Role of the Vitamin D in Leprosy

REVIEW ARTICLE

Role of the Vitamin D in Leprosy
Lu’o’ng, MD and Lan Thi Hoàng Nguyê~n, MD Khanh vinh quôc

Abstract: There is an evidence of abnormal metabolism in the vitamin D endocrine system of patients with leprosy. Bone deformities usually occur in patients with leprosy. Genetic factors, such as the vitamin D receptor, the major histocompatibility complex region, chromosome 20, human toll-like receptors, the natural resistance-associated macrophage protein 1, the nucleotide-binding oligomerization domain containing 2, phosphate-regulating gene with homologies to endopeptidase on the X chromosome and the tyrosine kinase growth factor receptor—ErbB-2, contribute to both vitamin D status and leprosy. The role of vitamin D in leprosy has been demonstrated by its effects on Bacillus Calmette-Guérin vaccination, vascular endothelial growth factor, prostaglandins, reactive oxygen species, reactive nitrogen intermediates, matrix metalloproteinases, antiphospholipid syndrome and the nerve growth factor. Vitamin D plays a definite role in leprosy. Vitamin D, itself, may effect on leprosy through the vitamin D receptors or may influence leprosy through indirect effects. Key Indexing Terms: Vitamin D; Calcitriol; Leprosy. [Am J Med Sci 2012;343(6):471–482.]

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he causative agent of leprosy, Mycobacterium leprae, was identified by Armauer Hansen in 1873. M leprae is an obligate intracellular pathogen that mainly infects macrophages and Schwann cells. There is evidence of aberrations in the vitamin D endocrine system in patients with leprosy. Hypercalcemia was documented in a patient with leprosy, which suppressed 1,25-dihyroxyvitamin-D3 (1,25OHD) levels.1 In other reports, serum 1,25OHD and calcium levels were elevated in patients with leprosy.2,3 However, a different hypercalcemic patient with leprosy had suppressed parathyroid hormone (PTH), parathyroid-related peptide and 25-dihydroxyvitamin D3 (25OHD) levels but had a normal 1,25OHD level.4 The total serum calcium levels were moderately below the normal range in 8 patients with leprosy but their ionized calcium levels were within normal limits; patients with lepromatous leprosy (LL) had lower total calcium, higher alkaline phosphatase and higher urinary hydroxyproline levels than borderline patients with leprosy.5 An altered calcium-binding ability of plasma proteins was suggested to be the cause of hypocalcemia in patients with LL.6 In Japan, patients with leprosy presented low bone mineral density and a higher risk of fracture of the lumbar spine and hips but benefited from treatment with risedronate.7 Ribeiro et al8 evaluated bone and mineral metabolism in patients recently diagnosed with leprosy. They reported that the T scores of the lumbar spine and total radius were significantly lower in patients with leprosy compared with healthy controls. The patients with leprosy also had significantly higher PTH levels and lower albumin levels than normal individuals but showed no differences in serum 25OHD levels. Therefore, we were interested in reviewing the role of vitamin D in patients with leprosy. From the Vietnamese American Medical Research Foundation, Westminster, California. Submitted July 26, 2011; accepted in revised form August 10, 2011. Correspondence: Khanh v. q. Lu’o’ng, MD, 14971 Brookhurst Street, Westminster, CA 92683 (E-mail: [email protected]).

