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Besides 1,25(OH)2D3, there are other vitamin D3-derived hydroxy-metabolites that exert hormone-like actions. Other studies have hinted at the supplements beneficial effects on the immune system. These factors will be reviewed in the next subsection. doi:10.1016/S1474-4422(06)70577-4, 72. Yi B, Huang J, Zhang W, Li AM, Yang SK, Sun J, et al. 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). Barragry JM, France MW, Corless D, Gupta SP, Switala S, Boucher BJ, et al. Sundqvist E, Brnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I. 66. 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. In summary, there is much plausibility for acquired vitamin D resistance playing a pathological role in the development of autoimmune diseases, in this way providing an important component for our understanding and explanation of these diseases. Glucocorticoids (cortisol, cortisone) are excreted as part of a stress reaction (fight or flight, psychological stress) and ensure the supply of energy needed to solve the problem at hand. Salazar JC, Duhnam-Ems S, La Vake C, Cruz AR, Moore MW, Caimano MJ, et al. doi:10.1016/j.jsbmb.2016.08.002, 69. Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. 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. 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). Carlberg C, Haq A. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). doi:10.1007/978-3-030-46227-7_4. Clin Dev Immunol (2013) 2013:261037. doi:10.1155/2013/261037, 19. However, because PTH elevation is causally responsible for an increased 1,25(OH)2D3 level, PTH is a clinically sufficient sensitive surrogate biomarker for vitamin D resistance (Figure 1). In vivo response of the human epigenome to vitamin D: A Proof-of-principle study. doi:10.1016/j.steroids.2012.10.019, 42. It is the correction of the target parameter, i.e. 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. It follows that a decreased 25(OH)D3/1,25(OH)2D3 ratio could be perceived as a biomarker for vitamin D resistance. Front Physiol (2014) 5:164. doi:10.3389/fphys.2014.00164, 43. Molecular evaluation of vitamin D responsiveness of healthy young adults. 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. Intestinal cholecalciferol absorption in the elderly and in younger adults. doi:10.2337/dc06-1267, 54. 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. Pramanik R, Asplin JR, Lindeman C, Favus MJ, Bai S, Coe FL. The development of their PTH concentrations is plotted in Figure 3 and shows a significant decline at three months follow-up. Morgan JW, Reddy GS, Uskokovic MR, May BK, Omdahl JL, Maizel AL, et al. 85. 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. Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications. doi:10.1016/j.jns.2016.08.045, 21. Finally, we would briefly like to mention the opinion held bysome therapists that vitamin D administration is counterindicated in patients with vitamin D resistance. 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. Ciulei G, Orasan OH, Coste SC, Cozma A, Negrean V, Procopciuc LM. The role of polymorphisms in vitamin D-related genes in response to vitamin D supplementation. Marini F, Falcini F, Stagi S, Fabbri S, Ciuffi S, Rigante D, et al. Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. 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. Nutr Clin Pract (1986) 1:578. , 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:10.1006/bbrc.2000.3050, 4. Another study showed that dexamethasone, another synthetic glucocorticoid, is able to potentiate the VDR-mediated transcription of CYP24A1 by a mechanism involving the recruitment of the glucocorticoid receptor to the CYP24A1 promoter region and its cooperation with C/EBP; since CYP24A1 catalizes the first step of 1,25(OH)2D3 degradation, dexamethasone effectively reduced 1,25(OH)2D3 concentrations (51). Gnagnarella P, Raimondi S, Aristarco V, Johansson HA, Bellerba F, Corso F, et al. 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). J Steroid Biochem Mol Biol (2017) 165:35662. They may require individually varying, but larger doses. DL and BS collected the data. 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. Seuter S, Neme A, Carlberg C. Epigenome-wide effects of Vitamin D and their impact on the transcriptome of human monocytes involve CTCF. *Correspondence: Dirk Lemke, lemke@schweiger-waldkirch.de; Rainer Johannes Klement, rainer_klement@gmx.de, ORCID: Rainer Johannes Klement, orcid.org/0000-0003-1401-4270, These authors have contributed equally to this work, The Hypothesis of Acquired Vitamin D Resistance, https://doi.org/10.3389/fimmu.2021.655739, https://www.frontiersin.org/articles/10.3389/fimmu.2021.655739/full#supplementary-material, Creative Commons Attribution License (CC BY). Ann Epidemiol (2009) 19:738. Int J Environ Res Public Health (2018) 15:1777. doi:10.3390/ijerph15081777, 76. Bone (1998) 23:297302. Eur J Hum Genet (2010) 18:134952. J Endocrinol (2005) 185:57792. 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. Diabetes Care (2007) 30:838. Parathyroid hormone and vitamin Dmarkers for cardiovascular and all cause mortality in heart failure. Binding of 1,25(OH)2D3 induces translocation of cytosolic VDR into the nucleus in a dose-, time- and temperature-dependent manner (40). Am J Dis Child (1937) 54:52947. Vitamin D resistance. The intracellular distribution of the VDR is usually 75-80% in the nucleus, 15-20% in the cytosol and 3-5% in the plasma membrane (39). doi:10.1002/jbmr.5650070105, 56. Lancet Neurol (2006) 5:88794. The hypothesis of acquired vitamin D resistance thus provides a plausible pathomechanism for the development of autoimmune diseases. 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. 50. Cell Mol Life Sci (2010) 67:424956. Lutz N, Steffen P, Nigg L. Nebenwirkung einer nicht evidenzbasierten MS-Therapie. Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, et al. Rushton C. Vitamin D hydroxylation in youth and old age. 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. Slominski AT, Kim TK, Shehabi HZ, Tang EKY, Benson HAE, Semak I, et al. Age Ageing (1978) 7:915. Polymorphisms of the HLA system for example constitute the most significant genetic influence on MS (79). 