CONFLICTING TREATMENTS FOR AUTOIMMUNE DISEASE
Vitamin D proponents have failed to recognize that many of the positive effects of vitamin D are due to the immunosuppressive effect of elevated 25(OH) D3or to make the connection with the fact that immunosuppression is contraindicated because of the probable presence of intracellular infection underlying autoimmune disorders. When the immune system is suppressed, clinical disease markers and symptoms are reduced but immunosuppression does not address an underlying cause of persistent bacteria, thus relapse is common (H. M. Kim, Chung, & Chung, 2010).
Much of current research focuses on finding drugs to suppress inflammation associated with autoimmune disease (Collins, 2011), 95 % of these studies have failed to find drugs to suppress inflammation. It seems clear a better direction is needed. Immunotherapy which restores VDR competence, corrects dysregulated vitamin D metabolism and eliminates intracellular bacteria could be the answer.
Studies report that Vitamin D appears to have a positive effect on autoimmune disease due to immune system suppression (Griffin, Xing, & Kumar, 2003).
Immune suppression is behind the proposed positive effect, as vitamin D inhibits LPS bacterial activation and cytokine production in monocytes/macrophages (Y. Zhang et al., 2012).
Encouraging use of vitamin D and touting the benefits of Immune suppression, is still considered by “experts” to be therapeutically beneficial for autoimmune diseases (Böhm, Luger, Schneider, Schwarz, & Kuhn, 2006).
The current medical model buys into these studies, causing poor treatment protocols and widening the gap between treatment and effective outcome. Vitamin D is frequently prescribed by rheumatologists to prevent and treat osteoporosis. Several observations have shown that vitamin D inhibits proinflammatory processes by suppressing the enhanced activity of immune cells that take part in the autoimmune reaction (Ishizawa et al., 2008).
This information supports a health restoration protocol that includes the discontinuance of vitamin D3 supplements in the treatment of these conditions.
MEASURING VITAMIN D3 DYSREGULATION
Vitamin D3 dysregulation can be identified by rising levels of active vitamin D (1-25 D) and lower levels of inactive vitamin D (25-D).
(Blaney, Albert, & Proal, 2009)
HIGH VITAMIN D AND AUTOIMMUNE DISEASE
The current recommendations for adequate vitamin D3 and lab normal ranges are based on levels found in unhealthy populations. These populations are over supplemented, overweight, undernourished, immune suppressed and toxic study subjects. This “madness” must be ended if we are to change healthcare and the poor outcomes of our overpriced so called healthcare system. New research is now revising the current medically recommended levels.
Vitamin D supplementation makes autoimmune disease worse due to its steroidal suppressive effect on the immune system (Y. Zhang et al., 2012). However, vitamin D proponents have failed to recognize that these suppressive effects are due to the immunosuppressive effect of elevated 25(OH) D and seemingly fail to grasp the scientifically backed fact this very same immunosuppression is contraindicated because of the probable presence of intracellular infection. When the immune system is suppressed, clinical disease markers and symptoms are reduced but immunosuppression does not address an underlying cause of persistent bacteria, thus relapse is common (H. M. Kim et al., 2010). Unfortunately, immune suppression is considered therapeutically beneficial for autoimmune diseases (Arnson, Amital, & Shoenfeld, 2007).
High levels, not low levels of Vitamin D are associated with autoimmune disease which does not follow our model for Vitamin D being protective. Elevated levels of serum Vitamin D3 were found in 85% of patients in the Pacific Northwest diagnosed with autoimmune disease. The treatment of inflammatory disease had poor result with the use of vitamin D supplementation over long periods of time (Blaney et al., 2009).
This can be explained as the result of the presence of L forms. High levels of 1,25-D result when dysregulation of the VDR by bacterial ligands prevents the receptor from expressing enzymes necessary to keep 1,25-D in a normal range (Blaney et al., 2009).
ASSOCIATION DOES NOT EQUAL CAUSATION
ACTIVE VITAMIN D3 IS A MORE ACCURATE FOR DIAGNOSING CHRONIC INFLAMMATORY DISEASE THAN STORED VITAMIN D3.
