a 2015 review considered the effects of vitamin D3 toxicity.

On average, the people affected had taken a total of 3,600,000 IU of the vitamin in fewer than 3 months. They experienced several side effects, including acute kidney damage.

3. Irregular heartbeat and heart attack

Extreme hypercalcemia can reduce or change the ability of the heart's cells to function, and people with severe hypercalcemia often experience irregularities in the heartbeat.

A person with severely high levels of calcium or phosphate in the blood may also develop calcium deposits, or plaques, in the arteries or valves of the heart.

In 2012, doctors reported the case of a 70-year-old woman who received calcium injections in the equivalent of 80,000 IU/day over 30 days.

She experienced hypercalcemia and complete heart blockage, which required a permanent pacemaker.

Some signs of heart complications associated with vitamin D toxicity include:

• an irregular heartbeat, which may be temporary or continual
• chest pain
• unexplained exhaustion
• high blood pressure
• pain when exercising
• dizziness
• chest pain

4. Brittle bones and bone pain

When there is too much calcium circulating freely in the bloodstream, the body may not have enough hormones to bind the mineral to the bones effectively.

Vitamin D toxicity can cause hypercalcemia and subsequent problems with the bones. Some symptoms include:

• aching or painful bones
• instability
• an increased rate of falling
• bones that are prone to fracture or break
• severely stooped posture
• severe back or joint pain
• loss of height or length of limb

5. Dehydration

Elevated levels of calcium in the blood can harm the kidney's ability to concentrate urine.

This can result in a person producing and passing unusually large quantities of urine, which is called polyuria.

Researchers are not entirely sure why this occurs. One theory is that high calcium levels reduce the effects of antidiuretic hormones.

These hormones encourage the kidneys to retain water, and fewer hormones may result in larger quantities of diluted urine.

When a person passes a lot of diluted urine, they lose large quantities of water and electrolytes. For this reason, a person with vitamin D toxicity may be prone to dehydration.

Symptoms of moderate dehydration include:

• a dry mouth and tongue
• restlessness
• irritability
• sunken eyes
• increased thirst
• decreased urinary output
• decreased tear production and dry eyes
• skin that is slow to return to normal after being pinched

Severe dehydration can result in life-threatening conditions. Other signs and symptoms of this condition include:

• a weak or absent pulse
• low blood pressure
• unexplained exhaustion
• very little or no urine output
• unconsciousness

6. Pancreatitis

Hypercalcemia can cause acute pancreatitis, which is the term for inflammation of the pancreas.

In 2017, researchers published a review of the features and treatment of vitamin D toxicity-induced acute kidney injury.

They studied the experiences of 19 people with the toxicity. Each had taken an average of 6,000,000 IU of the vitamin over 1–3 months.

Two of the 19 people experienced acute pancreatitis as a complication.

Signs of pancreatitis include:

• upper stomach pain that extends to the back
• nausea and vomiting
• a rapid pulse
• weight loss
• fever

7. Lung damage

When high levels of calcium and phosphate in the blood bind to form crystals, these deposit in soft tissues.

The crystals are especially likely to deposit in soft-tissue organs that act as filters, such as the lungs.

If many of these calcium salt deposits, or ectopic calcifications, are present in the lungs, they can impair the organ's function.

Some signs of the resulting lung damage include:

• coughing
• trouble breathing
• chest pain

Many people take high doses of vitamin D supplements, and the rate of adverse side effects is relatively low.

However, long-term or excessive consumption of vitamin D in supplements or foods can cause adverse side effects.

The body stores vitamin D in fat tissues, and it can take weeks or months for the effects of vitamin D toxicity to fully wear off.

However, some prescription formulas contain a combination of vitamin D and calcitriol. A person with vitamin D toxicity who has taken this combination will usually recover within a few days because calcitriol breaks down quickly in the body.

Vitamin D supplements are not right for everyone.

The supplements can interact with some medications. People on any of the following medicines should consult a doctor before taking vitamin D supplements:

• steroids
• phenobarbital and phenytoin, which can treat epilepsy
• orlistat, a weight loss medication
• cholestyramine, which can reduce cholesterol

Also, some medical conditions can increase sensitivity to vitamin D. A person with any of the following conditions should consult a doctor before using vitamin D supplements:

• primary hyperthyroidism
• cancer
• sarcoidosis
• granulomatous tuberculosis
• metastatic bone disease
• Williams syndrome

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Unexplained exhaustion may be a sign of too much vitamin D.

