Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients

Mandal, Debasmita; Reja, Abu Hena Hasanoor; Biswas, Nabanita; Bhattacharyya, P.; Patra, P.K.; Bhattacharya, Bhaswar B.

doi:10.1016/j.nmni.2015.04.001

Cited by 25 publications

(24 citation statements)

References 12 publications

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“…Similarly, Ribeiro et al (2007) noted same serum level of vitamin D in leprosy patients in comparison to healthy controls [16]. To the best of our knowledge there is no report on vitamin D level in leprosy patients in India except one reported by Mandal et al (2015) wherein leprosy cases with reactions were shown to have a lower levels of vitamin D compared to HC [17]. Differences which have been noted in the level of vitamin D in these studies might be due to differences in cultural behaviors, exposure to sunshine and dietary intake of vitamin D in the participants.…”

Section: Discussionmentioning

confidence: 93%

“…Further, vitamin D in massive doses was used along with sulfones in the treatment tuberculoid leprosy which modified the clinical course of the disease [6]. Recently, Mandal et al (2015) reported significantly lower levels of vitamin D in leprosy patients compared to their household controls [17]. In the light of above-mentioned facts, we hypothesize that there might be an association between vitamin D level with the leprosy and that VDR gene polymorphism may show association with leprosy and also VDR mRNA gene expression may be associated with the disease status.…”

Section: Introductionmentioning

confidence: 99%

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VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population

et al. 2018

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BackgroundLeprosy is a chronic infectious disease caused by Mycobacterium leprae and mainly affects skin, peripheral nerves. Vitamin D receptor (VDR) gene polymorphism has been found to be associated with leprosy. Vitamin D has been shown to control several host immunomodulating properties through VDR gene. Vitamin D deficiency was also found to be linked to an increased risk for several infections and metabolic diseases.ObjectiveIn the present study, we investigated the association of VDR gene polymorphism, mRNA gene expression of VDR and the vitamin D levels with leprosy and its reactional states.MethodologyA total of 305 leprosy patients consisting of tuberculoid (TT), borderline tuberculoid (BT), borderline lepromatous (BL), lepromatous leprosy (LL), as well as 200 healthy controls were enrolled in the study. We identified single nucleotide polymorphisms (SNPs) of VDR Taq1, Fok1 and Apa1, as well as the expression of VDR mRNA gene using PCR-based restriction fragment length polymorphism (RFLP) analysis and real-time PCR respectively. We also performed ELISA to measure vitamin D levels.ResultWe observed that SNP of VDR gene (Fok1 and Taq1) are associated with the leprosy disease. The allelic frequency distribution of T and t allele (p = 0.0037), F and f allele (p = 0.0024) was significantly higher in leprosy patients and healthy controls. ff genotype of Fok1 was found to be associated with leprosy patients [p = 0.0004; OR (95% CI) 3.148 (1.662–5.965)]. The recessive model of Fok1 genotype was also found to be significantly associated in leprosy patients in comparison to healthy controls [p = 0.00004; OR (95% CI) 2.85 (1.56–5.22)]. Leprosy patients are significantly associated with t-F-a haplotype. Further, VDR gene expression was found to be lower in non-reaction group compared to that of reaction group of leprosy and healthy controls. Paradoxically, we noted no difference in the levels of vitamin D between leprosy patients and healthy controls.ConclusionBlood levels of vitamin D do not play any role in clinical manifestations of any forms of leprosy. ff genotype of Fok1 and tt genotype of Taq1 was found to be associated with leprosy per se. Association of t-F-a haplotype with leprosy was found to be significant and could be used as a genetic marker to identify individuals at high risk for developing leprosy. VDR gene expression was lower in TT/BT and BL/LL groups of leprosy in comparison to that of healthy controls.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population

et al. 2018

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“…Vitamin D deficiency was common in our study, with more than 50% of participants affected even with using the lower limit of accepted values for 25(OH)D. 45,46 In prior studies, vitamin D deficiency has been associated with both MB disease and reactions, possibly because of the prominent role of VDR in the pathogenesis of leprosy. 25,47 Vitamin A insufficiency was more common than vitamin A deficiency and was present in 11% of study participants. Although there were no associations between reactions and these deficiencies in this pilot study, the prevalence of these vitamin deficiencies call for larger studies comparing patients with leprosy with healthy controls, as vitamin supplementation could be a straightforward adjunctive treatment for both leprosy and associated reactions.…”

