:10.1159/000486078. doi:10.1002/

2022.07.31
why does my kitten chew on everything

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doi:10.1159/000486078. doi:10.1002/dmrr.719, 32. doi:10.1016/j.mce.2013.12.012, 11. Hormones.

doi:10.4161/derm.26738, 3. In the nucleus, the liganded VDR forms a heterodimer with the unliganded retinoid-X receptor which then binds to DNA and recruits either coactivator or corepressor proteins and other transcription factors to exert gene regulatory functions (39). They will only exert physiological effects in this way, the underlying vitamin D resistance acts protective against what would normally be considered a potentially toxic dose. Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men. 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. doi:10.1016/j.jns.2016.08.045, 21.

J Biol Chem (1994) 269:1343743. Thereby it is almost irrelevant how high the injected insulin dose actually is. Only recently, Carlberg et al. Nevertheless, PTH provides a valuable and easy-to-measure biomarker for the clinical therapist.

Focusing on the PTH feedback system alone, a total of 25% of the patients showed no adequate response of this laboratory parameter. 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). Therefore, a dysfunction within the HLA system predisposes for the development of autoimmune diseases.

Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders. Eur J Heart Fail (2011) 13:62632.

From rickets prophylaxis to general preventive healthcare. Eftekharian MM, Noroozi R, Sayad A, Sarrafzadeh S, Toghi M, Azimi T, et al.

In addition, the therapy requires the patient to take some precautionary measures. Furthermore, PTH increases the conversion of 25(OH)D3 into 1,25(OH)2D3 in the kidneys with subsequent release into circulation. Slominski AT, Kim TK, Li W, Postlethwaite A, Tieu EW, Tang EKY, et al.

doi:10.1177/088453368600100118, 74. Gilad LA, Bresler T, Gnainsky J, Smirnoff P, Schwartz B. Isr Med Assoc J (2017) 19:43843. Grber U, Spitz J, Reichrath J, Kisters K, Holick MF. Vitamin D and the insulin-like growth factor system: Implications for colorectal neoplasia. London: Academic Press (2015). These examples demonstrate that the response of the VDR can be modulated by a variety of physiological influences.

Peiser M. Role of Th17 cells in skin inflammation of allergic contact dermatits.

Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-. Parathyroid hormone and vitamin Dmarkers for cardiovascular and all cause mortality in heart failure. It is known that certain haplotypes of VDR polymorphisms can influence its mRNA expression levels, stability and protein translation efficiency (47).

Vitamin D-resistant diseases.

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.

Yi B, Huang J, Zhang W, Li AM, Yang SK, Sun J, et al. Bone (1998) 23:297302. 67. They may require individually varying, but larger doses. 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. Tam CC, OBrien SJ, Petersen I, Islam A, Hayward A, Rodriguez LC.

For example aluminum, which has been found in high concentrations in brain tissue from MS patients (75), was able to decrease renal CYP27B1 activity in the chick (76). Adv Exp Med Biol (2020) 1268:53114. High frequency of Vitamin D receptor gene polymorphism FokI in Brazilian Type 1 diabetes mellitus patients with clinical autoimmune thyroid disease.

T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors ROR and ROR. There could be reasons you shouldnt take them.. Genes Immun (2020) 21:15068. doi:10.1194/jlr.R031534, 5.

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. This is a larger dose than the standard 400 IU recommended by health organisations such as the UKs Department of Health and Social Care. Bouillon R, Verstuyf A, Mathieu C, Van Cromphaut S, Masuyama R, Dehaes P, 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 Polymorphisms of genes within the vitamin D system constitute the basis for a susceptibitly towards developing vitamin D resistance, and hence autoimmune diseases.

Table 2 Key points discussed in this paper.

Vitamin D deficiency is associated with a plethora of cardiovascular and metabolic diseases including cancer, hypertension, infectious and autoimmune diseases (2, 7, 34). Figure 1 Vitamin D metabolism and the sites of vitamin D resistance acquirement. Henry HL, Norman AW. Prolactin blocks nuclear translocation of VDR by regulating its interaction with BRCA1 in osteosarcoma cells. Cistromic and genetic evidence that the Vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases. 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. Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res (2014) 55:1331.