Most people who have taken too much vitamin D will experience at least two of the following symptoms within a few days of overdosing:

• unexplained exhaustion
• a loss of appetite and weight loss
• constipation
• dry mouth
• skin that is slow to return to normal after being pinched
• increased thirst and frequency of urination
• continuous headaches
• nausea and vomiting
• reduced reflexes
• confusion, disorientation, or trouble thinking
• an irregular heartbeat
• muscle weakness and reduced muscle tone
• changes in gait

People with severe or chronic vitamin D toxicity may develop life-threatening symptoms, including:

• extreme dehydration
• high blood pressure
• slowed growth
• trouble breathing
• temporary losses of consciousness
• heart failure and heart attack
• kidney stones and kidney failure
• hearing loss
• tinnitus (ringing in the ears)
• pancreatitis (inflammation of the pancreas)
• gastric ulcers
• coma

Vitamin D toxicity can cause a wide range of symptoms, and each individual may respond differently.

A person has a higher risk of experiencing toxicity if they have taken supplements over an extended period or taken excessive amounts. This can cause vitamin D to build up in the blood.

The risk of experiencing adverse side effects after absorbing vitamin D from the diet or exposure to the sun is very low.

Vitamin D 50 000 Units Side Effects

Source: https://www.medicalnewstoday.com/articles/322602

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Effects Of Vitamin D Deficiency

Effects Of Vitamin D Deficiency

J Investig Med. Author manuscript; available in PMC 2012 Aug 1.

Published in final edited form as:

PMCID: PMC3166406

NIHMSID: NIHMS291217

Vitamin D and the Immune System

Cynthia Aranow

Feinstein Institute for Medical Research, Manhasset, N.Y.

The publisher's final edited version of this article is available at J Investig Med

See other articles in PMC that cite the published article.

Abstract

It is now clear that vitamin D has important roles in addition to its classic effects on calcium and bone homeostasis. As the vitamin D receptor is expressed on immune cells (B cells, T cells and antigen presenting cells) and these immunologic cells are all are capable of synthesizing the active vitamin D metabolite, vitamin D has the capability of acting in an autocrine manner in a local immunologic milieu. Vitamin D can modulate the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity as well as an increased susceptibility to infection. As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis.

The immune system defends the body from foreign, invading organisms, promoting protective immunity while maintaining tolerance to self. The implications of vitamin D deficiency on the immune system have become clearer in recent years and in the context of vitamin D deficiency, there appears to be an increased susceptibility to infection and a diathesis, in a genetically susceptible host to autoimmunity.

The classical actions of vitamin D are to promote calcium homeostasis and to promote bone health. Vitamin D enhances absorption of calcium in the small intestine and stimulates osteoclast differentiation and calcium reabsorption of bone. Vitamin D additionally promotes mineralization of the collagen matrix in bone. In humans, vitamin D is obtained from the diet or it is synthesized it in the skin (reviewed in [1]). As vitamin D is cutaneously produced after exposure to UV B light, its synthesis is influenced by latitude, season, use of sunblock and skin pigmentation. Melanin absorbs UVB radiation inhibiting the synthesis of vitamin D from 7-dihydrocholesterol. This initial vitamin D compound is inactive and it is next hydroxylated in the liver to form 25 OH vitamin D3 (25 D). 25 D is also an inactive compound, but is the most reliable measurement of an individual's vitamin D status. It is converted in the kidney to the active compound 1,25 dihydroxy vitamin D (1,25 D) or calcidiol by 1-α-hydroxylase (CYP27B1), an enzyme which is stimulated by PTH . 1,25 D may be further metabolized to the inactive 1,24,25 vitamin D by 24-hydroxylase (CYP24). 1,25 D levels are tightly regulated in a negative feedback loop. 1,25 D both inhibits renal 1-α-hydroxylase and stimulates the 24-hydroxylase enzymes, thus maintaining circulating levels within limited boundaries and preventing excessive vitamin D activity/signaling.

