doi:10.1016/j.jsbmb.2014.11.012, 23. We elaborate on this using the example of the glucocorticoids in relation to the VDR. The paraythroid glands sense Ca2+ levels, and secrete parathyroid hormone (PTH). We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. Polymorphisms of genes within the vitamin D system constitute the basis for a susceptibitly towards developing vitamin D resistance, and hence autoimmune diseases. doi:10.1371/journal.ppat.1000444, 65. Exp Oncol (2009) 31:926. Front Horm Res (2017) 50:14960. Cortisol secretion in patients with type 2 diabetes: Relationship with chronic complications. It could be that vitamin D helps the immune system to distinguish between self [normal body tissue] and non-self [such as disease-causing microbes], or that it helps to decrease inflammatory responses to self., Costenbader now advises her patients to take 2000 IU of vitamin D a day, if they are the right age and it is safe for them to do so. The hypothesis of acquired vitamin D resistance thus provides a plausible pathomechanism for the development of autoimmune diseases. Hormones. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co (2006). Slominski AT, Kim TK, Shehabi HZ, Tang EKY, Benson HAE, Semak I, et al. In summary, all these examples demonstrate a more or less potent influence on the vitamin D system via the VDR by physiological and pathophysiological influences. Looking beyond the box of autoimmune diseases to the mounting evidence of Vitamin D as a player in tumor development (81, 82), significant associations between SNPs of vitamin D system genes and common types of cancer (prostate, breast, colorectal and skin cancer) have been reported (83, 84), suggesting a similar predisposing role of SNPs for cancer as for autoimmune diseases. doi:10.1007/s00018-010-0441-4, 68. Figure 3 Longitudinal PTH measurements in a cohort of 41 relapsing-remitting multiple sclerosis patients treated by the corresponding author (DL) with the Coimbra protocol. confirmed this VDR blockade through EBV in B lymphocytes (66) and later showed that the EBNA-3 protein is responsible for this blockade by its affinity to bind to the VDR (67). doi:10.1001/archpedi.1937.01980030073005, 25. Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. doi:10.1172/JCI119158, 27. through pathogen infections. This study also provided an overview showing that the rs7116978 G allele and rs7116978 C allele reached high population prevalence of up to 40% or 70%, respectively, depending on ethnicity (46). The 46 chromatin strands, which measure up to 5 cm in length and have a diameter of approximately 0.01 mm, are thereby modified in a way that opens up the target genes for reading (44). Ann Neurol (2011) 70:75163. [Medical thesis]. Yenamandra SP, Hellman U, Kempkes B, Darekar SD, Petermann S, Sculley T, et al. However, as suggested by research on hereditary vitamin D resistance, the VDR is probably the most vulnerable part of the vitamin D metabolic system and constitutes the most likely or at least most potent manifestation of acquired vitamin D resistance. Basel: Karger;. Currently no causal and therefore reliable therapies exist for correcting a blockade of the VDR. Carlberg C, Campbell MJ. doi:10.3109/10408363.2010.536429, 57. The bolus dose, which raised 25(OH)D3 levels by 7.6 ng/ml after two days, resulted in a significant opening or closing of hundreds of gene loci, the most prominent of which belonged to the human leucocyte antigen (HLA) system coded on chromosome 6. FS and JS edited the manuscript. DL and BS collected the data. Koivisto O, Hanel A, Carlberg C. Key vitamin D target genes with functions in the immune system. doi:10.1016/S0021-9258(17)36851-5. Furthermore, the constellation of high serum 1,25(OH)2D3 concentrations with a concurrently physiological 25(OH)D3 concentration is known to occur in hereditary forms of vitamin D resistance or VDR knockout mice (29); it could therefore also be indicative of acquired vitamin D resistance. Liberman UA. Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men. In particular, binding of 1,25(OH)2D3 to the vitamin D receptor (VDR) has been shown to inhibit the differentiation and proliferation of B and T helper (Th) lymphocytes, promoting the shift of an inflammatory to a more tolerant immune status which may explain the protective effects of vitamin D against autoimmune diseases [reviewed in (8)]. A carefully conducted study has investigated the impact of Borrelia burgdorferi on the transcriptome of monocytes using whole genome microarrays [Supplementary Table S2 in (64)]. Zur Hausen H. Condylomata acuminata and human genital cancer. To achieve this goal, total daily insulin doses exceeding 100 I.U. Deng C, Ueda E, Chen KE, Bula C, Norman AW, Luben RA, et al. Pathogens such as A. salmonicida, Legionella pneumophila, E. coli or Yersinia spp. This is exemplified using a simplified analogy of insulin resistance therapy: The current practice in type 2 diabetes management consists of calculating the required external insulin dose according to blood glucose levels. vitamin D3 daily over 5 months of Finnish winter (22). Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Nevertheless, PTH provides a valuable and easy-to-measure biomarker for the clinical therapist. Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). doi:10.1038/gene.2016.12. Due to this property, the VDR is classified as a member of the nuclear receptor family. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. doi:10.1210/me.2008-0075, 61. Immunity (2008) 28:2939. Th17-derived cytokines, notably interleukin (IL)17, have been implicated in the etiology of autoimmune disorders such as psoriasis (18) and multiple sclerosis (MS) (19). This requires ultraviolet-B radiation (290-315 nm) of at least 18 mJ/cm2 intensity (1), inducing the formation of previtamin D3 from 7-dehydrocholesterol which subsequently converts to vitamin D3 (cholecalciferol) by body heat (2). Sundqvist E, Brnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I. Dermatoendocrinol (2013) 5:33147. James Lovelock says artificial intelligence is the start of new life, How lab-grown 'mini-brains' could help prevent motor neurone disease, Watch the moment bison were released into the UK, Rock pool science with marine biologist Helen Scales, James Webb Space Telescope images reveal dazzling view of the universe, Climate change made UK 40C heatwave at least 10 times more likely, Ultrasound stickers could continuously image internal organs for days, Artificial synapse could make neural networks work more like brains. doi:10.1111/imr.12091, 70. Wall DM, Mccormick BA. doi:10.1371/journal.pgen.1000369, 81. However, the majority of the biomarkers measured in the VitDbol study can only be determined in research laboratories. Ramos-Lopez E, Brck P, Jansen T, Herwig J, Badenhoop K. CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Previous studies on the effect of vitamin D on autoimmune conditions have looked at vitamin D levels in those with an autoimmune disease or in those who go on to develop one. Salazar JC, Duhnam-Ems S, La Vake C, Cruz AR, Moore MW, Caimano MJ, et al. Grber U, Kisters K, Spitz J, Adamietz IA. Swiss Med Forum - Schweizerisches Medizin-Forum (2020) 20:2303. Underlying the Coimbra protocol is the hypothesis of a non-hereditary, but acquired form of vitamin D resistance which this paper is going to examine. Front. Upon reaching the blood, vitamin D3 mainly binds to vitamin-D binding protein (DBP) and gets transported to the liver where it is transformed into its storage form calcidiol (25-hydroxyvitamin D3 or 25(OH)D3) through hydroxylation via the vitamin D3 25-hydroxylases CYP2R1, CYP27A1 or CYP27B1, all members of the cytochrome P450 enzyme family (3, 4). 85. These data provided an in vivo confirmation that there exists a spectrum of different vitamin D responsiveness, with approximately 25% of a population not responding adequately to conventional vitamin D3 doses. Slominski AT, Kim T, Shehabi HZ, Semak I, Tang EKY, Nguyen MN, et al. Journal reference: British Medical Journal, DOI: 10.1136/bmj-2021-066452, Sign up to our free Health Check newsletter for a round-up of all the health and fitness news you need to know, every Saturday, Magazine issue The blue flashes show where polymorphisms can interfere with normal vitamin D metabolism, building the basis for the development of acquired vitamin D resistance. Also the positive immune modulatory effect of low-dose cortisol treatment could be due to an influence on the VDR. An in vivo proof-of-principle study investigated chromatin accessibility in monocytes obtained from a human subject before and after a vitamin D bolus dose of 2000 g (80,000 I.U.) Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and autoimmune diseases: Is vitamin D receptor (VDR) polymorphism the culprit? You should tell your doctor if you start a supplement, she says. vitamin D3 per kg body weight can be administered safely. Ifergan I, Kebir H, Terouz S, Alvarez JI, Lcuyer MA, Gendron S, et al. Endocrinology (2009) 150:67986. Henry HL, Norman AW. Vitamin D supplements really do prevent people developing an autoimmune disease, at least for those over 50, in a study providing the first evidence of a causal link between the two. The main product of these reactions is 20-hydroxyvitamin D3 (20(OH)D3), which has a 20-30-fold lower concentration than 25(OH)D3 in human serum (9, 11) and is the initial substrate for the formation of further hydroxy-derivatives such as 20,23(OH)2D3, 17,20,23(OH)3D3 or 20,22(OH)2D3 [reviewed in (12)]. It is known that certain haplotypes of VDR polymorphisms can influence its mRNA expression levels, stability and protein translation efficiency (47). doi:10.1016/j.jsbmb.2016.09.024, 16. Meta-Analysis of the association between vitamin D receptor polymorphisms and the risk of autoimmune thyroid disease. The remaining authors declare that the research was conducted in the absense of any commercial or financial relationships that could be construed as a potential conflict of interest. Finally, environmental toxins could also be integrated into this hypothesis if they interfere with vitamin D metabolism. Critically, several VDR SNPs have been revealed that are increasingly associated with multiple autoimmune diseases, either individually or as haplotypes (3438). Within this context, the inhibition of the VDR appears logical, since it would ensure the shift of energy from the immune to motor systems. A reason could be that some cases of vitamin D resistance are based on SNPs in enzymes catalyzing production of 1,25(OH)2D3 such as CYP27B1, as originally proposed by Coimbra and his co-workers (30). This technique revealed a 60-fold downregulation of the VDR by live Borrelia. However, as discussed in more detail below, the vitamin D resistance appears to confer an intrinsic protection against hypercalcemia. Other studies have hinted at the supplements beneficial effects on the immune system. Ciulei G, Orasan OH, Coste SC, Cozma A, Negrean V, Procopciuc LM. In addition, single nucleotide polymorphisms (SNPs) of the RORA gene have been associated with MS (20). doi:10.4414/smf.2020.08365, Keywords: autoimmune diseases, Coimbra protocol, multiple sclerosis, vitamin D receptor (VDR), vitamin D, Citation: Lemke D, Klement RJ, Schweiger F, Schweiger B and Spitz J (2021) Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol. Barragry JM, France MW, Corless D, Gupta SP, Switala S, Boucher BJ, et al. The literature contains an increasing number of data confirming this hypothesis. Dhawan P, Christakos S. Novel regulation of 25-hydroxyvitamin D3 24-hydroxylase (24(OH)ase) transcription by glucocorticoids: Cooperative effects of the glucocorticoid receptor, C/EBP, and the vitamin D receptor in 24(OH)ase transcription. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. A blockade of the VDR was also revealed as the pathophysiological mechanism exploited by osteosarcoma cells (60). doi:10.1016/j.jsbmb.2010.03.081, 53. JSteroid Biochem Mol Biol (2018) 180:1428. Front Physiol (2014) 5:164. doi:10.3389/fphys.2014.00164, 43. Received: 21 January 2021; Accepted: 19 March 2021;Published: 07 April 2021. doi:10.1016/j.cca.2006.02.016, 48. Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells. Accordingly, individuals being vitamin D resistant would require very high doses of vitamin D3 supplementation to achieve an adequate physiological response, such as a reduction of PTH concentrations or the down-regulation of an activated adaptive immune system the latter effect is important for the treatment of autoimmune diseases as discussed further below. 