In addition, single nucleotide polymorphisms (SNPs) of the RORA gene have been associated with MS (20).

doi:10.1007/s00018-010-0441-4, 68. From an evolutionary perspective it appears plausible that such a conserved and seminal protein is subject to multiple influencing factors.

Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells. Vitamin D: Update 2013. J Steroid Biochem Mol Biol (2015) 151:2537.

We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis.

Glucocorticoids decrease vitamin D receptor number and gene expression in human osteosarcoma cells. Hidalgo AA, Trump DL, Johnson CS. In other words, SNPs of the VDR may predispose to acquired vitamin D resistance, which may become manifest during aging and lead to the development of an autoimmune disease, if additional factors accumulate that contribute to an impairment of VDR signaling. Tomei S, Singh P, Mathew R, Mattei V, Garand M, Alwakeel M, 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. J Steroid Biochem Mol Biol (2010) 121:3725. 25(OH)D3 is the main laboratory parameter to judge an individuals vitamin D status; concentrations <20 ng/ml (1ng/ml = 2,5nmol/l) are considered as vitamin D deficiency, and 40-60 ng/ml as ideal (2, 5). in turn are able to interact with, or activate caspase-3 within cells, in this way inhibiting the VDR and attenuating the immune response of their host (62, 63). Mol Endocrinol (2009) 23:22636. Saksa N, Neme A, Ryynnen J, Uusitupa M, De Mello VDF, Voutilainen S, et al.

The inactivation of 1,25(OH)2D3 occurs either systemically or locally within the cells of target tissues. Ciulei G, Orasan OH, Coste SC, Cozma A, Negrean V, Procopciuc LM.

Immunity (2008) 28:2939. 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. 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases.

Gonzlez-Sancho JM, Larriba MJ, Muoz A. Wnt and vitamin D at the crossroads in solid cancer. doi:10.1002/jcb.22645, 52.

doi:10.4161/derm.24808, 31.

For example, Seuter et al. thyroid disease iodine

The development of their PTH concentrations is plotted in Figure 3 and shows a significant decline at three months follow-up. In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland. Although this case highlights the possibility of high-dose vitamin D toxicity within the Coimbra protocol, it appears to be very rare. Dermatoendocrinol (2013) 5:22234. We know vitamin D does all kinds of wonderful things for the immune system in animal studies, says Karen Costenbader at the Brigham and Womens Hospital in Boston.

In contrast to these cases of hereditary vitamin D resistance, which is very rare and already diagnosed in childhood, the hypothesis investigated in this paper concerns a non-hereditary, acquired form of vitamin D resistance which promotes the development of autoimmune diseases. doi:10.1371/journal.ppat.1000444, 65. Gao XR, Yu YG. As we have just illustrated, susceptibility for vitamin D resistance could arise from multiple polymorphisms of genes expressing for different proteins within the vitamin D system: the cytochrome-P450 enzymes (hydroxylases) needed for the conversion of vitamin D2/D3 into the activated hormone form (CYP2R1, CYP27A1 and CYP27B1), the DBP needed for vitamin D transport, the cell-surface receptor megalin-cubilin, which is the membrane receptor for the 1,25(OH)2D3/DBP complex, the VDR itself or the recently discovered other receptors for vitamin D hydroxy derivatives such as ROR and ROR. doi:10.1001/archpedi.1937.01980030073005, 25. An increasing number of studies also describe the VDR as a strategic target of various pathogens. doi:10.1371/journal.pone.0000344, 71. Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. Koivisto O, Hanel A, Carlberg C. Key vitamin D target genes with functions in the immune system. doi:10.3109/10408363.2010.536429, 57. Int J Environ Res Public Health (2018) 15:1777. doi:10.3390/ijerph15081777, 76. 80. doi:10.1016/j.annepidem.2007.12.001, 6. Diabetes Care (2007) 30:838. doi:10.1006/bbrc.2000.3050, 4.