1,25 D acts on the intestine where it stimulates calcium reabsorption, and upon bone, where it promotes osteoblast differentiation and matrix calcification. The active hormone exerts its effects on these tissues by binding to the vitamin D receptor (VDR). This complex dimerizes with the retinoid X receptor (RXR) and the 1,25D-VDR-RXR heterodimer translocates to the nucleus where it binds vitamin D responsive elements (VDRE) in the promoter regions of vitamin D responsive genes and induces expression of these vitamin D responsive genes.

Many tissues other than the skeletal and intestine express the VDR including cells in the bone marrow, brain, colon, breast and malignant cells and immune cells suggesting that vitamin D may have functions other than calcium and bone homeostasis[2]. Additionally, tissues other than the kidney express 1-α-hydroxylase and are capable of converting 25 D to 1,25 D, in non-renal compartments[1, 3-4]. Therefore, in addition to its endocrine functions, vitamin D may act in a paracrine or autocrine manner. Some of the more recently recognized non-classical actions of vitamin D include effects upon cell proliferation and differentiation as well immunologic effects resulting in an ability to maintain tolerance and to promote protective immunity. As antigen presenting cells (macrophages and dendritic cells), T cells and B cells have the necessary machinery to synthesize and respond to 1,25 D, vitamin D may act in a paracrine or autocrine manner in an immune environment. Moreover, local levels of 1,25 D may differ from systemic, circulating levels as local regulation of the enzymes synthesizing and inactivating vitamin D are different from the controls originating in the kidney. The extrarenal 1-α-hydroxylase enzyme in macrophages differs from the renal hydroxylase as it is not regulated by PTH[5]. Instead, it is dependent upon circulating levels of 25 D or it may be induced by cytokines such as IFN-γ, IL-1 or TNF-α[6]. Furthermore, the macrophage 24 hydroxylase enzyme is a non-functional splice variant, so there is no negative feedback of local 1,25 D production by 1,25 D.

Vitamin D and Protective Immunity

Vitamin D has been used (unknowingly) to treat infections such as tuberculosis before the advent of effective antibiotics. Tuberculosis patients were sent to sanatoriums where treatment included exposure to sunlight which was thought to directly kill the tuberculosis. Cod liver oil, a rich source of vitamin D has also been employed as a treatment for tuberculosis as well as for general increased protection from infections[7].

There have been multiple cross-sectional studies associating lower levels of vitamin D with increased infection. One report studied almost 19,000 subjects between 1988 and 1994. Individuals with lower vitamin D levels (<30 ng/ml) were more likely to self-report a recent upper respiratory tract infection than those with sufficient levels, even after adjusting for variables including season, age, gender, body mass and race[8]. Vitamin D levels fluctuate over the year. Although rates of seasonal infections varied, and were lowest in the summer and highest in the winter, the association of lower serum vitamin D levels and infection held during each season. Another cross-sectional study of 800 military recruits in Finland stratified men by serum vitamin D levels[9]. Those recruits with lower vitamin D levels lost significantly more days from active duty secondary to upper respiratory infections than recruits with higher vitamin D levels (above 40nmol). There have been a number of other cross-sectional studies looking at vitamin D levels and rates of influenza [10] as well as other infections including bacterial vaginosis[11] and HIV[12-13]. All have reported an association of lower vitamin D levels and increased rates of infection.

Results of studies looking at potential benefits of administering vitamin D to decrease infection have not been consistent, most likely secondary to a number of methodologic concerns[14]. One recent well-designed prospective, double blind placebo study using an objective outcome, nasopharyngeal swab culture (and not self report), and a therapeutic dose of vitamin D showed that vitamin D administration resulted in a statistically significant (42%) decrease in the incidence of influenza infection[15].

The beneficial effects of vitamin D on protective immunity are due in part to its effects on the innate immune system. It is known that macrophages recognize lipopolysacharide LPS, a surrogate for bacterial infection, through toll like receptors (TLR). Engagement of TLRs leads to a cascade of events that produce peptides with potent bacterialcidal activity such as cathelocidin and beta defensin 4[16]. These peptides colocalize within phagosomes with injested bacteria where they disrupt bacterial cell membranes and have potent anti-microbacterial activity [17].

