Those "Lost" Nuclear Receptors
Homeless 1,25(OH)2D3 and VDR Deac
At normal levels, the active vitamin D metabolite, 1,25-D, serves an important role in host defense,52) but high levels of the hormone are immunosuppressive53) – if for no other reason than the fact that it is calcitriol (1,25-D) and its analogues are used widely to treat autoimmune disease. One of the mechanisms by which 1,25-D may be immunosuppressive (and contribute to symptoms of disease) is by interacting with the body's other nuclear receptors. Selvaraj et al. have suggested that the high levels of 1,25-D seen in patients with pulmonary tuberculosis “might lead to downregulation of VDR expression” and that “decreased VDR levels could result in defective VDR signaling.”54) More recently, Johan Lundqvist's 2011 study showed that, consistent with the 2009 study by Proal et al. that “1α,25-dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen production and metabolism.”55)
Molecular modeling data show that at high levels, 1,25-D not only binds the VDR but also has a strong affinity for other key receptors that control the body's major hormonal systems including those that regulate the body's sex, thyroid, and adrenal hormones. As 1,25-D rises, it pushes out the molecules that are meant to control these receptors. Compromising these receptors can disrupt the body's ability to regulate temperature, libido, and any number of other functions.[table of affinities needed] Indeed, in the human brain, the VDR tends to be most common in the hypothalamus, which is responsible for these functions.56)
Molecular research also shows that, like the VDR, several of these nuclear receptors (including the alpha/beta thyroid receptors, glucocorticoid receptor, and androgen receptor) also express many families of antimicrobial peptides. A recent analysis of AmP expression by Brahmachary showed that the glucocorticoid receptor, the androgen receptor, and the Vitamin D Receptor, seem to be in control of 20, 17 and 16 families respectively, out of 22 analyzed.57) This means that when elevated 1,25-D displaces their endogenous ligands, the body's overall AmP expression is thwarted to an even greater degree. This further impairs the innate immune system's ability to combat chronic pathogens.
Case in point: thyroid receptor
1,25-D has a very high affinity for the alpha thyroid nuclear receptor (ThRa) having a Kd value of 8.41. Normally levels of the endogenous ligand for ThRa known as T3 (which has a Kd 7.20 for ThRa) keep 1,25-D out of the binding pocket, but as 1,25-D rises due to VDR dysregulation it starts to proportionately displace T3 and block transcription by ThRa. The same thing should happen with thyroid beta – 1,25-D has a Kd of 8.44 for that receptor.
When 1,25-D displaces T3, the genes with ThRa promoters are no longer transcribed, resulting in the phenomenon known as thyroid hormone resistance. Since related nuclear receptors work as a group, when transcription by ThRa is dysregulated, system wide gene transcription is also affected.
Related article: Presentation - Vitamin D induced dysregulation of nuclear receptors may account for higher prevalence of some autoimmune diseases in women
Case in point: androgen receptor
1,25-D has a kD of 8.05 for the androgen receptor, and a Kd of 8.12 for the glucocorticoid receptor. Elevated 1,25-D can displace cortisol and testosterone from their target receptors as well, leading to an array of other hormonal imbalances.
https://mpkb.org/home/pathogenesis/vitamind/metabolism
Researchers have noted that the incidence of autoimmune diseases such as Hashimoto’s thyroiditis is markedly higher in women than in men, but to date the reason for this disparity has been unclear. The Vitamin D Nuclear Receptor (VDR) is expressed in the human cycling endometrium. Because the VDR controls expression of the Cathelicidin and beta Defensin antimicrobial peptides (AmPs), dysregulation of the receptor greatly compromises the innate immune response. Increasing evidence indicates the presence of a chronic, intraphagocytic metagenomic microbiota in patients with autoimmune disease that may survive by dysregulating the VDR. VDR dysregulation in turn prevents the breakdown of the active vitamin D metabolite 1,25-hydroxyvitamin D (1,25-D) by CYP24. In silico data suggest that when 1,25-D rises above its normal range it binds the alpha/beta thyroid receptors, the glucocorticoid receptor (GCR) and the androgen receptor (AR), displacing their native ligands and causing an array of hormonal imbalances. If T3 is displaced from alpha thyroid, thyroiditis may result. Since the VDR, GCR, and AR also express multiple families of AmPs, expression of these natural antibiotics further wanes in response to dysregulation by 1,25-D. The end result is a system-wide drop in AmP expression that may allow pathogens to spread with greater ease. Because women have an extra site of VDR expression in the endometrium, the drop in AmP expression associated with nuclear receptor dysregulation may disproportionately affect them. This would cause women to accumulate higher bacterial loads than their male counterparts, particularly during early pregnancy when 1,25-D levels rise by 40%.