Institute of Animal Reproduction and Food Sciences, Polish Academy of Sciences, Poland, University of Alabama at Birmingham, United States. 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). The literature contains an increasing number of data confirming this hypothesis. Clin Sci Mol Med (1978) 55:21320. Yenamandra et al. Mazziotti G, Formenti AM, Frara S, Doga M, Giustina A. Vitamin D and Glucocorticoid-Induced Osteoporosis. Although we acknowledge that the causes of insulin resistance are very different from those of vitamin D resistance, and high-dose insulin injections cause comparatively more side effects than high-dose vitamin D3 injections, the above analogy illustrates the principles of the Coimbra protocol: The calculation of the required vitamin D dose depends on the grade of vitamin D resistance and the stage of the particular disease and incorporates the PTH concentration in analogy to the insulin/blood glucose example. 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.

The mechanisms how pathogens disrupt vitamin D signaling may provide a missing link between the association of infections and autoimmune pathogenesis. Molecular evaluation of vitamin D responsiveness of healthy young adults. In vivo response of the human epigenome to vitamin D: A Proof-of-principle study. Ifergan I, Kebir H, Terouz S, Alvarez JI, Lcuyer MA, Gendron S, et al. 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).

Matsuoka LY, Wortsman J, Haddad JG, Hollis BW. 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). These factors will be reviewed in the next subsection. Rushton C. Vitamin D hydroxylation in youth and old age.

Because reference ranges and measurement units for PTH vary among different laboratories, it could be stated that a 25(OH)D3 measurement >40 ng/ml should be associated with a PTH value in the middle of the lower third of its laboratory-specific reference range.

doi:10.1042/cs0550213, 73. Salazar JC, Duhnam-Ems S, La Vake C, Cruz AR, Moore MW, Caimano MJ, et al.

Attention has also been paid to the link between EBV infection and MS development (71). ROR and ROR are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J (2014) 28:277589. 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). Sci Rep (2015) 5:14875. doi:10.1038/srep14875, 12.

Front Physiol (2014) 5:164. doi:10.3389/fphys.2014.00164, 43. (78). doi:10.2353/ajpath.2008.070690, 20. doi:10.2340/00015555-2226. doi:10.1210/jc.2016-1516, 55. J Bone Miner Res (2007) 22:1057. With up to approximately 1000 I.U. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al.

The Coimbra protocol follows a long medical tradition in which receptor resistances are compensated by applying higher doses. 1.

Finally, we would briefly like to mention the opinion held bysome therapists that vitamin D administration is counterindicated in patients with vitamin D resistance.

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.

Biochem Biophys Res Commun (2000) 273:97784. doi:10.1210/en.2008-1217, 63. Ann Neurol (2011) 70:75163. doi:10.1016/j.jsbmb.2016.08.002, 69.

bolus dose of vitamin D3 with similar low responder rates (23). Because PTH negatively regulates CYP24A1 and positively regulates the hydroxylases converting 25(OH)D3 to 1,25(OH)2D3, the presence of vitamin D resistance, which results in low intestinal calcium absorption and thus PTH stimulation, would lead to a constant elevation of 1,25(OH)2D3. As discussed in more detail below, such a form of vitamin D resistance could develop during aging based on an interaction between genetic susceptibility polymorphisms of the vitamin D system and an accumulation of environmental factors additionally impairing the hormonal signaling of the vitamin D-derived hydroxy-metabolites. Deng C, Ueda E, Chen KE, Bula C, Norman AW, Luben RA, et al. 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. With first evidence for a VDR in 550 million-year old boneless vertebrates, the VDR is a long-established regulatory protein (48). doi:10.1111/imr.12091, 70. Differential and overlapping effects of 20,23(OH)2 D3 and 1,25(OH)2 D3 on gene expression in human epidermal keratinocytes: Identification of AHR as an alternative receptor for 20,23(OH)2 D3.

39. doi:10.1016/j.cca.2006.02.016, 48.

Front. But we have never proven before that giving vitamin D can prevent autoimmune disease.. Black lines indicate the median, blue crosses the mean.

Vitamin D resistance. Eur J Hum Genet (2010) 18:134952. Morgan JW, Reddy GS, Uskokovic MR, May BK, Omdahl JL, Maizel AL, et al. Finally, low sun exposure and aging, which correlate with autoimmune diseases as well, will exacerbate this situation further.

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