Vitamin D plays an important part in the innate antimicrobial response. TLR binding leads to increased expression of both the 1-α-hydroxylase and the VDR[17-18]. This results in binding of the 1,25 D-VDR-RXR heterodimer to the VDREs of the genes for cathelocidin and beta defensin 4 and subsequent transcription of these proteins. Transcription of cathelocidin is absolutely dependent on sufficient 25 D[17]. It is now clear that transcription of beta defensin 4 requires binding of NFkB to appropriate response elements on the beta defensin 4 RNA[19]. TLR 2-1 signaling facilitates IL-1 receptor engagement which results in translocation of NFkB to its binding site[19].

Vitamin D and Autoimmune Disease

There is increasing epidemiologic evidence linking vitamin D deficiency and autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), diabetes mellitus (DM), inflammatory bowel disease and systemic lupus erythematosus (SLE) (reviewed in reference[20]. Reports of low serum vitamin D predicting development of autoimmune disease in the future have been published for MS, autoimmune DM and RA[21-23]. There is also data linking decreased in utero exposure to vitamin D and islet cell autoimmunity[24]. Lower in utero exposure assessed by a lower maternal intake of vitamin D during pregnancy in women whose prospective child was at risk of developing autoimmune DM is associated with a statistically increased risk of the child developing pancreatic autoimmunity.

Vitamin D has also been shown to facilitate progression of existing autoimmune disease. In one study, 161 patients with an early undifferentiated connective tissue disease were followed for a mean of over 2 years[25]. Most patients did not progress and remained in an undifferentiated state. Thirty-five (21%) patients went on to develop a defined rheumatologic diagnosis including RA, SLE, Mixed Connective Tissue Disease, and Sjogren's Disease while 126 did not progress. Baseline characteristics of the two groups were similar. Importantly, the mean vitamin D level was significantly lower in the group that progressed to a definitive disease.

There have been many studies of vitamin D status in lupus patients from across the globe (reviewed in [26]). Vitamin D levels are typically lower in patients than in disease or normal controls. Deficiency of vitamin D is extremely common, often with more than 50% of lupus patients with deficient levels and severe deficiency (vitamin D levels less than 10ng/ml) is not uncommon. Disease activity has been shown to correlate inversely with vitamin D in many but not all studies. Similar correlations between low levels of vitamin D and disease activity and severity have been observed in other autoimmune diseases such as MS and RA[27-30].

Vitamin D and Immunologic Function

Vitamin D has numerous effects on cells within the immune system. It inhibits B cell proliferation and blocks B cell differentiation and immunoglobulin secretion[31-32]. Vitamin D additionally suppresses T cell proliferation[33] and results in a shift from a Th1 to a Th2 phenotype[34-35]. Furthermore, it affects T cell maturation with a skewing away from the inflammatory Th17 phenotype[36-37] and facilitates the induction of T regulatory cells[38-41]. These effects result in decreased production of inflammatory cytokines (IL-17, IL-21) with increased production of anti-inflammatory cytokines such as IL-10 (Figure 1A). Vitamin D also has effects on monocytes and dendritic cells (DCs). It inhibits monocyte production of inflammatory cytokines such as IL-1, IL-6, IL-8, IL-12 and TNFα[42]. It additionally inhibits DC differentiation and maturation with preservation of an immature phenotype as evidenced by a decreased expression of MHC class II molecules, co-stimulatory molecules and IL12[43-45] (Figure 1B).

A. Effects of 1,25 Vitamin D on T cells include suppression of T cell proliferation, a shift from Th1 to a Th2 development, inhibition of Th17 cell development and facilitation of T regulatory cells. B. Effects of 1,25 Vitamin D on monocytes and dendric cells include inhibition of inflammatory cytokine production by monocytes and inhibition of dendritic cell differentiation and maturation.

Inhibition of DC differentiation and maturation is particularly important in the context of autoimmunity and the abrogation of self tolerance. Antigen presentation to a T cell by a mature DC facilitates an immune response against that antigen while antigen presentation by an immature DC facilitates tolerance. Self-antigens are abundant in the normal state from physiologic cell death and turnover. However, presentation of these self-antigens is usually by immature DCs so that tolerance to self is maintained.

