**2. Vitamin D and the immune system**

The classic function of vitamin D is to enhance intestinal absorption of calcium by regulating several calcium transport proteins in the small intestine [4]. However, various cells express the vitamin D receptor (VDR) and the vitamin D activating enzyme 1-α-hydroxylase. Various cells of the immune system also express the VDR and harbor 1-α-hydroxylase [10, 11]. Thus, cells of the immune system respond to vitamin D and also activate vitamin D in a paracrine or autocrine fashion. The extra-renal 1-α-hydroxylase is not upregulated by PTH, and thus, production of 1,25(OH)2D3 is dependent on concentrations of the substrate 25(OH)D3, and it may be regulated by inflammatory signals, such as lipopolysaccharide and cytokines [12, 13]. Cells of the immune system, which express the VDR and harbor 1-α-hydroxylase, are macrophages, T cells, dendritic cells, monocytes, and B cells (**Figure 1**) [9]. Vitamin D is involved in the regulation of the innate immunity as it enhances the defense system of the organism against microbes and other pathogenic organisms, and it modulates the adaptive immune system through direct effects on T-cell activation and on the phenotype and function of antigen-presenting cells, particularly dendritic cells.

#### **2.1 Vitamin D and the innate immune system**

The innate immune system is a first line of defense against infection. Vitamin D is a regulator of the innate immune system [1, 14]. The first data on the effect of vitamin D on the innate immune system have been generated on the treatment of diseases caused by mycobacteria, such as tuberculosis and leprosy [15–18]. Vitamin D has been used as a treatment of infections for more than 150 years. In 1849, Williams reported favorable results with the use of cod-liver-oil, an excellent source of vitamin D, in the treatment of patients with tuberculosis [19]. Fifty years later, Niels Finsen received the third Nobel Prize in Medicine for his description of using UV light, an effective method to increase vitamin D status, to treat lupus vulgaris, a cutaneous form of tuberculosis [20, 21]. Alfred Windaus contributed to the discovery of the chemical structure of vitamin D2 and vitamin D3 found in cod-liver-oil and received the Nobel prize [22–24]. Thereafter, several groups used vitamin D2 and D3 as a treatment for tuberculosis [22, 25]. Rook et al. [26] demonstrated in the 1980s that 1,25(OH)2D3 inhibited the proliferation of *Mycobacterium tuberculosis* in culture. Vitamin D enhances the production of defensin β2 and cathelicidin in response to infection by macrophages, monocytes, and keratinocytes [12]. Humans have only

**231**

*Vitamin D and Autoimmune Diseases*

*DOI: http://dx.doi.org/10.5772/intechopen.89707*

one cathelicidin, which is cleaved to form LL-37 [27]. Cells of the immune system including neutrophils and macrophages and cells lining epithelial surfaces that are constantly exposed to potential pathogens such as the skin, the respiratory, and the gastrointestinal tract produce cathelicidin [28–30]. Cathelicidin has broad antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as certain viruses and fungi [31]. The killing mechanism of cathelicidin involves bacterial lysis by destabilizing cell membrane [32]. Treatment with 1,25(OH)2D3 upregulates cathelicidin mRNA in several cell lines. Thus, it appears that 1,25(OH)2D3 upregulates antimicrobial peptide production, primarily cathelicidin, on a variety of different cells [33]. Studies indicate that 25(OH)D3, the major circulating form of vitamin D to determine vitamin D status, is important for local production of 1,25(OH)2D3 to upregulate cathelicidin production in the skin and macrophages. Exposing human monocytes to pathogens increases the expression of both 1,25(OH)2D3 and VDR, thus increasing both the local production of 1,25(OH)2D3 and the ability of the cell to respond to it [12]. Since keratinocytes also possess 25-α-hydroxylase, UV light may directly stimulate cathelicidin production by providing the substrate 25(OH) D3 directly from vitamin D3 produced within the skin [34, 35]. Macrophages also respond to vitamin D increasing their antimicrobial activity, however, heterogeneously [36, 37]. Macrophages formed after interleukin-15 stimulus respond to vitamin D increasing their antimicrobial activity, whereas macrophages formed after

stimulation by interleukin-10 respond to vitamin D stimulus weakly.

local production and the feedback system to function.

**2.2 Vitamin D and autoimmunity**

inflammation and tissue damage.

Data regarding other infections also exist. Thus, children with low vitamin D status may be more prone to urinary tract infections due to low production of cathelicidin and defensin β2 [38, 39]. Also, adults with asthma may be less prone to infection after treatment with vitamin D due to increased production of cathelidicin and modulation of inflammatory cytokines [40, 41]. Low levels of vitamin D may be related to chronic obstructive pulmonary disease severity [42]. Vitamin D may increase resistance to HIV infection. Low levels of vitamin D have been associated with disease progression and mortality [43]. The ability of the immune cells to hydroxylate 25(OH)D3 locally suggests that in patients with infections, it may be better to administer 25(OH)D3 rather than hydroxylated metabolites to allow for

The natural history of autoimmunity remains largely unknown. However, the theory is that both genetic susceptibility and environmental factors play a role in the development of clinical autoimmune disease. Vitamin D has known immunomodulatory effects on a wide range of immune cells, including T and dendritic cells [44, 45]. Each of these immune cells expresses VDR and produces the enzymes 1-α-hydroxylase and 24-hydroxylase and is therefore capable of locally producing active 1,25(OH)2D3 [46–49]. Activation of CD4+ T cells results in a significant increase in VDR expression enabling regulation of many genes responsive to 1,25(OH)2D3 [50]. 1,25(OH)2D3 suppresses T-cell receptor induced T cell proliferation and changes their cytokine expression. The overall shift is away from T helper Th1 phenotype toward a more tolerogenic Th2 response [51–53]. Vitamin D appears to directly inhibit Th1 cells and may additionally modulate a skewing toward a Th2 response [54]. Th17 cells are a subset of CD4+ T cells involved in organ-specific autoimmunity playing a role in maintaining inflammation, which can lead to tissue damage. 1,25(OH)2D3 suppresses autoimmunity and tissue destruction by inhibiting the Th17 response at several levels [55, 56]. Altogether, the evidence suggests an important role for vitamin D in influencing T-cell responses and in tempering

**Figure 1.** *Cells of the immune system regulated in part by vitamin D.*

#### *Vitamin D and Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.89707*

*Vitamin D Deficiency*

particularly dendritic cells.

