**Author details**

of this vitamin in these very patients may have certain beneficial effects [88, 99], but there is still no prospective studies proving them. Hypothesis of statins as VitD analogues has not still been tested in well‐designed, randomized prospective trials [78]. However, since its proposal, there have been many experimental and small clinical studies confirming statins therapeutic value in APS patients, particularly in those with its thrombotic form [99–103]. So, future studies are badly needed to determine all the aspects of VitD repletion in APS prevention/therapy (choice between VitD precursors, its active form or VitD analogues, their dosage and treatment

**•** Prevalence of metabolic syndrome in APS, primary or associated with certain rheumatic

**•** Atherogenic dyslipidaemia is the most prevalent characteristic of metabolic syndrome in

**•** Prevalence of thrombotic events was significantly higher in APS patients with coexisting metabolic syndrome, compared with APS patients without metabolic syndrome character‐

**•** Among APS patients, prevalence of vitamin D deficiency was significantly higher in patients

**•** Among APS patients, vitamin D level was also significantly lower in patients with previous

**•** In the contemporary literature, there are much more data in favour of pathogenic than therapeutic role of vitamin D in thrombotic events characterizing APS and/or metabolic syndrome. So, prospective studies designed to test all the aspects of VitD repletion in prevention and/or therapy of thrombotic events in APS and/or metabolic syndrome are

Elucidating interrelationships between vitamin D deficiency, metabolic syndrome phenotype and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of

with coexisting metabolic syndrome, compared with those without it.

thrombotic events than in those without them.

modifiable risk factors and vitamin D supplementation.

goals).

**8. Key messages**

194 A Critical Evaluation of Vitamin D - Clinical Overview

diseases, is high.

APS patients.

badly needed.

**9. Conclusions**

istics.

Svetlana Jelic1,2\*, Dejan Nikolic1,2, Dragomir Marisavljević1,2 and Ljudmila Stojanovich2

\*Address all correspondence to: svetlana.jelic@mfub.bg.ac.rs

1 School of Medicine, University of Belgrade, Belgrade, Serbia

2 University Medical Center Bezanijska Kosa, Belgrade, Serbia

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#### **Therapeutic and Prophylactic Potential of Vitamin D for Multiple Sclerosis Therapeutic and Prophylactic Potential of Vitamin D for Multiple Sclerosis**

Sofia F.G. Zorzella-Pezavento, Larissa L.W. Ishikawa, Thais F.C. Fraga-Silva, Luiza A.N. Mimura and Alexandrina Sartori Sofia F.G. Zorzella-Pezavento, Larissa L.W. Ishikawa, Thais F.C. Fraga-Silva, Luiza A.N. Mimura and Alexandrina Sartori

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/64501

#### **Abstract**

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1398.061.

A plethora of investigations demonstrated that vitamin D (VitD) has a broad immuno‐ modulatory potential. It induces tolerogenic dendritic cells *in vitro* leading to the development of regulatory T cells that have a key role in immunomodulation of autoimmune diseases including multiple sclerosis (MS). Studies showed that many MS patients present lower serum levels of VitD than healthy subjects. In addition, VitD supplementation has been associated with a reduced relative risk of developing MS. Considering the alterations in VitD levels in patients and also the immunomodulatory properties of VitD, it would be interesting to evaluate VitD potential as a tolerogenic adjuvant in experimental models of MS. In this context, our research team has been investigating strategies employing VitD to establish an *in vivo* tolerance state toward central nervous system antigens in experimental autoimmune encephalomyelitis (EAE). We observed that the association between a myelin peptide and VitD determined both therapeutic and prophylactic effects on EAE development.

**Keywords:** vitamin D, multiple sclerosis, experimental autoimmune encephalomyeli‐ tis, immunomodulation, myelin peptides

### **1. Introduction**

The immune system is well known by its ability to defend the host against infections. In this sense, it is academically subdivided into innate and adaptive immune responses. Innate immunity is the first defense line and includes the microbicidal activity of macrophages and