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). Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PloS Genet (2009) 5:e1000369. bolus dose of vitamin D3 with similar low responder rates (23). Gonzlez-Sancho JM, Larriba MJ, Muoz A. Wnt and vitamin D at the crossroads in solid cancer. Genes Immun (2020) 21:15068. In patients with autoimmune diseases this negative feedback loop is disturbed. The VDR is a steroid receptor expressed in almost all cell types of the human body, in particular most immune cells (38). Finally, low sun exposure and aging, which correlate with autoimmune diseases as well, will exacerbate this situation further. doi:10.1016/j.cellimm.2005.03.004, 62. of vitamin D3 daily, his calcium concentration at hospital admission was 3.0 mmol/L, his 25(OH)D3 level 697 ng/ml (1742 nmol/l), and his PTH was 96ng/l. PloS One (2007) 2:e344. Eur J Heart Fail (2011) 13:62632. doi:10.1210/en.2008-1217, 63. Endocrinology (2009) 150:67986. Hormones. [Medical thesis]. In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland. An attenuation of these anti-proliferative effects would confer a growth advantage for tumor cells. J Steroid Biochem Mol Biol (2017) 173:4256. doi:10.1177/088453368600100118, 74. Blockade of the VDR has also been described for other pathogens. doi:10.1093/ageing/7.2.91, 75. 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. The 1,25(OH)2D3 concentration is determined on the one hand by the activity of the enzymes CYP2R1, CYP27A1 and CYP27B1 that catalyze production of 1,25(OH)2D3 and on the other hand CYP24A1 which catalyzes 1,25(OH)2D3 degradation. Crit Rev Clin Lab Sci (2010) 47:18195. Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions. J Neurol Sci (2016) 369:25962. 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. Vitamin D Status: Measurement, Interpretation, and Clinical Application. The literature contains an increasing number of data confirming this hypothesis. 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. It is noteworthy that the patient described in the case report wanted the authors to provide a brief account of his own standpoint according to which he and other patients he knew had improved their MS symptoms significantly on the protocol (88). doi:10.1016/j.jsbmb.2014.11.012, 23. doi:10.1016/j.immuni.2007.11.016, 18. Practically, this requires close and regular contact with a certified Coimbra practitioner. 79. Schierbeck LL, Jensen TS, Bang U, Jensen G, Kber L, Jensen JEB. Mol Endocrinol (2009) 23:22636. For approximately 15 years, patients with autoimmune diseases, particularly MS, have been successfully treated using a high-dose vitamin D protocol. identified a number of key genes of the immune system which are expressed by the VDR upon 1,25(OH)2D3 activation (48). Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, et al. The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.655739/full#supplementary-material. 1st ed. doi:10.1016/S0021-9258(17)36851-5. Lemke D. Die Bedeutung von Lebensstilfaktoren fr die Sekundrprvention der Multiplen Sklerose. doi:10.1007/s00018-010-0441-4, 68. 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). J Lab Clin Med (1989) 114:3015. A high PTH concentration in turn is associated with a higher all-cause-mortality in epidemiological studies (28). 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. Genetic polymorphisms of vitamin D receptor (VDR), CYP27B1 and CYP24A1 genes and the risk of colorectal cancer. 49. 3372 Critically, several VDR SNPs have been revealed that are increasingly associated with multiple autoimmune diseases, either individually or as haplotypes (3438). Finamor DC, Sinigaglia-Coimbra R, Neves LCM, Gutierrez M, Silva JJ, Torres LD, et al. 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. can be utilized (87). 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). Also the positive immune modulatory effect of low-dose cortisol treatment could be due to an influence on the VDR. 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. Cancers (Basel) (2020) 12:2413. doi:10.3390/cancers12092413, 83. Estrogens appear to positively stimulate vitamin D metabolism through a direct effect on the VDR (56, 57). 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. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. 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. Can vitamin D supplements help protect against covid-19? 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. Biochem Biophys Res Commun (2000) 273:97784. Vitamin D in der onkologischen Intervention: Update 2015. Novel activities of CYP11A1 and their potential physiological significance. 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. In general, both inhibitory and activating tissue-specific effects on the VDR could be observed upon dexamethasone administration (52, 55). Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, et al. Exp Oncol (2009) 31:926. Currently no causal and therefore reliable therapies exist for correcting a blockade of the VDR. In such a case, high PTH values are indicative for vitamin D resistance, assuming that dietary calcium and phosphate intake are adequate and a differential diagnosis of hyperparathyroidism has been ruled out. The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. 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. Polymorphisms of genes within the vitamin D system constitute the basis for a susceptibitly towards developing vitamin D resistance, and hence autoimmune diseases. doi:10.1038/ejhg.2010.113, 33. Pathogens such as A. salmonicida, Legionella pneumophila, E. coli or Yersinia spp. Due to this property, the VDR is classified as a member of the nuclear receptor family. Int J Endocrinol (2018) 2018:2846943. doi:10.1155/2018/2846943, 37. Therefore, a dysfunction within the HLA system predisposes for the development of autoimmune diseases. doi:10.1002/ana.22519, 78. 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. Acta Derm Venereol (2016) 96:16972. Figure 1 Vitamin D metabolism and the sites of vitamin D resistance acquirement.

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