http://www.ncbi.nlm.nih.gov/pubmed/19758159
Taking “Vitamin D” with the pathogens destroying health today, is equivalent to pouring gasoline on a fire.
Not only do your Doctors deny the severity of these bugs, they deny most are infected at all. And, they clearly don’t realize they block the actions of Vitamin D.
Leprosy has plagued mankind throughout history, but is far, far older than stories about the disease in the Bible, according to scientists. A new study claims the disease is probably the oldest infectious disease in humans with roots stretching back millions of years.
https://www.google.com/amp/s/www.dailymail.co.uk/sciencetech/article-2568579/amp/Leprosy-oldest-disease-humans-Bacteria-existed-MILLIONS-years-infected-ancestors-claims-study.html
Leprosy blocked the action of Vitamin D, it blocked the creation of the “Chemical Warriors”.
MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy
Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274599/
Epstein-Barr Virus physically blocking the VDR’s.
Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes
Epstein-Barr virus (EBV) is a human gamma herpes virus that infects B cells and induces their transformation into immortalized lymphoblasts that can grow as cell lines (LCLs) in vitro. EBNA-3 is a member of the EBNA-3-protein family that can regulate transcription of cellular and viral genes. The identification of EBNA-3 cellular partners and a study of its influence on cellular pathways are important for understanding the transforming action of the virus. In this work, we have identified the vitamin D receptor (VDR) protein as a binding partner of EBNA-3. We found that EBNA3 blocks the activation of VDR-dependent genes and protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis. The presented data shed some light on the anti-apoptotic EBV program and the role of the EBNA-3-VDR interaction in the viral strategy.
http://www.ncbi.nlm.nih.gov/pubmed/20593215
https://www.sciencedirect.com/science/article/abs/pii/S0165572819304837
There are folks out there who will suggest the short half-life of the active form of Vitamin D (1,25(OH)2D3), which is 8-12 hours, is a valid reason to not test it. To put this in a realistic context you should know that Vitamin D Receptor’s half-life is only 4-6 hours before it is broken apart by caspase-3 and protease activity.
Inactivation of the Human Vitamin D Receptor by Caspase-3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646540/
With such short half-life it is easy for the body to NULL expression of the VDR’s.
The vitamin D receptor and the etiology of RANTES/CCL-expressive fatty-degenerative osteolysis of the jawbone: an interface between osteoimmunology and bone metabolism
Recent research on vitamin D indicates that our current understanding of the factors leading to chronic inflammation should be revised. One of the key mechanisms by which microbial immunosuppression occurs is the suppression of one of the most common endogenous cell nucleus receptors: the vitamin D receptor (VDR). Autoimmune diseases may be correlated with VDR deactivation (VDR-deac) which occurs when the receptor is no longer able to transcribe antimicrobial agents. Excess 1,25-dihydroxyvitamin D (1,25D) is not converted to 25-hydroxyvitamin D (25D); thus, high 1,25D levels may be accompanied by low 25D values.
Since 1,25D promotes osteoclast activity and may thereby cause osteoporosis, fatty-degenerative osteolysis of the jaw (FDOJ), as described by our team, may also be associated with VDR-deac.
Conclusion
The clinical data demonstrate the interaction between VDR-deac and proinflammatory RANTES/CCL5 overexpression in FDOJ patients.