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

polymorphonuclear cells.Hostdefense againstmicroorganisms isdependentuponrecognition ofpathogen‐associatedmolecularpatterns,mainly by toll‐like receptors (TLRs)presentinthese cells. Otherwise, adaptive immunity requires specific antigen recognition by B and T lympho‐ cytes. Differently from B cells that can directly recognize the antigens, T cells require previous antigen processing and interaction of epitopes with major histocompatibility complex proteins thatarethenexpressedatthesurfaceofantigen‐presentingcells(APCs)as,forexample,dendritic cells (DCs). Due to their strong potential for proliferation and activation, B and T cell activity needs tobe regulated.AspecialT‐cell subpopulationcalledregulatoryT(Treg) cellplaysamajor role in controlling inflammatory immune responses. To maintain its homeostasis, the immune system has to manage a balance between inflammatory and anti‐inflammatory responses. The imbalance of these immune responses leads to the development of many diseases such as autoimmune pathologies. In this context, other T‐cell subpopulations such as T helper type 1 (Th1) and type 17 (Th17) cells, which are inflammatory, and type 2 cells (Th2), which are predominantly anti‐inflammatory, are also involved. Besides its ability to eliminate pathogens and restore the host homeostasis, the immune system has also a mechanism to hamper the development of an immune response against the body's own tissues. This mechanism, called self‐tolerance, can be disrupted by the combination of a variety of genetic, environmental, and immunologicalfactors thatleadto autoimmunity.The relevance of vitaminD(VitD)inmultiple sclerosis (MS), which is an autoimmune disease involving the central nervous system (CNS), is discussed in this chapter.

## **2. VitD metabolism**

The history of VitD is strongly linked to rickets and its treatment with cod liver oil. In 1922, McCollum [1] coined the term vitamin D to refer to the antirachitic factor found in cod liver oil [2]. For this reason and for a long time, the most widely accepted physiological role of VitD was related to calcium and phosphorus metabolism and bone mineralization [3]. How‐ ever, since the 1980s, many researches implicated VitD on the cardiovascular, endocrine, and central nervous system (CNS), as well as on the immune system physiology. The active form of VitD (1α,25‐dihydroxyvitamin D3) determines pleiotropic effects in human body through binding to vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily found in a variety of human cells. The biological effects of VitD can be elicited by non‐genomic and genomic mechanisms depending on the cell location of VDR. The non‐genomic (rapid) mechanisms consist in VitD direct effect on the cells through membrane VDR binding. These effects include, for example, the activation of protein kinase C in different organs [4]. The genomic mechanism is determined by intracellular VDR that heterodimerizes with retinoic X receptor after binding to active VitD. This heterodimer is then translocated to the nucleus leading to activation or inhibition of a vast diversity of genes [5].

Some of the most important aspects of VitD epidemiology have been established by the scientist Michael Holick and his collaborators. As many people do not have an adequate sunlight exposure due to skin cancer risk, sedentary lifestyle, darker skin, or during the winter in countries far from the equator, there is an increasing number of persons with VitD deficiency around the world [6]. In the past few years, VitD deficiency has been associated with the etiology of many chronic diseases, like Crohn's disease, infections of the upper respiratory tract, cancer, myocardial infarction, Alzheimer's disease, autoimmune diseases, and others [7]. According to current knowledge, VitD serum levels should be between 30 and 100 ng/mL in healthy humans. VitD insufficiency is related to levels between 21 and 29 ng/mL, whereas a pronounced VitD deficiency is considered in individuals whose VitD levels are below 20 ng/mL. On the other hand, serum levels over 150 ng/mL can determine intoxication VitD intoxication [8]. Excessive oral intake of VitD may cause a hypervitaminosis condition with toxic effects such as hypercalcemia and hypercalciuria. Theories concerning the mechanisms of VitD toxicity involve elevated plasma concentration of VitD itself or its metabolites that culminates in overexpression of a variety of genes [9]. Although solubility of vitamins (fat or water) has no direct effect on toxicity, the ability of fat‐soluble vitamins such as VitD to accumulate in the adipose tissue determines their higher toxic potential than water‐soluble vitamins. For example, subcutaneous fat necrosis releases tissue‐accumulated VitD that leads to hypervitaminosis and its toxic effects [10].