Why are levels of Vitamin D3 often elevated in patients with autoimmune diagnosis when we expect them to be low? When inflammation goes down, we see that the active levels of vitamin drop into a normal range. The active 1,25-D rather than the stored 25-D serves as a more accurate measure of a chronic inflammatory disease state (Blaney et al., 2009). In the presence of L-form bacteria and a compromised immune system, the tissues start to convert any stored D3 to active D3, making the active D3 elevated in the blood as overflows from the tissues. Unlike a healthy state, this tissue dominance of D3 production, in not regulated by the kidneys and requires a unique approach to measurement and analysis.
This is the result of tissue cells producing high levels of the steroid active vitamin D in an effort to stimulate the VDR which are blocked by the L-form bacteria, the stored form of vitamin D can be low or negligible. It is important to measure the active vitamin D3 as well as the stored vitamin D count. An abnormal ratio of stored to active D3 ratio will tell the story. Do not supplement Vitamin D until ratios normalize as steroidal vitamin D suppresses the immune system and leads to higher levels of infection (Blaney et al., 2009).
SECTION V: THE HUMAN MICROME AND AUTOIMMUNE DISEASE
Antibiotics interfere with cell wall replication. Bacteria survive the antibiotics by loss of the cell wall and become intracellular. They act like terrorist bacteria as they take over the VDR of the cell nucleus in order to suppress immune system function. Antibiotics are now unable to kill the L-form bacteria because they have become cell wall deficient (CWD) and the immune system becomes ineffective in killing them because it is now suppressed.
A good discussion of this can be found on The Marshall Protocol website mpkb.org/. Effective antibiotics were discovered in the early-mid 20th century and came into wide use after World War II. Antibiotic use has increased dramatically with rates approximating one course of antibiotics per year for the average child in the USA (McCaig, Besser, & Hughes, 2002).
ANTIBIOTICS IN CHILDHOOD AND RELATED CHRONIC DISEASE
Chronic conditions such as asthma and skin disorders have been associated with childhood antibiotic use. The long-term consequences of such disruption for the human-microbial population are more difficult to discern but result from an altered intestinal microbiota (Kozyrskyj, Ernst, & Becker, 2007; Marra et al., 2006; Noverr & Huffnagle, 2005; Prioult & Nagler-Anderson, 2005).
FURTHER UNDERSTANDING VITAMIN D3
Comprehensive vitamin D3 analysis
THE FORMATION OF VITAMIN D
The term vitamin D refers to a family of compounds that are derived from cholesterol. What we know as vitamin D is essentially a collective term for two types of calciferol: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D3 is made in the skin of all vertebrates when exposed to sunlight, while D2 is produced by invertebrates such as fungi and plants when exposed to sunlight.
CLARIFYING THE SOMETIMES CONFUSING NAMES FOR VITAMIN D
Stored or inactive vitamin D3 is sometimes referred to as D2, and active vitamin D3 is sometimes referred to simply as D3. Technically, Vitamin D2 (ergocalciferol) is the form of vitamin D from plants.
The story of vitamin D3 begins when a pre-vitamin D precursor is eaten or generated from exposure from sunlight. The precursor we get from plants is called ergosterol and the precursor we get from eating animal tissues is called 7-dehydrocholesterol. The animal origin substance is converted to what is called vitamin D3 or cholecalciferol, while the plant substance becomes vitamin D2 or ergocalciferol. The animal origin hormone as it is the most metabolically active. Both of these compounds are inactive precursors of potent metabolites and therefore fall into the category of prohormones. This is true not only for cholecalciferol and ergocalciferol obtained from the diet but also for cholecalciferol that is generated from 7-dehydrocholesterol in the skin during exposure to ultraviolet light (Bikle, 2014).
Vitamin 25(OH)D3 circulating in the blood is bound to vitamin D binding protein (DBP) and can travel to the liver or be activated by enzymes in the kidneys and tissues when needed. Supplemented D2 or D3 must be absorbed from the intestines, with the help of bile salts, and be transported in the lymph by chylomicrons to the liver.
STORED VITAMIN D2 FROM PLANTS AND D3 FROM ANIMALS
Vitamin D2 (ergocalciferol) can be synthetically made from radiating a compound (ergosterol) from the mold ergot. Vitamin D2 is inefficiently metabolized by humans (Allain & Dhesi, 2003). The plant form of vitamin D2 (ergocalciferol) has potency that is less than 30% of that of vitamin D3 (cholecalciferol) in humans, and has a much shorter duration of action (Houghton & Vieth, 2006). The active vitamin D3 is present in small amounts and is more efficiently metabolized than D2 (ergocalciferol from plants) (Armas, Hollis, & Heaney, 2004).