The etiology of chronic inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and arteriosclerosis, has not been elucidated. It is widely acknowledged that several factors are linked to the development of such diseases, including genetic predisposition and environmental and dietary factors. Recently, modern metagenomic research on intra- and extracellular genes has shown that over the course of centuries, thousands of microbes have succeeded in establishing themselves permanently in our bodies. A clever mechanism directed to this end is the deactivation of the vitamin D receptor (VDR); intraphagocytic bacteria produce ligands that deactivate the VDR. In turn, pathogenic bacteria have developed mechanisms to alter and evade the host immune response.1,2 In this way, interleukin (IL)-2 and interferon gamma (IFN-γ) switch off the body’s own innate immunity which makes possible an immunogenic reaction, particularly in the case of intracellular microorganisms.3 Researchers have found that autoimmune disease markers can be greatly increased in the presence of chronic mycobacterial infections.4 Advances in detection techniques using improved genome-based cultivation methods are highly likely to significantly expand the number of known pathogens involved in chronic diseases.5–7 It is increasingly recognized that bacteria can persist as cell wall-deficient variants (otherwise known as L-forms)5–7 and as “persistent” forms within metagenomic bacterial communities.8,9 By means of the VDR, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3/1,25D) regulates the immune system which is present in most immune cell types, particularly monocytes, macrophages and dendritic cells.10 In general, the innate immune system is enhanced and the adaptive immune system is inhibited by 1,25D.11,12 Thus, an effective immune response is heavily dependent on the vitamin D endocrine system which is responsible for balancing inflammatory and anti-inflammatory processes.13 The VDR transcribes over 1,400 genes which accounts for 4% of all human genes and which are no longer able to be transcribed when the VDR is deactivated. The VDR also affects parathormone and calcium-sensitive receptors and is thus essential for maintaining well-regulated calcium homeostasis in the bone. Hence, the VDR is further implicated in systemic disorders of calcium metabolism, as well as vitamin D utilization in fatty-degenerative osteolysis of the jawbone (FDOJ).14
The direct detection of VDR-deac is not yet possible in standard laboratories, however, since it is a cell nucleus receptor that is found in the mitochondria. In practice, a simple reliable measurement is necessary to determine the status of the complex system of vitamin D regulation. It is possible to infer from the discussion in the relevant literature that a ratio >1.3 may be considered as a reference value for VDR-deac.
As noted previously, microbes – including Mycobacterium tuberculosis, Borrelia and Epstein-Barr virus (EBV) – downregulate VDR activity. In the event, thereby, that the physiologically active 1,25D form exceeds normal values, this may result in a corresponding reduction of 25D. Consequently, more vitamin D experts are beginning to reconsider vitamin D supplementation among the general population.25
Autoimmune diseases often correlate with high 1,25D values and low 25D values (which is associated with a presumed “vitamin D deficiency”), and this is also the case in the FDOJ study cohort exclusively affected by ISDs: low 25D levels are inversely correlated with high 1,25D levels. Consistent with the disease patterns exhibited by the FDOJ cohort, abnormally low levels of the metabolite 25D are associated with general mortality and an increased incidence of at least 40 different chronic infections.27 Certainly, vitamin D intake is often purported to confer immunosuppressive effects. For instance, according to Arnson et al, “Vitamin D affects the immune system on many levels and via a number of mechanisms. Vitamin D has several immunosuppressive properties and, on the whole, has such an effect”.28
The phenomenon of deactivation of vitamin D receptor
The clinical evidence available for a wide range of autoimmune diseases shows that the innate immune function can be induced by restoring VDR function.29 Bacteria-induced ligands of the VDR deactivate this function. The infiltration of microorganisms into the cell is known to occur in the case of viruses. It is less known, however, whether bacteria can migrate into the cell by shape changing. The conversion of bacteria into so-called “cell wall-deficient forms” is a condition for their uptake within the cells. The bacteria that most effectively infiltrate the cells at the VDR are well-known agents of chronic infections (e.g., tuberculosis; borelliosis; Chlamydia infections; infections caused by all forms of herpes virus, EBV, cytomegaly virus; and Aspergillus sp. infections). Intracellular bacteria can modulate cytokine production30 and in monocytes and macrophages cytokine activation markedly inhibits 1,25D/VDR gene transcription. Capnines are the active substances