Given the importance of vitamin D for a functional immune system and the profound deficiency observed in autoimmune disease, as well as the correlation of deficiency with more active disease, an important issue is whether or not the immune components in autoimmune disease are capable of responding appropriately to vitamin D. Immune cells (B cells, T cells, monocytes, DCs) from multiple autoimmune diseases appear to respond to the immunomodulatory effects of vitamin D. Examples of vitamin D responsiveness by immunologic components in different autoimmune disease follow: B cells: Abnormalities of B cells from lupus patients may be partially reversed by vitamin D. Both spontaneous and stimulated immunoglobulin production from B cells from active lupus patients are significantly decreased by pre-incubating cells with 1,25 vitamin D[46]. Additionally, preincubation with vitamin D significantly decreases spontaneous production of anti-DNA antibodies by approximately 60%[46]. T cells: T cells from patients with MS respond to vitamin D. The proliferation of stimulated CD4 cells from MS patients and controls are similarly inhibited after preincubation in increasing concentrations of vitamin D[27]. Moreover, Th17 polarized T cells from both controls and MS patients respond when incubated with vitamin D; both are downregulated with diminished production of IL-17 and gamma interferon[27]. Monocytes: Vitamin D inhibits the production of inflammatory cytokines (IL-1, TNFα) by monocyes. Cytokine production by monocytes from both normal controls and from patients with autoimmune diabetes (type 1 or latent autoimmune diabetics) is significantly diminished by vitamin D[47]. TLR 4 stimulation by LPS or LTA (leipoteichoic acid) is similarly inhibited by exposure to vitamin D[47]. DCs: Lupus DCs are susceptible to the effects of vitamin D. LPS induced DC maturation is inhibited by preincubation with vitamin D resulting in suppressed expression of HLA class II and co-stimulatory molecules. The response of lupus cells to LPS stimulation is similarly suppressed by vitamin D[48]. Furthermore, vitamin D affects the expression of the interferon (IFN) signature in SLE. Interferon is produced by plasmacytoid DCs; the IFN signature refers to the overexpression of IFN α inducible genes in peripheral blood mononuclear cells (PBMC s) of lupus patients[49]. The signature occurs in approximately 50% of patients and correlates with disease activity[50-52]. We have observed that interferon inducible genes are overexpressed in lupus patients with low serum vitamin D compared to normal serum vitamin D (Figure 2A). Expression of these interferon inducible genes may be diminished in lupus patients after receiving vitamin D supplementation (Figure 2B). In fact, we have observed that an IFN signature response, the decrease in expression of IFN inducible genes is 2.1 times more likely to occur in vitamin D supplemented lupus patients (unpublished data Ben-Zvi, I). There is currently a double-blind placebo controlled NIH sponsored trial (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00710021","term_id":"NCT00710021"}}NCT00710021) assessing the potential ability of vitamin D to suppress the interferon signature in patients with SLE.

A. Relative expression of 2 IFNα inducible genes, Mx1 and Ifit1 in SLE patients with vitamin D deficiency (≤ 20ng/ml) and sufficiency (>20ng/ml). Relative expression of these genes was determined by RTPCR on PBMCs from clinically stable SLE patients. Expression of interferon inducible genes is higher in patients with SLE with low serum vitamin D (unpublished data Ben-Zvi, I). B. Relative expression of 3 IFNα inducible genes (Mx1, Ifi1 and Ifit44) before and after (+D₃) supplementation with vitamin D₃ in 3 SLE patients. Vitamin D supplementation reduces expression of IFNα inducible genes (unpublished data Ben-Zvi, I).

Conclusions

Vitamin D has important functions beyond those of calcium and bone homeostasis which include modulation of the innate and adaptive immune responses. Vitamin D deficiency is prevalent in autoimmune disease. Cells of the immune system are capable of synthesizing and responding to vitamin D. Immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D suggesting that the beneficial effects of supplementing vitamin D deficient individuals with autoimmune disease may extend beyond effects on bone and calcium homeostasis.

Footnotes

Address for reprints: same as corresponding author

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Effects Of Vitamin D Deficiency

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166406/

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