The American Journal of the Medical Sciences



Genetic Role of the Vitamin D in Leprosy Genetic studies provide an excellent opportunity to link molecular variations with epidemiological data. DNA sequences variations, such as polymorphisms, exert modest and subtle biological effects. Receptors play a crucial role in the regulation of cellular functions, and small changes in receptor structure can influence intracellular signal transduction pathways. Calcitriol binds to a nuclear vitamin D receptor (VDR), which is associated with specific recognition sequences called vitamin D-responsive elements. The commonly occurring linked single-nucleotide genetic markers (polymorphisms) at the 3΄ end of VDRs are restriction fragment length polymorphisms of BsmI, ApaI and TaqI and the exon 2 slice site Fok polymorphism. A significant association in the TT genotype of the VDR gene was observed in patients with LL in Mexico.9 In tuberculoid leprosy (TL), the tt genotype was reported to occur at a significantly higher frequency than in the healthy controls. The heterozygous of Tt genotype was found to occur less frequently in both leprosy types (tuberculoid and lepromatous) compared with the healthy controls.10 VDR polymorphisms may influence leprosy susceptibility by affecting by the type and strength of the host immune response; tt homozygotes tend to produce Th1-type immune responses and TT homozygotes produce a Th-2 type response, based on a study of patients from India.10 TL is associated with a predominantly Th1-type pattern of cytokine production in T cells from the skin and peripheral blood; conversely, LL is associated with a more Th2-shifted pattern of cytokine production.11,12 In Brazil, the combination of the tt genotype and a negative Mitsuda test, that is, the absence of a granulomatous reaction to an intradermal injection of lepromin, was associated with a 13-fold higher probability compared with healthy controls.13 These reports suggest that there is no association between VDR genotypes or alleles and results of the Mitsuda test and that the VDR may be an immune response gene that regulates leprosy susceptibility in humans. VDR polymorphisms, however, were not associated with leprosy phenotypes in Nepal.14 In vitro experiments, vitamin D has been shown to inhibit the generation of Th1 responses by previously activated T cells.15 Linkage and/or association studies have suggested that several genes in the major histocompatibility complex (MHC) region promote susceptibility to leprosy. Located in the MHC region, human leukocyte antigen (HLA) genes have been implicated in leprosy susceptibility. Numerous case-controlled studies have shown associations between class II HLA genes and leprosy. DQ alleles have been reported to be associated with TL in Thailand, Korea, India and Japan16–19 and with LL in Japan and India.20,21 HLA-DR3 was found to be associated with TL in Surinam, Venezuela and Mexico22–24 but HLA-DR3 was present at lower frequencies in LL patients.25 HLA-DR2 was present at a higher frequency in both TL and LL patients compared with healthy controls.26 Notably, calcitriol is known to stimulate phagocytosis but suppresses MHC class II antigen expression in human mononuclear phagocytes.27,28 Calcitriol also decreases interferon-gamma-induced HLA-DR antigen expression on normal and transformed human keratinocytes.29,30

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A genomic DNA clone for 1,25OHD 24-hydroxylase has been isolated from human chromosome 20 using a DNA library.31 In a genome-wide association study, a variant at the 20q locus was identified as a risk factor for vitamin D insufficiency.32 A region of chromosome 20 has been linked to leprosy susceptibility in the Tamil Nadu region of south India.33 Human toll-like receptors (TLRs) are a group of glycoproteins that function as surface trans-membrane receptors and are involved in innate immune responses to exogenous pathogenic microorganisms. All bacteria contain ligands for many TLRs; these pathogen-specific ligands initiate a signal transduction pathway with in the host cell. The production of interleukin-12, tumor necrosis factor-alpha and nitric oxide (NO) are induced mostly by macrophages soon after the innate recognition of mycobacteria through TLRs.34 Polymorphisms in the TLR1 gene are linked to leprosy and leprosy reactions.35,36 However, among white Europeans, the TLR1 6O2 S variant exhibits deficiencies in cell surface trafficking and responsiveness and is associated with a decreased incidence of leprosy.37 The TLR1 108G genotype is also associated with protection from leprosy reversal reaction (RR).38 TLR2-TLR1 heterodimers mediate cell activation by killed M leprae; TLR2 and TLR1 were found to be more strongly expressed in lesions from patients with localized TL compared with those with disseminated LL.39 TLR2 polymorphisms have been detected in patients with LL and are associated with RR in patients with leprosy.40,41 In contrast, TLR4 polymorphisms are associated with protection against leprosy.42 The antimicrobial peptide cathelicidin LL-37 possesses antimycobacterial activity and levels of this peptide are low in patients with leprosy.43 Conversely, calcitriol down-regulates monocyte expression and triggers hyporesponsiveness to pathogen-associated molecular patterns.44 Calcitriol has been shown to down-regulate intracellular TLR2, TLR4 and TLR9 expression in human monocytes.45 The vitamin D derivative, 1a-calcidol, has been demonstrated to modulate major human monocyte antigens, TLR2 and TLR4 in vitro.46 TLR activation results in the expression of the VDR and 1a-vitamin D hydroxylase in human monocytes.47 In addition, 1,25OHD can cause vitamin D-induced expression of cathelicidin in bronchial epithelial cells48 and may also enhance the production of LL-37.49 The addition of a VDR antagonist inhibited the induction of cathelicidin mRNA by .80%; consequently, the protein expression of this antimicrobial agent was reduced by approximately 70%.47 Furthermore, knockdown of cathelicidin in primary monocytes results in a loss of TLR-mediated antimicrobial activity against intracellular mycobacteria.50 Calcitriol also induces autophagy in human monocytes via cathelicidin and leads to the localization of mycobacterial phagosomes with autophagosomes in human macrophages in a cathelicidin-dependent manner.51 The natural resistance-associated macrophage protein 1 (NRAMP1, now renamed solute carrier family 11a member 1, SLC11a1) gene regulates the concentration of divalent cations in the phagosomes of macrophages.52 NRAMP1 protein expression parallels the accumulation of mRNA and is localized in the phagosomal membrane after phagocytosis.53 The antibacterial role of NRAMP1 could be a result of the extrusion of protons and divalent metal ions such as Mn2+ from the phagosomal lumen toward the cytoplasm.54 Calcitriol genomic effects stimulate NRAMP1 transcription and protein expression in maturing phagocytes.55 Polymorphisms in the VDR and NRAMP1 genes are associated with M tuberculosis susceptibility in the Han Chinese and Iranian populations.56,57 The susceptibility to leprosy and the results of the Mitsuda test are linked to the human NRAMP1 gene in Vietnamese nuclear families with