polymorphonuclear cells.Hostdefense againstmicroorganisms isdependentuponrecognition ofpathogen‐associatedmolecularpatterns,mainly by toll‐like receptors (TLRs)presentinthese cells. Otherwise, adaptive immunity requires specific antigen recognition by B and T lympho‐ cytes. Differently from B cells that can directly recognize the antigens, T cells require previous antigen processing and interaction of epitopes with major histocompatibility complex proteins thatarethenexpressedatthesurfaceofantigen‐presentingcells(APCs)as,forexample,dendritic cells (DCs). Due to their strong potential for proliferation and activation, B and T cell activity needs tobe regulated.AspecialT‐cell subpopulationcalledregulatoryT(Treg) cellplaysamajor role in controlling inflammatory immune responses. To maintain its homeostasis, the immune system has to manage a balance between inflammatory and anti‐inflammatory responses. The imbalance of these immune responses leads to the development of many diseases such as autoimmune pathologies. In this context, other T‐cell subpopulations such as T helper type 1 (Th1) and type 17 (Th17) cells, which are inflammatory, and type 2 cells (Th2), which are predominantly anti‐inflammatory, are also involved. Besides its ability to eliminate pathogens and restore the host homeostasis, the immune system has also a mechanism to hamper the development of an immune response against the body's own tissues. This mechanism, called self‐tolerance, can be disrupted by the combination of a variety of genetic, environmental, and immunologicalfactors thatleadto autoimmunity.The relevance of vitaminD(VitD)inmultiple sclerosis (MS), which is an autoimmune disease involving the central nervous system (CNS), is

The history of VitD is strongly linked to rickets and its treatment with cod liver oil. In 1922, McCollum [1] coined the term vitamin D to refer to the antirachitic factor found in cod liver oil [2]. For this reason and for a long time, the most widely accepted physiological role of VitD was related to calcium and phosphorus metabolism and bone mineralization [3]. How‐ ever, since the 1980s, many researches implicated VitD on the cardiovascular, endocrine, and central nervous system (CNS), as well as on the immune system physiology. The active form of VitD (1α,25‐dihydroxyvitamin D3) determines pleiotropic effects in human body through binding to vitamin D receptor (VDR), which is a member of the steroid hormone receptor superfamily found in a variety of human cells. The biological effects of VitD can be elicited by non‐genomic and genomic mechanisms depending on the cell location of VDR. The non‐genomic (rapid) mechanisms consist in VitD direct effect on the cells through membrane VDR binding. These effects include, for example, the activation of protein kinase C in different organs [4]. The genomic mechanism is determined by intracellular VDR that heterodimerizes with retinoic X receptor after binding to active VitD. This heterodimer is then translocated to the nucleus leading to activation or inhibition of a vast diversity of

Some of the most important aspects of VitD epidemiology have been established by the scientist Michael Holick and his collaborators. As many people do not have an adequate

discussed in this chapter.

206 A Critical Evaluation of Vitamin D - Clinical Overview

**2. VitD metabolism**

genes [5].

The highest amounts of VitD are synthesized by the skin exposed to sunlight. Ultraviolet radiation converts 7‐dehydrocholesterol in pre‐vitamin D3. Then pre‐vitamin D3 suffers a spontaneous thermal isomerization into vitamin D3, named cholecalciferol [11]. Due to this essential role of sunlight, this vitamin has been called "sunshine vitamin" [12]. Smaller amounts of VitD can be obtained from intake of certain foods such as mushrooms, fish, milk, and eggs [13]. To become a metabolically active hormone, cholecalciferol needs to be hydroxy‐ lated twice. The first hydroxylation takes place in the liver and converts cholecalciferol into 25‐dyhidroxyvitamin D (calcidiol) via the enzyme 25‐hydroxilase [14]. Plasma calcidiol levels are usually used as a parameter of VitD status because it increases in proportion to VitD intake [15]. After that, calcidiol binds to a carrier molecule, known as the vitamin D‐binding protein, to be systemically transported to tissues that express 1α‐hydroxylase (CYP27B1) [16]. The second hydroxylation, which generates the bioactive metabolite 1,25‐dihydroxyvitamin D3 (calcitriol), occurs at the renal proximal tubular cells that are rich in CYP27B1 [17]. This reaction involves the sequentialreduction of flavoprotein,renal ferredoxin, and cytochrome P‐450 [18]. A critical physiological role in skeletal homeostasis is mediated by calcitriol. Concisely, hypocalcemia stimulates parathyroid glands to release parathyroid hormone, which activates renal CYP27B1 enzyme function, resulting in calcitriol production. Besides, parathyroid hormone stimulates osteoclast maturation to release calcium and phosphate from the bones. Calcitriol also reduces renal calcium excretion and increases calcium absorption from foods in the intestine. When normal calcium levels are obtained, calcitriol exerts a feedback regulation in the parathyroid gland, downregulating CYP27B1 activity to avoid VitD intoxi‐ cation [14]. Besides the kidneys, 1α‐hydroxylase has been reported in many tissues including bone, placenta, prostate, and parathyroid gland. In addition, several cancer cells and immune cells, such as macrophages, T lymphocytes, and DCs, are also able to produce this enzyme [19,20].