**2.1 Vitamin D and the innate immune system**

**2. Vitamin D and the immune system**

The classic function of vitamin D is to enhance intestinal absorption of calcium by regulating several calcium transport proteins in the small intestine [4]. However, various cells express the vitamin D receptor (VDR) and the vitamin D activating enzyme 1-α-hydroxylase. Various cells of the immune system also express the VDR and harbor 1-α-hydroxylase [10, 11]. Thus, cells of the immune system respond to vitamin D and also activate vitamin D in a paracrine or autocrine fashion. The extra-renal 1-α-hydroxylase is not upregulated by PTH, and thus, production of 1,25(OH)2D3 is dependent on concentrations of the substrate 25(OH)D3, and it may be regulated by inflammatory signals, such as lipopolysaccharide and cytokines [12, 13]. Cells of the immune system, which express the VDR and harbor 1-α-hydroxylase, are macrophages, T cells, dendritic cells, monocytes, and B cells (**Figure 1**) [9]. Vitamin D is involved in the regulation of the innate immunity as it enhances the defense system of the organism against microbes and other pathogenic organisms, and it modulates the adaptive immune system through direct effects on T-cell activation and on the phenotype and function of antigen-presenting cells,

The innate immune system is a first line of defense against infection. Vitamin D is a regulator of the innate immune system [1, 14]. The first data on the effect of vitamin D on the innate immune system have been generated on the treatment of diseases caused by mycobacteria, such as tuberculosis and leprosy [15–18]. Vitamin D has been used as a treatment of infections for more than 150 years. In 1849, Williams reported favorable results with the use of cod-liver-oil, an excellent source of vitamin D, in the treatment of patients with tuberculosis [19]. Fifty years later, Niels Finsen received the third Nobel Prize in Medicine for his description of using UV light, an effective method to increase vitamin D status, to treat lupus vulgaris, a cutaneous form of tuberculosis [20, 21]. Alfred Windaus contributed to the discovery of the chemical structure of vitamin D2 and vitamin D3 found in cod-liver-oil and received the Nobel prize [22–24]. Thereafter, several groups used vitamin D2 and D3 as a treatment for tuberculosis [22, 25]. Rook et al. [26] demonstrated in the 1980s that 1,25(OH)2D3 inhibited the proliferation of *Mycobacterium tuberculosis* in culture. Vitamin D enhances the production of defensin β2 and cathelicidin in response to infection by macrophages, monocytes, and keratinocytes [12]. Humans have only

**230**

**Figure 1.**

*Cells of the immune system regulated in part by vitamin D.*

one cathelicidin, which is cleaved to form LL-37 [27]. Cells of the immune system including neutrophils and macrophages and cells lining epithelial surfaces that are constantly exposed to potential pathogens such as the skin, the respiratory, and the gastrointestinal tract produce cathelicidin [28–30]. Cathelicidin has broad antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as certain viruses and fungi [31]. The killing mechanism of cathelicidin involves bacterial lysis by destabilizing cell membrane [32]. Treatment with 1,25(OH)2D3 upregulates cathelicidin mRNA in several cell lines. Thus, it appears that 1,25(OH)2D3 upregulates antimicrobial peptide production, primarily cathelicidin, on a variety of different cells [33]. Studies indicate that 25(OH)D3, the major circulating form of vitamin D to determine vitamin D status, is important for local production of 1,25(OH)2D3 to upregulate cathelicidin production in the skin and macrophages. Exposing human monocytes to pathogens increases the expression of both 1,25(OH)2D3 and VDR, thus increasing both the local production of 1,25(OH)2D3 and the ability of the cell to respond to it [12]. Since keratinocytes also possess 25-α-hydroxylase, UV light may directly stimulate cathelicidin production by providing the substrate 25(OH) D3 directly from vitamin D3 produced within the skin [34, 35]. Macrophages also respond to vitamin D increasing their antimicrobial activity, however, heterogeneously [36, 37]. Macrophages formed after interleukin-15 stimulus respond to vitamin D increasing their antimicrobial activity, whereas macrophages formed after stimulation by interleukin-10 respond to vitamin D stimulus weakly.

Data regarding other infections also exist. Thus, children with low vitamin D status may be more prone to urinary tract infections due to low production of cathelicidin and defensin β2 [38, 39]. Also, adults with asthma may be less prone to infection after treatment with vitamin D due to increased production of cathelidicin and modulation of inflammatory cytokines [40, 41]. Low levels of vitamin D may be related to chronic obstructive pulmonary disease severity [42]. Vitamin D may increase resistance to HIV infection. Low levels of vitamin D have been associated with disease progression and mortality [43]. The ability of the immune cells to hydroxylate 25(OH)D3 locally suggests that in patients with infections, it may be better to administer 25(OH)D3 rather than hydroxylated metabolites to allow for local production and the feedback system to function.