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leprosy.58,59 These observations suggest that NRAMP1 allelic variants could be a risk for the development of major mycobacterial diseases in humans. In Indonesia, NRAMP1 variants (INT4 polymorphisms) are reported to be associated with the paucibacillary (PB) type of leprosy but not the multibacillary (MB) type of leprosy.60 The mutant genotype 274 TT of the NRAMP1 gene is predominated in negatively associated with the RR and in positivity associated with the erythema nodosum leprosum,61 which suggested that the 274 polymorphism of the NRAMP1 gene may aid in determining the susceptibility to type II reactions among patients with leprosy. However, NRAMP1 polymorphisms were not found to be associated with leprosy in patients from India and French Polynesia.10,62 The human NRAMP1 gene is located in chromosome region 2q35.63 In addition, other reports failed to detect a linkage between leprosy and the distal human chromosome 2q in patients from Pakistan, Brazil and the South Pacific.64,65 The NRAMP1 gene may exert an influence on the clinical presentation of leprosy, possibly by influencing the type of cellular immune responses.66 The innate immune system is responsible for nonspecific defense against pathogens; stimulation of this system triggers the release of cytokines and chemokines. Nucleotide-binding oligomerization domain-like receptors are a diverse set of 22 innate immune receptors that are involved in the cytoplasmic detection of bacteria and the activation of inflammatory cascades.67,68 The nucleotide-binding oligomerization domain containing 2 (NOD2) protein detects the cell wall building block muramyl dipeptide and plays a role in the immune response to many pathogens.69 NOD2 stimulation has been shown to augment both Th1-dependent and Th2-dependent responses.70,71 Ferwerda et al72 demonstrated the role of NOD2 in the recognition of mycobacteria. Nonsynonymous NOD2 polymorphisms have been associated with active tuberculosis in African Americans.73 NOD2 genetic variants are also linked to leprosy and the development of reactive states of leprosy.74 In addition, Zhang et al75 reported that genes in the NOD2-mediated signaling pathway are associated with the susceptibility to infection with M leprae in China. Calcitriol strongly stimulates NOD2 expression in differentiated human THP-1 macrophage-like cells, primary human monocytes and keratinocytes.76 In individuals with leprosy, bones deformities usually persist even after treatment; the small bones of the extremities and face are most frequently affected. M leprae down-regulates the expression of phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX), which is abundantly expressed in osteoblasts and Schwann cells.77 PHEX mutations are associated with X-linked hypophosphatemia, which is the most prevalent heritable form of rickets and is characterized by renal phosphate wasting, abnormal vitamin D metabolism and defects in bone mineralization metabolism.78,79 In X-linked hypophosphatemia, phosphate and calcitriol treatment improves bone deformities and height; the VDR promoter genotype seemed to be a key predictor of growth during treatment with calcitriol, including those with established PHEX alterations.80 ErbB-2 is a membrane protein with an extracellular region comprising 4 domains, a single transmembrane helix and an intracellular region with a tyrosine kinase domain.81 There is increasing evidence that the overexpressing of tyrosine kinase growth factor receptors, such as ErbB-2, may play important roles in the development of biliary tract carcinomas and in human cancer derived from a variety of tissues.82,83 ErbB-2 has also been suggested to be a key molecule in the Volume 343, Number 6, June 2012