Cholecalciferol is more than three times as effective as ergocalciferol in elevating 25-hydroxyvitamin D3 and maintaining those levels for a longer time. Cholecalciferol metabolites have superior affinity for vitamin D-binding proteins in plasma, relative to ergocalciferol (Allain & Dhesi, 2003).
“PARACRINOLOGY” IS LOCAL CONTROL OF CELL SIGNALLING
Over 36 tissues, particularly within the immune system and various epithelial cells of the tissues, are able to express 1-α-hydroxylase enzymes and to synthesize calcitriol locally. Activation of Vitamin D3 is facilitated by these hydroxylase enzymes
The amount of active Vitamin D3 calcitriol that tissues can produce locally depends on the availability of the stored form, 25(OH) D3.
FUNCTIONS OF VITAMIN D3
The more recent description of the function of vitamin D includes three concepts:
(1) The bulk of the daily metabolic utilization of vitamin D is by way of the peripheral pathway.
(2) Locally synthesized concentrations of the stored 25(OH) D3 calcitriol are higher than typical serum concentrations of active 1-25(OH)2 D3 (calcitriol) which is broken down immediately after it acts, and no calcitriol enters the circulation due to action of the degrading enzyme 24-hydroxylase. However, blockage of the receptors by L form bacteria results in dramatically elevated production of the active D3 in the tissues which is reflected in elevated levels in the circulation.
(3) Vitamin D is biphasic. Low levels of the active vitamin D3, calcitriol stimulates the cell to produce the proteins needed for tissue-specific responses. High levels of active 1-25(OH) 2 D3 bind to the VDR with a resulting inhibitory reaction the immune system. Immune system signaling is downregulated, resulting in suppressive action, similar to steroids.
The downregulated VDR, greatly reduces the ability of the cell to respond adequately to pathologic and physiologic signals, (Heaney, 2008). For example, the ductal epithelium of the breast requires vitamin D3 to mount an adequate response to cyclic variation in estrogen and progesterone (Zinser, Packman, & Welsh, 2002). Dysregulation of cellular cycles results in abnormal cell proliferation and disease.
KIDNEY ACTIVATION OF VITAMIN D3 INCREASES CALCIUM UPTAKE
Inactive vitamin D3 is further metabolized by the enzyme CYP27B1 in the kidney to produce the active 1-25(OH) 2 D3 (calcitriol) in response to calcium needs. When dietary calcium intake is inadequate to satisfy the body’s calcium requirement, 1, 25(OH) 2 D3, along with parathyroid hormone (PTH), mobilizes calcium stores from the bone. In the kidney, 1, 25(OH)2D3 increases calcium reabsorption by the distal renal tubules (Institute of Medicine (US), 2011).
“AUTOCRINOLOGY” IS INTRA-CELLULAR CONTROL OF CELL SIGNALLING
Vitamin D has roles in a variety of biological actions such as calcium regulation, cell replication and cell differentiation. Most of these biological actions of vitamin D are now considered to be exerted through the nuclear vitamin D receptor (VDR)-mediated control of target genes (Kato, 2000).
The vitamin D receptor binds several forms of vitamin D3. Its affinity for active vitamin D3 is 1000 times more than inactive vitamin D3.
Vitamin D metabolism in the nucleus acts like a genetic switch, and is needed in the interaction of Vitamin D – VDR – RXR activation in the vitamin D response element (VDRE) complex of the DNA. Binding of this complex activates the RNA polymerase stimulation and suppression functions in the genetic transcription of DNA within the nucleus.
The Vitamin D Receptor (VDR) is also known as Calcitriol Receptor. It is also termed the NR1I1 (nuclear receptor subfamily 1, group I, member 1).The Vitamin D receptor (VDR) is a nuclear receptor and a member of the steroid hormone receptor family of nuclear receptors.
IMMUNE CELLS HAVE VITAMIN D RECEPTORS (VDR)
It is now recognized that vitamin D plays a critical role in the regulation of the innate and the adaptive immune systems (Aranow, 2011). The discovery of VDRs in activated immune cells particularly has stimulated research into the role of vitamin D in immune function (Schwalfenberg, 2011).