Section: Discussionmentioning

confidence: 98%

“…[20][21][22] In the case of leprosy, vitamin A deficiency, which also suppresses cell-mediated immunity, could lead to a Th2 prominent response with a subsequent shift to the MB end of the spectrum, which has been shown from observational studies. 23,24 In addition, Mandal et al 25 showed lower vitamin D3 levels and vitamin D receptor (VDR) expression in those with T2R.…”

Section: Introductionmentioning

confidence: 99%

The Burden of Helminth Coinfections and Micronutrient Deficiencies in Patients with and without Leprosy Reactions: A Pilot Study in Minas Gerais, Brazil

Fairley

Ferreira²,

Oliveira

et al. 2019

The American Journal of Tropical Medicine and Hygiene

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Leprosy reactions are immune-mediated complications occurring in up to 50% of patients. The immune consequences of helminth infections and micronutrient deficiencies suggest a potential role in type 1 reactions (T1R) or type 2 reactions (T2R). We conducted a case-control study in Minas Gerais, Brazil, to evaluate whether comorbidities and other factors are associated with reactions in patients with multibacillary leprosy. Stool and serum were tested for helminth infections. Deficiencies of vitamin A, D, and iron were measured using serum retinol, 25-hydroxyvitamin D, and ferritin, respectively. Logistic regression models identified associations between reactions and helminth infections, micronutrient deficiencies, and other variables. Seventy-three patients were enrolled, 24 (33%) with T1R, 21 (29%) with T2R, 8 (15%) with mixed T1R/T2R, and 20 (27%) without reactions. Evidence of helminth infections were found in 11 participants (15%) and included IgG4 reactivity against Schistosoma mansoni, Strongyloides, and Ascaris antigens. Thirty-eight (52%) had vitamin D deficiency, eight (11%) had vitamin A insufficiency, 21 (29%) had anemia, and one (1.4%) had iron deficiency. Multivariable logistic regression showed no statistically significant associations between helminth coinfections and total reactions (adjusted odds ratios [aOR]: 1.36, 95% CI: 0.22, 8.33), T1R (aOR: 0.85, 95% CI: 0.17, 4.17), or T2R (aOR: 2.41, 95% CI: 0.29, 20.0). Vitamin D deficiency and vitamin A insufficiency were also not statistically associated with reactions. However, vitamin deficiencies and helminth infections were prevalent in these patients, suggesting a potential role for additional treatment interventions. Studying reactions prospectively may further clarify the role of comorbidities in the clinical presentation of leprosy.

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“…There is a well characterized genetic and functional association of the vitamin D pathway with leprosy. Single nucleotide polymorphisms in the VDR gene are associated with the different forms of leprosy [ 15 , 34 ], as is expression levels of the protein itself [ 35 ]. However, the use of vitamin D to treat mycobacterial disease has been studied in clinical trials, which have shown inconsistent benefits [ 6 , 10 , 11 , 36 – 39 ].…”

Section: Discussionmentioning

confidence: 99%

Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN

et al. 2018

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Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. leprae in macrophages that is inhibited by the pathogen. Upon infection of monocytes with M. leprae, there was no upregulation of CYP27B1 nor its enzymatic activity converting the inactive prohormone form of vitamin D (25-hydroxyvitamin D) to the bioactive form (1,25α-dihydroxyvitamin D). Given that M. leprae-induced type I interferon (IFN) inhibited monocyte activation, we blocked the type I IFN receptor (IFNAR), revealing the intrinsic capacity of monocytes to recognize M. leprae and upregulate CYP27B1. Consistent with these in vitro studies, an inverse relationship between expression of CYP27B1 vs. type I IFN downstream gene OAS1 was detected in leprosy patient lesions, leading us to study cytokine-derived macrophages (MΦ) to model cellular responses at the site of disease. Infection of IL-15-derived MΦ, similar to MΦ in lesions from the self-limited form of leprosy, with M. leprae did not inhibit induction of the vitamin D antimicrobial pathway. In contrast, infection of IL-10-derived MΦ, similar to MΦ in lesions from patients with the progressive form of leprosy, resulted in induction of type I IFN and suppression of the vitamin D directed pathway. Importantly, blockade of the type I IFN response in infected IL-10 MΦ decreased M. leprae viability. These results indicate that M. leprae evades the intrinsic capacity of human monocytes/MΦ to activate the vitamin D-mediated antimicrobial pathway via the induction of type I IFN.

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Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients

Cited by 25 publications

References 12 publications

VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population

VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population

The Burden of Helminth Coinfections and Micronutrient Deficiencies in Patients with and without Leprosy Reactions: A Pilot Study in Minas Gerais, Brazil

Intrinsic activation of the vitamin D antimicrobial pathway by M. leprae infection is inhibited by type I IFN

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