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pathogenesis of leprosy.84 Tapinos et al85 demonstrated that a direct mechanism of demyelination induced by M leprae depends on the binding of the pathogen to the receptor tyrosine kinase ErbB-2 on Schwann cells through a complex process. PKI-166, the dual ErbB-1-ErbB-2 kinase, can effectively abrogate M leprae-induced myelin damage in vitro and in vivo models.86 The presence of the VDR B allele significantly correlated with the overexpression of the ErbB-2 oncogene.87 A Gemini vitamin D analog suppresses ErbB-2-positive mammary tumor growth through regulation of ErbB-2/AKT/ERK signaling pathways.88 The genetic role of the vitamin D in leprosy has been summarized in Table 1. Biological Role of the Vitamin D in the Leprosy The Bacillus Calmette-Guérin (BCG) vaccination was initially developed as a vaccine to provide protection against tuberculosis; it has also been demonstrated to offer protection against leprosy. Because BCG was introduced into northern Malawi, central Africa, the overall incidence rate of leprosy has been reduced by 18%. Protection was estimated to be 50% or greater against leprosy and was higher for MB diseases (84%) than PB diseases (51%).89,90 In Venezuela, one or more BCG scars was associated with a protective efficacy of 56% against leprosy.91 The protective effect was also significantly higher among males and was greater in individuals with MB leprosy than in those with PB leprosy. In Brazil, the presence of one or more scars was associated with an estimated 90% protective efficacy of BCG against leprosy.92 However, there was no significant difference in patient age, sex, socioeconomic level and clinical form of the disease. In India, a significant protective association between BCG and leprosy was observed; the overall vaccine effectiveness was estimated to be 60%.93 The vaccine was more effective during the first decade of life, among female patients and in patients in a lower socioeconomic class. In a meta-analysis studying the role of BCG in the prevention of leprosy, researchers included 7 experimental studies and 19 observational studies. The experimental studies demonstrated an overall protective effect of 26% and the observational studies overestimated the protective effect.94 Interestingly, BCG-vaccinated infants were almost 6 times more likely to have sufficient vitamin D concentrations than unvaccinated infants after 3 months post-BCG vaccination, and the association remained strong even after adjusting for season, ethnic group and sex.95 Among the vaccinated group, there was also a strong inverse correlation between the interferon-gamma (IFN-g) response to M tuberculosis PPD and the vitamin D concentration; infants with higher vitamin D concentrations had lower IFN-g responses. Similarly, tuberculosis in cattle usually presents a rapid transient increase in serum calcitriol within the first 2 weeks after infection with M bovis96; 1,25OHD-positive mononuclear cells were later identified in all tuberculous granulomas. During tuberculosis infection, alveolar macrophage-produced calcitriol plays a beneficial role by limiting inflammation-mediated tissue injury, potentiating NO production by stimulated monocytes/macrophages, inhibiting IFN-g production by stimulated CD4+ cells and suppressing the growth of M tuberculosis.97,98 Calcitriol also negatively interferes with the development of a Th-1 cytokine production.99 In persons with positive tuberculin test results, calciferol is able to suppress the tuberculin reaction.100 A single dose of vitamin D supplementation has been reported to enhance the immunity to Mycobacteria.101 The VDR genes have also been suggested to influence the cell-mediated immune response to M tuberculosis antigen in tuberculosis patients.102 In 1948, Capurro and Guillot103 reported the treatment of a tuberculoid Ó 2012 Lippincott Williams & Wilkins

reaction with a high dose of vitamin D2. They observed that the use of vitamin D shortened and favorably modified the clinical characteristics of leprosy; the plaques lost their characteristic form and color and showed a parallel lessening of infiltration and epithelial desquamation. In addition, symptoms of neuritis improved without the use of any special antineuralgic or antineuritic medications. Similarly, another report used vitamin D in massive doses, 9,000,000 to 12,000,000 IU for periods of 90 to 120 days as an adjuvant to sulfones in the treatment of TL.104 Of the 3 reactional cases, 1 was completely cleared of lesions and the other 2 were partly cleared. These patient’s neuritis pains disappeared and the motility of joints was restored. Of the 5 nonreactional cases, 4 cases were completely cleared of their lesions and the other one was partly cleared. The formation of new blood vessels from preexisting capillaries is strictly regulated and normally does not occur, except during developmental and repair processes. These processes are tightly controlled through the balance of positive and negative factors.105 Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis.106 VEGF is expressed in normal adult tissues, including the epidermis.107 VEGF enhances the permeability of normal venules and small veins and is a selective mitogen for endothelial cells.108 VEGF has been identified as a potential plasma marker of the type 2 leprosy reaction109 and is overexpressed in type 1 leprosy reactions.110 There are distinct patterns of microvasculature in the cutaneous lesions of patients with leprosy111 and 2 microvascular architectural patterns can be clearly distinguished: lepromatous lesions present as a dense and tortuous mesh of microvessels among M leprae-glutted macrophages, whereas the microvessels in the tuberculoid lesions are restricted to the periphery of the granulomatous regions and are not seen among the central epithelial cells. Calcitriol inhibits angiogenesis in vitro and in vivo.112 Calcitriol significantly inhibits VEGF-induced endothelial cell spouting and elongation in a dose-dependent manner and decreases the production of VEGF.113 A vitamin D analog also reduces the expression of VEGF in lung carcinoma cell lines.114 Prostaglandins (PGs) play a role in inflammatory processes.115 Cyclooxygenase (COX) participates in the conversion of arachidonic acid into PGs. High concentration of PG E2 and the overexpression of COX-2 have been reported in LL and TL lesions.116 In addition, COX-2 is also expressed in the blood vessels and nerves in patients with RR leprosy.117 In murine leprosy, the expression of COX-2 has been noted in developing lesions.118 In experimental models, VEGF stimulates the expression of COX-2 and PG E synthase in response to cell activation.119 Calcitriol has been reported to regulate the expression of several key genes involved in the PG pathways, causing a decrease in PG synthesis.120 Calcitriol and its analogs have been shown to selectively inhibit the activity of COX-2.121 Patients with leprosy display diminished macrophage phagocytosis and reduced phagocytic chemotaxis.122,123 Reactive oxygen species (ROS) are produced by activated phagocytes as a part of their microbicidal function. ROS are capable of damaging the host tissue by lipid peroxidation. The end product of lipid peroxidation, malondialdehyde (MDA), serves as a marker of cellular damage. Increased lipid peroxidation has been reported in individuals with leprosy; MDA levels are increased significantly in the tissues of patients with both PB and MB leprosy.124 The levels of MDA are increased in MB patients and are gradually decreased with clinical improvement after treatment.125 Superoxide dismutase (SOD) traps free radicals and acts as a free radical scavenging system. Compared with tissue of the healthy controls, SOD