The binding of 1, 25-dihydroxyvitamin D3 (1, 25(OH) 2D3) with the Vitamin D Receptor (VDR) results in the modulation of many biological activities in tissues and systems including:
- CNS – neural tissue
- The immune system
- The Endocrine (hormonal) systems, including calcium and phosphorous homeostasis
- Cellular control, including apoptosis and cell differentiation
HORMONAL OR GENE ACTIVATION BY ACTIVE VITAMIN D3 IN THE TISSUES
The active calcitriol vitamin D3 binds to vitamin D receptors in the nucleus of the cell and works in conjunction with a retinoid X receptor (RXR) partner, binding to the vitamin D response elements (VDRE) located in the promoter regions of genes. This entire group then allows the binding of co-activator protein complexes linking the RXR-VDR group to transcription sites. The resulting enzymes can alter the function of the tissues (“Monograph: Vitamin D,” 2008). This is called the endocrine function of D3 because the hormone moves into the circulation to affect cells distant from the source of production (J. Zhang et al., 2011).
MITOCHONDRIA AND VITAMIN D RECEPTORS
Note mitochondria location proximity to VDR indicating that mitochondrial function is very important to the proper functioning of the VDR and mitochondrial disease will affect this main nuclear receptor leading to many diseases.
Recent findings show that mitochondria possess vitamin D receptors. The receptors for vitamin D are controlled by the Permeability Transition Pore in Human Keratinocyte Cell Line (Silvagno, Consiglio, Foglizzo, Destefanis, & Pescarmona, 2013).
Mitochondrial dysfunction leads to disease (adapted from (Marcovina et al., 2013)
STRESS AND MITOCHONDRIA DISEASE
Mitochondria are the main producers of reactive oxygen species (ROS) leading to the development of hypertension and insulin resistance which contribute to cardiovascular disease. Reactive oxygen species /ROS is the common denominator in regulating the immune system. Hypertension and vitamin D diabetes is also associated with oxidative stress from ROS. High levels of ROS damage cells, having the potential to trigger both mitochondrial-mediated apoptosis (cell death) and the degradation of the mitochondrial DNA (Ferder, Inserra, Manucha, & Ferder, 2013; Min, 2013; Montezano & Touyz, 2012).
Vitamin D receptors and Angiotensin Type II receptors in the cell are located in close proximity to mitochondria (Abadir et al., 2011; García et al., 2012; Silvagno et al., 2010).
A key to understanding the interaction of mitochondria and chronic diseases, such as hypertension and diabetes, is understanding how mitochondria are affected by VDR through ATP/energy related diseases. In the big picture, mitochondrial support of the vitamin D receptors is important in maintaining proper microme balance as these receptors modulate immune function.
OBESITY AS AUTOIMMUNE DISEASE
Obesity meets three out of four requirements to be designated as an autoimmune disease, lacking only the expression of auto antibodies (Autoimmunity Research Foundation). Obesity is a chronic disease which involves the following dysfunctions which indicate autoimmune disease.
- Extensive infiltration of adipose tissue by immune cells;
- The cloning or increase of T cell receptor (TCR);
- Hi levels of Th1 cytokine secretion, activation of the complement system, activation of inflammatory M1-macrophages and low numbers of regulatory T (Treg) cells. Obesity results in elevated inflammatory markers which show up for both in women and men (Mortensen et al., 2009; Nijhuis et al., 2009).
Obesity lacks only the expression of a self-antigen in the adipose tissue targeted by auto reactive immune responses to be officially classified an autoimmune disease.
Both experimental and clinical evidence involve stress response that activate the body’s system for controlling blood pressure called the Renin Angiotension System (RAS). Activation of RAS induces insulin resistance, resulting in increases in reactive oxygen species (ROS) levels. High levels of ROS are harmful to cells, having the potential to trigger both mitochondrial-mediated apoptosis and the degradation of the mitochondrial DNA (Seddon, Looi, & Shah, 2007).
This points to the relevancy of vitamin D receptor status and hypertension. When imbalanced, stress leads to imbalance in the microme and is a direct cause of the proliferation of opportunistic L-form creation (Markova, Slavchev, Michailova, & Jourdanova, 2010). Under stress bacteria can undergo drastic morphological and functional changes, leading to L-form conversion whereby the bacteria now exist without rigid walls (Glover, Yang, & Zhang, 2009).
The mutation of the bacteria in the microme is due to the response elicited by the microbes to nitric oxide stimulation released under stress (Yan & Kustu, 1999). The beta receptors stimulate release of nitric oxide by the enzyme eNOS (Fleming, 2010).