produced by these microbes and are capable of disabling the VDR. If VDR-deac is present, it is increasingly likely that the body will not attack its own tissues in autoimmune diseases; rather, antibodies are produced that are directed against certain parts of the metagenome communities of microbes.31 Intracellular microbes living in nuclear cells can interfere with DNA transcription and repair mechanisms, allowing them to trigger many of the dysfunctions associated with autoimmune diseases. Microbe immunosuppression succeeds as a result of VDR suppression.32 Defects in VDR signal transduction have previously been associated with bacterial infections and chronic inflammation.33 As early as 2010, Proal et al31 reported that VDR influences at least 1,400 genes, many of which are associated with autoimmune disorders and cancer.34 In 2005, Wang et al35 used in silico emulation to demonstrate that the sulfonolipid capnin, which is created by the biofilm bacterial species of the genera Cytophaga, Capnocytophaga, Sporocytophaga and Flexibacter, could bind to the VDR and thereby reduce its activity.33 Published models predict that as the increased concentrations of 1,25D accumulate in the nucleated cells, they will increasingly occupy the ligand-binding pockets of these receptors, thus displacing their endogenous ligands.36
The research has shown that in response to 1,25D, normal osteoclasts increase their production of acid hydrolases and subsequently increase their cell count. This means that osteoclast-mediated bone resorption is increased as a function of 1,25D. High 1,25D values, in turn, are the result of chronic inflammation in conjunction with VDR-deac. Therefore, it is the chronic inflammatory process itself that causes osteoporosis and not “vitamin D deficiency”. Low 25D values are only a consequence of the aforementioned contexts. Attempts to promote healing in FDOJ cases with excessive vitamin D supplementation are thus immunologically counterproductive.
Simultaneously, the VDR-deac prevents 1,25D from contributing to the expression of antimicrobial peptides (AMPs), such as cathelicidin and beta-defensin, which help to eliminate pathogens.44,45 In general, the innate immune system is stimulated by 1,25D, and the adaptive immune system is inhibited.46,47 Thus, an effective immune response is highly dependent on the vitamin D3 endocrine system responsible for the balance of proinflammatory and anti-inflammatory elements. This relationship is illustrated by Blaney et al48 in a study of 100 patients with autoimmune and chronic diseases: 85% of patients showed 1,25D levels that were >46.2 ng/L without hypercalcemia. Furthermore, large and reliable studies conducted with Danish population data found that the mean 1,25D value in a normal population was 29 ng/L with a standard deviation of 9.5. In addition, a review of the literature49 confirmed the association of elevated 1,25D levels with bone metabolism. It has been found that elevated 1,25D regulates VDR activity in the small intestine. This, in turn, transcribes and multiplies the genes that transport calcium and phosphorous across the intestinal epithelium. The mucosal response, and calcium and phosphorus resorption, is thus dependent on a competently activated VDR, while increased 1,25D reduces VDR competence. The fact that calcium and phosphorous resorption may be inhibited when VDR activity is impaired by increased 1,25D is illustrated by a study of Crohn’s disease patients with elevated 1,25D levels and low bone mineral density.50 It was concluded that treating the underlying chronic inflammation improved the metabolic bone disease. Brot et al51 found that elevated 1,25D levels were associated with markedly reduced bone density and bone content as well as increased bone turnover. At levels >42 ng/L, 1,25D stimulates osteoclast activity in the bone. This leads to osteoporosis development, tooth fractures and soft tissue calcification.52 Accordingly, it was found that a combination of high 1,25D and low 25D levels is associated with the lowest bone mineral levels and poorest bone health.50 The schematic overview in Figure 8 illustrates the interconnection between VDR-deac, autoimmune and systemic diseases, and FDOJ.
Conclusion
During the course of evolution, reactions to microbes have resulted in finely tuned immune responses.56 The present study brings the discussion on the subjects of the microbiome, as well as intracellular infections, and dysregulations of bone metabolism and signaling pathways into focus. We detail the interconnection between deactivated VDR, autoimmune and systemic diseases, disturbed bone metabolism and FDOJ osteolysis. In doing so, attention is drawn to the question of whether systemic cross-linking of VDR-deac and FDOJ-derived R/C overexpression may be responsible for the development of otherwise inexplicable systemic inflammatory reactions. We found that VDR-deac and metabolic regulation in the mineral matrix of the jawbone, combined with systemic dysregulated signal transduction, play a critical role in the development of the inflammatory condition FDOJ.