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TABLE 1. The genetic role of the vitamin D in leprosy Leprosy Vitamin D receptor (VDR)

TT genotype observed in lepromatous leprosy (LL) in Mexico tends to produced Th-1 type immune response. tt genotype reported in tuberculoid leprosy (TL), produces a Th-2 type response. Tt genotype occurs less in leprosy than healthy controls. VDR polymorphisms are not associated with leprosy in Nepal. Major histocompatibility DQ alleles associated with TL in complex (MHC)/human Thailand, Korea, India and Japan, leukocyte antigen (HLA) and with LL in Japan and India. HLA-DR3 associated with TL in Surinam, Venezuela and Mexico but lower frequencies in LL. HLA-DR2 presents in both TL and LL. Chromosome 20 A region of chromosome 20 linked to leprosy susceptibility in south India.

Toll-like receptor (TLR)

TLR1 polymorphisms linked to leprosy and leprosy reactions. 602S variant exhibits deficiencies in cell surface trafficking and responsiveness, associated with a decreased in incidence of leprosy, 108G genotype associated with protection from leprosy reaction. TLR2 polymorphisms detected in LL. TLR4 polymorphisms protected against leprosy. Cathelicidin levels are low in leprosy.

The natural resistanceassociated macrophage protein 1 (NRAMP1)

The susceptibility to leprosy and the results of the Mitsuda test linked to NRAMP1 allelic gene in Vietnamese nuclear families with leprosy. In Indonesia, NRAMP1 variants (INT4 polymorphisms) associated with the paucibacillary type of leprosy. The mutant genotype 274 TT of the NRAMP1 gene is predominated in negatively associated with the leprosy reversal reaction. NRAMP1 polymorphisms were not associated with leprosy in patients from India and French Polynesia.

Vitamin D Vitamin D inhibits the generation of Th-1 responses by previously activated T cells.

Calcitriol stimulates phagocytosis but suppress MHC class II antigen expression in human mononuclear phagocytes. Calcitriol decreases interferon-gamma-induced HLA-DR antigen expression on normal and transformed human keratinocytes. Genomic DNA clone for 1,25OHD 24hydroxylase isolated from human chromosome 20. Variant at the 20q locus identified as a risk factor for vitamin D insufficiency. Calcitriol down-regulates monocyte expression and triggers hyporesponsiveness to pathogenassociated molecular patterns.

Calcitriol down-regulates intracellular TLR2, TLR4 and TLR9 expression in human monocytes. In vitro 1a-calcidol modulates TLR2 and TLR4. In human monocytes, TLR activation results in the expression of the VDR and 1a-vitamin D hydroxylase. Calcitriol causes vitamin D-induced expression of cathelicidin in bronchial epithelial cells and enhances the production of LL-37. VDR antagonist inhibits the induction of cathelicidin mRNA by more than 80%. Calcitriol stimulates NRAMP1 transcription and protein expression in maturing phagocytes.

(Continued)

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TABLE 1. (Continued ) Leprosy The Nucleotide-binding Oligomerization Domain containing 2 (NOD2)

Phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX)

Tyrosine kinase growth factor receptors/ErbB-2

Vitamin D

NOD2 genetic variants linked to leprosy and the development of reactive states of leprosy. Gene in the NOD2-mediated signaling pathway associated with the susceptibility to infection with M leprae in China. M leprae down-regulates the expression of PHEX, which is abundantly expressed in osteoblast and Schwann cells.

