Mold M, Chmielecka A, Rodriguez MRR, Thom F, Linhart C, King A, et al. Virus infection, antiviral immunity, and autoimmunity. 1,25(OH)2D3 binds to the vitamin D receptor (VDR) to promote intestinal calcium (Ca) absorption and other Ca-mobilization pathways (e.g. Clin Dev Immunol (2013) 2013:261037. doi:10.1155/2013/261037, 19. (78). Parathyroid hormone and vitamin Dmarkers for cardiovascular and all cause mortality in heart failure. Finally, human cytomegalovirus induced a 88% inhibition of VDR expression in infected cells, leading to a gradual increase of the CYP27B1 gene to 970%; notably, no downregulation of the VDR was observed for influenza or adenovirus infection (68). Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, et al. Front. Koivisto O, Hanel A, Carlberg C. Key vitamin D target genes with functions in the immune system. 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.
Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men. Genetic polymorphisms of vitamin D receptor (VDR), CYP27B1 and CYP24A1 genes and the risk of colorectal cancer. Mol Endocrinol (1998) 12:136779. Slominski AT, Kim T, Shehabi HZ, Semak I, Tang EKY, Nguyen MN, et al. In vivo response of the human epigenome to vitamin D: A Proof-of-principle study. Aluminium in brain tissue in multiple sclerosis. doi:10.1210/jc.2016-1516, 55. 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). 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. Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. doi:10.1159/000486078. Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells. Especially since, according to our experience, a disturbed 25(OH)D3/1,25(OH)2D3 ratio is perceived as not sufficiently reliable. Clin Sci Mol Med (1978) 55:21320. London: Academic Press (2015). The high importance of the VDR is underscored by the great number of genes that it regulates, both as a classical transcription factor and through epigenetic effects (42). Weinheim, Germany: Wiley-VCH Verlag GmbH & Co (2006). It has later been shown that resistance to 1,25(OH)2D3 in such children is frequently caused by hereditary VDR defects, resulting in hypocalcemia, secondary hyperparathyroidism, rickets and in about one half of the patients alopecia (2527). 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. Immunity (2008) 28:2939. by inhibiting CYP24A1 which catalyzes the first degradation step of 1,25(OH)2D3. , 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. doi:10.1016/j.jsbmb.2018.01.002. Cancers (Basel) (2020) 12:3434. doi:10.3390/cancers12113434, 82. doi:10.1016/j.jsbmb.2016.09.024, 16. 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). Copyright 2021 Lemke, Klement, Schweiger, Schweiger and Spitz. doi:10.1002/dmrr.719, 32. The team tracked the participants for around five years to measure the development of autoimmune conditions, including rheumatoid arthritis, autoimmune thyroid disease and psoriasis. doi:10.1016/S0021-9258(17)36851-5. Im very excited and really quite bowled over by these results, says Costenbader. 2. JSteroid Biochem Mol Biol (2018) 180:1428. doi:10.1111/cmi.12368, 64. The hypothesis of acquired vitamin D resistance thus provides a plausible pathomechanism for the development of autoimmune diseases. doi:10.5301/jbm.5000248, 84. The binding of 1,25(OH)2D3, 20(OH)D and other vitamin D hydroxy-metabolites to both ROR and ROR, result in IL17 inhibition (14), thus providing another mechanism distinct from VDR signaling how vitamin D may protect from, or alleviate symptoms of, autoimmune diseases. identified a number of key genes of the immune system which are expressed by the VDR upon 1,25(OH)2D3 activation (48). There also is an epigenetic influence of the VDR on genes of the immune system. Nucleic Acids Res (2016) 44:4090104. BMC Neurol (2019) 19:339. doi:10.1186/s12883-019-1577-y, 46. Int J Endocrinol (2018) 2018:2846943. doi:10.1155/2018/2846943, 37. Basel: Karger;. Mechanistically, multiple different effects of 1,25(OH)2D3 on the immune system have been described, including, but not limited to, chemotaxis, phagocytosis, proliferation, differentiation, cytokine production, antigen presentation, antibody, cathelicidin and hydrogen peroxide production and memory cell buildup (34). doi:10.1093/nar/gkv1519, 44. Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications. doi:10.1016/j.steroids.2012.10.019, 42. Hence, the recommended optimal 25(OH)D3 level of >40ng/ml should correlate physiologically with an optimal PTH concentration. Molecular evaluation of vitamin D responsiveness of healthy young adults. These nonclassical vitamin D metabolites also act as hormones: besides being partial agonists of the VDR, they have high affinity as agonists of the aryl hydrocarbon receptor (AhR) (13) and as inverse agonists of the retinoid-related orphan receptors (ROR) and (14, 15). doi:10.1016/S1474-4422(06)70577-4, 72. doi:10.1172/JCI110759, 26. doi:10.1016/j.bbagrm.2018.05.006, 45. 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. 