3rd ed. 50. Saksa N, Neme A, Ryynnen J, Uusitupa M, De Mello VDF, Voutilainen S, et al. In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1. Clin Dev Immunol (2013) 2013:261037. doi:10.1155/2013/261037, 19. 25(OH)D3 then gets converted to the active hormone 1,25(OH)2D3 by a second hydroxylation which occurs mainly in the kidneys or in other tissues through paracrine production. Attention has also been paid to the link between EBV infection and MS development (71). Slominski AT, Kim TK, Janjetovic Z, Broyna AA, mijewski MA, Xu H, et al. Biochim Biophys Acta - Gene Regul Mech (2018) 1861:697705. Binding of 1,25(OH)2D3 induces translocation of cytosolic VDR into the nucleus in a dose-, time- and temperature-dependent manner (40). Gilad LA, Bresler T, Gnainsky J, Smirnoff P, Schwartz B. The focus of this work was on the effects of vitamin D3 supplementation on mRNA expression of twelve of the vitamin D-regulated genes and several vitamin D-affected laboratory parameters. J Clin Invest (1983) 71:192200. doi:10.1002/jcb.22645, 52. These effects could be compensated by the administration of 1,25(OH)2D3 (50). Costenbader and her colleagues randomly split nearly 26,000 people in the US who were 50 or over into two groups, giving them either vitamin D supplements or a placebo. could cluster their patients in 24% low responders, 51% mid responders and 25% high responders. Confirmation of association between multiple sclerosis and CYP27B1. doi:10.1016/S1474-4422(06)70577-4, 72. The researchers are now extending the trial to see how long the benefits last and hope to start a new trial in younger people. However, it alsohighlights the need for a diagnostic assessment of hyperparathyroidism prior to initiating the protocol as well as a regular endocrinological monitoring during therapy. In other words: If 25(OH)D3 levels are high, PTH should be low and vice versa. For multiple tumor cell lines an anti-proliferative effect of 1,25(OH)2D3 has been described (34). Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-. Gonzlez-Sancho JM, Larriba MJ, Muoz A. Wnt and vitamin D at the crossroads in solid cancer. Eur J Heart Fail (2011) 13:62632. Germany: University of Mainz (2019). This revealed that a dose of 2000 international units (IU) of vitamin D per day reduced the development of autoimmune disease by 22 per cent, compared with the placebo. Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, et al. Indeed, inactivating polymorphisms of the CYP2R1 (31) or CYP27B1 (32) genes, promoter polymorphisms of CYP24A1 (33) or RORA (20), and SNPs of the VDR gene (3438) have all been associated with autoimmune diseases. blood glucose, which is pivotal. Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, et al. Immunol. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. Am J Dis Child (1937) 54:52947. 49. Additional factors that impair vitamin D signaling are highlighted in blue boxes. in bone), so that ionized Ca levels in serum rise. The inactivation of 1,25(OH)2D3 occurs either systemically or locally within the cells of target tissues. Peiser M. Role of Th17 cells in skin inflammation of allergic contact dermatits. doi:10.1006/bbrc.2000.3050, 4. Vitamin D is a secosteroid and prohormone which can be obtained from food (as either vitamin D2 or D3), but whose main source is endogenous production in the skin. Age Ageing (1978) 7:915. RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis. As mentioned above 1,25(OH)2D3 and PTH stand in a direct relationship with each other. Int J Environ Res Public Health (2018) 15:1777. doi:10.3390/ijerph15081777, 76. bolus dose of vitamin D3 with similar low responder rates (23). Finamor DC, Sinigaglia-Coimbra R, Neves LCM, Gutierrez M, Silva JJ, Torres LD, et al. 86. zur Hausen H. Infections Causing Human Cancer. The proof of VDR expression in multiple cell types of the immune system such as CD4+/CD8+ lymphocytes, neutrophils and activated T-cell lymphocytes or antigen presenting cells (monocytes, macrophages or dendritic cells) underlines the importance of this receptor within this system (38). Only recently, Carlberg et al. The only effective therapy to date is the high-dose vitamin D protocol, known after its inventor as the Coimbra protocol (30). Sign up to read our regular email newsletters, It has long been suspected that vitamin D could help reduce the risk of developing an autoimmune disease, and now we have evidence this is the case at least for people over 50. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Tam CC, OBrien SJ, Petersen I, Islam A, Hayward A, Rodriguez LC. Murdaca G, Tonacci A, Negrini S, Greco M, Borro M, Puppo F, et al. For example, infections with campylobacter, EBV or influenza viruses have been causally connected to the development of Guillain-Barr syndrome (70). With the help of these biomarkers, the group was able to show in 2015 that even supposedly adequate high vitamin D3 doses (3200 I.U.) Thereby, it is possibly necessary to inhibit cellular vitamin D metabolism. The VDR is a steroid receptor expressed in almost all cell types of the human body, in particular most immune cells (38). Here, future research on the effects of environmental toxins such as aluminum and cadmium on the vitamin D system is urgently needed. Theoretically, people with acquired vitamin D resistance should also be found with this protocol as outliers with extremely low response indices. 12:655739. doi: 10.3389/fimmu.2021.655739. Endogenously produced nonclassical vitamin D hydroxy-metabolites act as biased agonists on VDR and inverse agonists on ROR and ROR. vitamin D3 per kg body weight, the highest therapeutic vitamin D starting doses are thereby administered for the treatment of MS. For other autoimmune diseases much lower doses appear sufficient (Table 1). doi:10.4161/derm.24808, 31. Giovannoni G, Cutter GR, Lunemann J, Martin R, Mnz C, Sriram S, et al. doi:10.1194/jlr.R031534, 5. PloS Pathog (2009) 5:e1000444. doi:10.1016/j.jns.2016.08.045, 21. The expression of the VDR as a gene regulatory protein in almost all tissues of the human body suggests functional roles well beyond those classically associated with calcium metabolism. Isr Med Assoc J (2017) 19:43843. There are tonnes of potential mechanisms, says Costenbader. If ionized calcium concentrations in blood are low, the parathyroid glands release PTH which stimulates calcium release from bones. Vitamin D3 is mainly produced in the skin through solar ultraviolet-B (UVB) radiation and gets transported through blood by binding to vitamin D binding protein (DBP). Liberman UA, Eil C, Marx SJ. It follows that a decreased 25(OH)D3/1,25(OH)2D3 ratio could be perceived as a biomarker for vitamin D resistance. A hallmark of acquired vitamin D resistance, if it exists, would be an elevated parathyroid hormone (PTH) concentration despite 25(OH)D3 levels being in the ideal range and thus indicating sufficient production of 1,25(OH)2D3. An attenuation of these anti-proliferative effects would confer a growth advantage for tumor cells. In their article The concept of the personal vitamin D response index, Carlberg and Haq (21) proposed the following: A screening using a single vitamin D bolus treatment and measurements at days 0 and 2 paired with a simplified protocol of the molecular analysis used in the VitDbol study [ ] may be the easiest way to identify persons with a low vitamin D response index (21). A possible explanation is that the patient was a carrier of the Multiple Endocrine Neoplasia, type 1 (MEN1) gene and had a history of elevated PTH levels already prior to starting the Coimbra protocol. At three months follow-up, PTH levels had dropped significantly compared to the baseline measurement (Wilcoxon rank sum test, p<0.001), while there were no significant differences between any of the follow-up measurements. Gao XR, Yu YG. Can vitamin D supplements help protect against covid-19? doi:10.2337/dc06-1267, 54. Vitamin D in der onkologischen Intervention: Update 2015. Especially since, according to our experience, a disturbed 25(OH)D3/1,25(OH)2D3 ratio is perceived as not sufficiently reliable. doi:10.1016/j.jsbmb.2016.08.002, 69. More recently, Slominski and colleagues have revealed alternative pathways of vitamin D metabolism mediated by the mitochondrial enzyme CYP11A1 which is able to hydroxylate the side chain of vitamin D2/D3 (911). , published 5 February 2022, How a Cotswolds river may show the way to clean up England's waterways, Frogs regrow amputated legs