ErbB-2 suggested as a key molecule in the pathogenesis of leprosy. PKI-166, the dual ErbB-1ErbB-2 kinase, can effectively abrogate M leprae-induced myelin damage in vitro and in vivo models.

activity is decreased significantly in the tissue of PB and MB patients, while SOD activity in erythrocytes was found to be decreased significantly in MB patients.123 Patients with leprosy lasting longer than 4 years have decreased generation of ROS (superoxide anion, O2ˉ and hydroxyl radical).126 However, monocytes from patients with leprosy were found to be capable of producing normal amounts of hydrogen peroxide and superoxide.127 The glutathione antioxidant system comprising glutathione peroxidase, glutathione reductase and glutathione (GSH) protects cells from ROS toxicity and lipid peroxidation. GSH, glutathione antioxidant system comprising glutathione peroxidase and glutathione reductase levels are significantly lower in leprosy compared with healthy controls.128 The levels of SOD, GSH and the total antioxidant status are decreased significantly in individuals with MB leprosy and gradually increase with clinical improvement with treatment.129 These findings suggest that oxidative stress is associated with diminished antioxidant defense potential in individuals with leprosy. The M leprae cell wall lipids seem to down-regulate phagocytosis and the oxidative respiratory burst in macrophages.129 Similarly, calcitriol has been reported to exert a receptor-mediated effect on the secretion of hydrogen peroxide by human monocytes.130 Human monocytes in culture gradually lose their capability to produce superoxide when stimulated. The addition of calcitriol, lipolysaccharide or lipoteichoic acid restored the ability of stimulated monocytes to produce superoxide and increases the oxidative capacity compared with unstimulated monocytes.131 Calcitriol can also protect nonmalignant prostate cells from oxidative stress-induced cell death by eliminating ROSinduced cellular injuries.132 Vitamin D metabolites and vitamin D analogs were reported to induce lipoxygenase mRNA expression, lipoxygenase activity and ROS production in a human bone cell line.133 Vitamin D can also reduce the extent of lipid peroxidation and induce the SOD activity of the hepatic antioxidant system in rats.134 Cytokine-activated macrophages produce reactive nitrogen intermediates to combat pathogen. NO is known to contribute to the pathogenesis of several neurological diseases Ó 2012 Lippincott Williams & Wilkins

Calcitriol stimulates NOD2 expression in differentiated human macrophage-like cells, primary human monocytes and keratinocytes.

PHEX mutations are associated with X-linked hypophosphatemia (XLH), which characterized by abnormal vitamin D metabolism and defects in bone mineralization metabolism. In XLH, phosphate and calcitriol treatment improves bone deformities and height. VDR B allele significantly correlated with the overexpression of the ErbB-2 oncogene. A Gemini vitamin D analog suppress ErbB-2-positive mammary tumor growth through regulation of ErbB-2/AKT/ERK signaling pathway.

and has been detected in the tissues and urine of patients with leprosy; these levels are significantly lower after treatment.135,136 NO levels were also reported in serum and mononuclear cell cultures from patients with leprosy with type II reaction.137 Expression of inducible NO synthase (iNOS) and NO synthesis are increased in macrophage-rich granulomas in the peripheral nerves of patients with leprosy.138 In granulomatous diseases, such as tuberculosis, the activation of macrophages 1a-hydroxylase results in an increase in 1,25OHD, which inhibits iNOS expression and reduces NO production by lipopolysaccharide (LPS)-stimulated macrophages.139 This calcitriol production by macrophages may provide protection against oxidative injuries caused by the NO burst. Calcitriol is known to inhibit LPS-induced immune activation in human endothelial cells.140 In experimental allergic encephalomyelitis, calcitriol inhibits the expression of iNOS in the rat central nervous system.141 Astrocytes play a pivotal role in central nervous system detoxification pathways, where GSH is involved in the elimination of oxygen and nitrogen reactive species, such as nitric oxide; calcitriol also enhances intracellular GSH pools and significantly reduced nitrite production induced by LPS.142 Matrix metalloproteinases (MMPs) are proteolytic enzymes responsible for extracellular matrix remodeling and the regulation of leukocyte migration through the extracellular matrix, an important step in inflammatory processes and infectious diseases. MMPs are produced by many cell types including lymphocytes, granulocytes, astrocytes and activated macrophages. Postactivation of MMPs is controlled by metalloproteinase tissue inhibitors (TIMP). Excessive MMP secretion is related to tissue damage in many inflammatory disorders.143,144 High MMP production is associated with immune activation and leukocyte migration in leprosy reactional lesions.145 In individuals with leprous neuropathy, nerves with inflammatory infiltrates and fibrosis have higher TNF, MMP-2 and MMP-9 mRNA levels than do nerves in healthy controls.146,147 These findings suggest the involvement of MMPs in the pathogenesis of leprous neuropathy. However, the VDR TaqI polymorphism is associated with the decreased