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. The great thing about randomised trials is they really answer the question of causation, says Costenbader. Kedia R, Desouza C, Smith LM, Shivaswamy V. A retrospective review of insulin requirements in patients using U-500 insulin hospitalized to a Veterans Affairs Hospital. Finally, low sun exposure and aging, which correlate with autoimmune diseases as well, will exacerbate this situation further. Wall DM, Mccormick BA. Table 2 Key points discussed in this paper. 86. zur Hausen H. Infections Causing Human Cancer. J Clin Invest (1983) 71:192200. These are doses that would normally be toxic in the absence of an underlying insulin resistance. Critically, several VDR SNPs have been revealed that are increasingly associated with multiple autoimmune diseases, either individually or as haplotypes (3438). could cluster their patients in 24% low responders, 51% mid responders and 25% high responders. The only effective therapy to date is the high-dose vitamin D protocol, known after its inventor as the Coimbra protocol (30). Nevertheless, PTH provides a valuable and easy-to-measure biomarker for the clinical therapist. can be utilized (87). 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. Nutrients (2020) 12:988. doi:10.3390/nu12040988, 8. Biochem Biophys Res Commun (2000) 273:97784. Prolactin blocks nuclear translocation of VDR by regulating its interaction with BRCA1 in osteosarcoma cells. doi:10.1016/j.jsbmb.2014.11.012, 23. Such subjective improvements of autoimmune disease patients as well as safety data have also been collected within the network of Coimbra protocol physicians in Germany; these will be subject to future publications. Vitamin D deficiency is associated with a plethora of cardiovascular and metabolic diseases including cancer, hypertension, infectious and autoimmune diseases (2, 7, 34). Besides the epigenetic influence, this finding also underlines the transcriptional effect of vitamin D on the pathogenesis of this disease. bolus dose of vitamin D3 with similar low responder rates (23). Slominski RM, Tuckey RC, Manna PR, Jetten AM, Postlethwaite A, Raman C, et al. As mentioned above 1,25(OH)2D3 and PTH stand in a direct relationship with each other. Matsuoka LY, Wortsman J, Haddad JG, Hollis BW. doi:10.1038/s41435-020-0096-6, 17. Godschalk M, Levy JR, Downs RWJ. There are tonnes of potential mechanisms, says Costenbader. Eur J Hum Genet (2010) 18:134952. Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-. In addition, the therapy requires the patient to take some precautionary measures. 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). 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. Administration of 10 mg prednisolone, an artificial glucocorticoid, for seven days to healthy males resulted in enhanced renal calcium excretion, an elevation of biomarkers of bone degeneration and an increase in PTH levels.
Grber U, Kisters K, Spitz J, Adamietz IA. Biochim Biophys Acta - Gene Regul Mech (2018) 1861:697705. J Steroid Biochem Mol Biol (2018) 175:127. Am J Dis Child (1937) 54:52947. Although this case highlights the possibility of high-dose vitamin D toxicity within the Coimbra protocol, it appears to be very rare. doi:10.1038/ejhg.2010.113, 33. Lutz N, Steffen P, Nigg L. Nebenwirkung einer nicht evidenzbasierten MS-Therapie. High frequency of Vitamin D receptor gene polymorphism FokI in Brazilian Type 1 diabetes mellitus patients with clinical autoimmune thyroid disease. We thus propose the hypothesis that an interplay between acquired blockades of the VDR and polymorphisms affecting autoimmune disease susceptibility in either the VDR or other genes of the vitamin D system are able to cause a progressively severe form of low vitamin D responsiveness, which we refer to as acquired vitamin D resistance and which ultimately mediates the development of an autoimmune disease (Figure 2). In summary, we have reviewed evidence for the hypothesis of an acquired form of vitamin D resistance, developing on the basis of a genetic susceptibility from certain SNPs within the vitamin D system and its interplay with chronic stress and/or pathogen infections that are able to partially block the VDR. One key role of 1,25(OH)2D3 is to enhance intestinal calcium absorption. doi:10.1371/journal.pone.0000344, 71. Gnagnarella P, Raimondi S, Aristarco V, Johansson HA, Bellerba F, Corso F, et al. In addition, further pathophysiological mechanisms have emerged during the evolution of life. 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. All authors contributed to the article and approved the submitted version. Due to the profound influence of vitamin D on the immune system it appears reasonable from an evolutionary standpoint to view the VDR as a strategically important target for pathological insults that aim to evade the immune system. 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. 
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