after treatment with a chemical cocktail. Chiodini I, Adda G, Scillitani A, Coletti F, Morelli V, Di Lembo S, et al. The liver is the systemic production site of 25(OH)D3 via the enzymes CYP2R1, CYP27A1 or CYP27B1. Partial blockades of the vitamin D receptor through pathogens, glucocorticoids (chronic stress) and putatively environmental toxins such as heavy metals may interact with such a susceptibility so that vitamin D resistance emerges. doi:10.1007/BF02557831, 77. Initially, in the VitDmet study, 71 elderly prediabetic individuals were supplemented with either 0, 1600 or 3200 I.U. Figure 2 The etiology of acquired vitamin D resistance. doi:10.1016/j.jdiacomp.2017.02.008, 88. Nutr Clin Pract (1986) 1:578. Vitamin D receptor down-regulation is associated with severity of albuminuria in type 2 diabetes patients. J Steroid Biochem Mol Biol (2015) 148:27582. doi:10.1093/ageing/7.2.91, 75. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PloS Genet (2009) 5:e1000369. Marini F, Falcini F, Stagi S, Fabbri S, Ciuffi S, Rigante D, et al. Notably, CYP11A1 is expressed in immune cells (16) and ROR and ROR are expressed by inflammatory Th17 cells in which they synergistically regulate differentiation and inflammatory cytokine production (17). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. In patients with autoimmune diseases this negative feedback loop is disturbed. This hypothesis is inconsistent with the medical experience and understanding according to which resistances can be compensated with normal-to-high doses as described above. Copyright 2021 Lemke, Klement, Schweiger, Schweiger and Spitz. Clin Chim Acta (2006) 371:112. In particular, the pathogen-mediated temporary or chronic blockade of the VDR can be explained from an evolutionary view in which pathogens have developed ways to attack this key target in order to downregulate their hosts immune response. Nurminen V, Neme A, Seuter S, Carlberg C. The impact of the vitamin D-modulated epigenome on VDR target gene regulation. Virus infection, antiviral immunity, and autoimmunity. However, one case of a 39-year old symptomatic MS patient with hypercalcemia and renal insufficiency has been reported by a Swiss team of physicians (88). Im very excited and really quite bowled over by these results, says Costenbader. 3372 Novel activities of CYP11A1 and their potential physiological significance. doi:10.1096/fj.12-208975, 10. Besides the avoidance of milk products and a minimum fluid intake of 2.5 l/day, patients will need to consistently monitor multiple blood parameters and undergo regular sonographic checks of their kidneys. In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland. In 2017, the group was able to reproduce these findings in the VitDbol study, in which a cohort of healthy Finnish students received a 80,000 I.U. Hallau J, Hamann L, Schumann RR, Worm M, Heine G. A promoter polymorphism of the vitamin D metabolism gene Cyp24a1 is associated with severe atopic dermatitis in adults. Institute of Animal Reproduction and Food Sciences, Polish Academy of Sciences, Poland, University of Alabama at Birmingham, United States. J Bone Miner Res (2007) 22:1057. Study of vitamin D status and vitamin D receptor polymorphisms in a cohort of Italian patients with juvenile idiopathic arthritis. Indeed, the idea of vitamin D resistance has first been proposed in 1937 by Albright, Butler and Bloomberg based on the observation that in rare cases of rickets in children, very high doses of vitamin D were required to relieve symptoms (24). Therefore, an elevated PTH concentration can result from vitamin D resistance mediated by dysfunctional VDR signaling. Besides the epigenetic influence, this finding also underlines the transcriptional effect of vitamin D on the pathogenesis of this disease. Glucocorticoid regulation of the vitamin D receptor. Am J Pathol (2008) 172:14655. Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. In two intervention studies, Carlberg and colleagues found evidence that different individuals display a different molecular and biochemical response to the same dose of either long-term or single-bolus vitamin D3 supplementation (21).
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