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TABLE 2. The biological role of vitamin D in leprosy Leprosy Bacillus Calmette-Guérin vaccination (BCG)

Vitamin D

Vascular endothelial growth factor (VEGF)

Prostaglandins (PGs)/ Cyclooxygenase-2 (COX-2)

Reactive oxygen species (ROS)

Reactive nitrogen intermediates (RNI)

Since BCG was introduced into northern Malawi, the overall incidence rate of leprosy reduced by 18%. Protection was estimated to be 50% or greater against leprosy and was higher for multibacillary (MB) Leprosy (84%) than paucibacillary(PB) leprosy (51%). In Venezuela, one or more BCG scars associated with a protective efficacy of 56% against leprosy. In India, the overall BCG vaccine effectiveness was estimated to be 60%. In a meta-analysis study, BCG vaccination demonstrated an overall protective effect of 26% against leprosy. A single dose of vitamin D supplementation reported to enhance the immunity to Mycobacteria. The use of vitamin D shortened and favorably modified the clinical characteristics of leprosy. Vitamin D in massive doses used as an adjuvant to sulfones in the treatment of tuberculoid leprosy (TL). VEGF identified as a potential plasma marker of the type 2 leprosy reaction and is overexpressed in type 1 leprosy reactions.

High concentration of PGE2 and the overexpression of COX-2 reported in lepromatous leprosy (LL) and TL lesions. COX-2 expressed in the blood vessels and nerves in patients with leprosy reversal reaction. In murine leprosy, the expression of COX-2 noted in developing lesions. Increased lipid peroxidation reported in patients with leprosy. The malondialdehyde (MDA) levels, the end product of lipid peroxication, increased significantly in the tissues of both PB and MB patients with leprosy. Superoxide dismutase (SOD) activity decreased in the tissue of patients with PB and MB leprosy, while SOD activity in erythrocytes was decreased in patients with MB leprosy. Glutathione (GSH), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) are lower in patients with leprosy than normal individuals. These levels improved with treatment. Nitric oxide (NO) contributed to the pathogenesis of several neurological diseases and detected in the tissue and urine of patients with leprosy; these levels are lower after treatment. Expression of inducible NO synthase (iNOS) and NO synthesis are increased in macrophage-rich granulomas in the peripheral nerves of patients with leprosy.

Vitamin D BCG-vaccinated infants were almost 6 times more likely to have sufficient vitamin D concentrations than unvaccinated infants after 3 months postBCG vaccination.

Among the vaccinated group, there was a strong inverse correlation between the interferon-gamma response to Mycobacterium tuberculosis PPD and the vitamin D concentration. Tuberculosis in cattle usually presents a rapid transient increase in serum calcitriol within the first 2 weeks following infection with M bovis. In persons with positive tuberculin test results, calciferol is able to suppress the tuberculin reaction.

Calcitriol inhibits angiogenesis in vitro and in vivo. Calcitriol significantly inhibits VEGF-induced endothelial cell spouting and elongation in a dosedependent manner and decreases the production of VEGF. Vitamin D analog reduces the expression of VEGF in lung carcinoma cell lines. Calcitriol regulated the expression of several key genes involved in the PG pathways, causing a decrease in PG synthesis. Calcitriol and vitamin D analog selectively inhibit the activity of COX-2.

Calcitriol exerts a receptor-mediated effect on the secretion of hydrogen peroxide by human monocytes. Calcitriol protects non-malignant prostate cells from oxidative stress-induced cell death by eliminating ROS-induced cellular injuries. Vitamin D metabolites and its analogs induced lipoxygenase mRNA expression, lipoxygenase activity and ROS production in a human bone cell lines. Vitamin D reduces the extent of lipid peroxidation and induces the SOD activity of the hepatic antioxidant system in rats. Calcitriol enhances intracellular GSH pools in rat primary astrocytes. In granulomatous diseases, calcitriol-induced by activated macrophages inhibits iNOS expression and reduces NO production. In experimental allergic encephalomyelitis, calcitriol inhibits the expression of iNOS in the rat central nervous system. (Continued)

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TABLE 2. (Continued ) Leprosy

Vitamin D

Matrix metalloproteinases (MMPs)

High MMP secretion is associated with immune activation and leukocyte migration in leprosy reactional lesions. In individuals with leprous neuropathy, nerves with inflammatory infiltrates and fibrosis have higher MMP-2 and MMP-9 mRNA levels than do nerves in healthy controls.

Antiphospholipid Syndrome (APS)/anti-beta-2 glycoprotein I antibodies (anti-b2GPI-Abs)

APS may precede a diagnosis of lepromatous leprosy. High prevalence of antiphospholipid antibodies (aPL) and anti-b2GPI-Abs reported in patients with leprosy. b2 glycoprotein gene polymorphism may represent a genetic risk factor for anti-b2GPIAbs and a PL productions and APS in individuals with Multibacillary leprosy. Keratinocyte NGF affinity receptor (trkA)positive nerve fibers are reduced only in affected leprosy skin. NGF levels depleted in patients with leprosy.

The VDR TaqI polymorphism is associated with the decreased production of TIMP-1, which is a natural inhibitor of MMP-9. Calcitriol modulates tissue MMP expression under experimental conditions. Vitamin D analog reduced the expression of MMP-2 and MMP-2 in Lewis lung carcinoma cells. Calcitriol down-regulates MMP-9 levels in keratinocytes and may attenuate deleterious effects due to excessive Tumor necrosis factor- (TNF-a) induced proteolytic activity associated with cutaneous inflammation. Vitamin D deficiency is common among APS.

Nerve growth factor (NGF)

In vivo, macrophage secretory products suppressed the production of NGF by leprosyinfected neurofibroblasts.

production of TIMP-1, which is a natural inhibitor of MMP-9.148 Calcitriol modulates tissue MMP expression under experimental conditions.149 Calcitriol down-regulates MMP-9 levels in keratinocytes and may attenuate deleterious effects due to excessive tumor necrosis factor-alpha-induced proteolytic activity associated with cutaneous inflammation.150 In addition, a vitamin D analog was also reported to reduce the expression of MMP-2, MMP-9, VEGF and PTH-related protein in Lewis lung carcinoma cells.114 Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis, obstetric complications and the presence of antiphospholipid antibodies (aPL), such as antibeta2 glycoprotein I antibodies (anti-b2GPI-Abs). aPL have been reported not only in individuals with autoimmune disorders but also in those with various infectious diseases. APS may precede a diagnosis of LL.151 A high prevalence of aPL and anti-b2GPI-Abs has been reported in patients with leprosy.152,153 Another reports suggested that b2 glycoprotein gene polymorphism may represent a genetic risk factors for anti-b2GPI-Abs and aPL productions and APS in individuals with MB leprosy.154,155 Interestingly, vitamin D deficiency is common among APS.156 In vitro, vitamin D inhibited antib2GPI-mediated tissue factor expression.157 M leprae infects the Schwann cells of the peripheral nervous system and blocks myelin production. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes and acts via its high affinity receptor (trk A) on nociceptor nerve fibers to increase their sensitivity, particularly in inflammation. Keratinocyte trk A-positive nerve fibers are reduced only in Ó 2012 Lippincott Williams & Wilkins

In vitro, vitamin D inhibited anti-b2GPI-mediated tissue factor expression.

A high dose of topical vitamin D reduced the postherpetic neuralgia. In vitro, calcitriol regulated the expression of the VDR gene and stimulated the expression of the NGF gene in Schwann cells. In mouse fibroblasts, calcitriol and vitamin D analogs are reported to enhance NGF induction by increasing AP-1 binding activity in the NGF promoter.

affected leprosy skin.158 NGF levels have been depleted in patients with leprosy.159 In vivo, macrophage secretory products suppressed the production of NGF by leprosy-infected neurofibroblasts.160 A high dose of topical vitamin D has been reported to reduce the postherpetic neuralgia because of its ability to reduce glial inflammation and NO production.161 In vitro, calcitriol regulated the expression of the VDR gene and stimulated the expression of the NGF gene in Schwann cells.162 In mouse fibroblasts, calcitriol and vitamin D analogs are reported to enhance NGF induction by increasing AP-1 binding activity in the NGF promoter.163,164 These findings suggest a role for vitamin D in the peripheral nervous system. The biological role of vitamin D in leprosy has been summarized in Table 2. In summary, host factors may influence the control of the initial infection with M leprae, and the host immune response plays a significant role in the outcome of M leprae infection. The relationship between vitamin D and leprosy, via the influence of environmental and genetic factors, has been discussed. Vitamin D, itself, may have a direct effect on leprosy through its receptors, VDR, or may influence leprosy through indirect effects. REFERENCES 1. Ryzen E, Singer FR. Hypercalcemia in leprosy. Arch Intern Med 1985;145:1305–6. 2. Hoffman VN, Korzeniowski OM. Leprosy, hypercalcemia, and elevated serum calcitriol levels. Annals Intern Med 1986;105:890–1.

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