By Ed Hill
Vitamin D3 (Vitamin 1,25(OH)2 D3) is a naturally occurring bodily substance that many believe to exert a protective effect in multiple sclerosis - both in the development of the disease and in limiting its progression. It is naturally produced in the skin in response to sunlight but is also present in certain foodstuffs (particularly oily fish). It is also available as a dietary supplement from health food stores.
Strictly speaking, because your body can produce it, Vitamin D3 isn't a vitamin. It's a type of steroid hormone and among other things, a powerful mediator of immune function.
D3 is best known for it's effects on calcium metabolism. Proper levels are necessary to maintain bone mineral density and serum (blood) calcium levels. This is especially true among the very young where it is used to treat rickets and in combination with vitamin A for the treatment of osteoporosis in the elderly, particularly post menopausal women who are often subject to fractures due to loss of bone density.
In studies, Vitamin D has been found helpful against autoimmunity for the down-regulation of Th1 and up-regulation of Th2 cells. It has also been shown to regulate the neurotrophins NGF (Nerve Growth Factor), NT-3 (NeuroTrophin 3) and NT-4. In addition, D3 has also been found to promote differentiation and cell death in neuroblastoma (brain tumour) cell lines as well as cancers in general making it a possible weapon against tumours.
D vitamin supplements available over the counter (cholecalciferol) and those included in foodstuffs like milk (D2) are precursors to transcriptionally active D3, actually to 1,25(OH)2 D3 the active form of vitamin D.
1,25(OH)2 D3 is created by your body in the following way.
UV or sunlight at between 290 and 315nm and heat on the skin results in the conversion of a molecule called 7-dehydrocholesterol (pro-vitamin D) into cholecalciferol.
The cholecalciferol or pre-vitamin then goes through two hydroxylations (additions of hydrated oxygen atoms -OH). The first usually happens in the mitochondria (a cytoplasmic organelle) of liver and kidney endothelial cells. This creates the relatively abundant 25OHD3. that's a weak form of Vitamin D3 which has a sterol or steroid "ring" structure. 25OHD3 then goes through another hydroxylation, mostly in the kidney's mitochondria, resulting in 1,25(OH)2 D3 which is really the subject here.
These hydroxylations are also performed by immune system cells under specific conditions. This "extrarenal" synthesis seems to have an "autocrine" role in certain types of cellular immune responses which mediate lymphoid cells (both B and T cells) as well as myeloid cells.
The process by which solar or U.V. light initiates VD3 synthesis is self limiting, so too much such exposure is unlikely to ever cause VD3 overdose.
As with all hormones and other messenger proteins, VD3 is only one part of the story. The communication requires a means of "hearing" and then acting on the message.
The active form of D3 has a particular molecular "tail" called a "side chain". That tail fits receptors in many cells in your body like a key into a lock. These receptors are called VDR or vitamin D receptors. Fitting themselves into these receptors, the VD3 molecules might be thought of as flipping switches that, depending on the cells in question, set any of several processes in motion by allowing the VDR to interact with a variety of VDRE (Vitamin D Response Elements).
In reality, a VDR (vitamin D receptor) usually forms a heterodimer with an RXR receptor. Thats "hetero" as in differing and "dimer" meaning a pair. So the VDR is almost always really an VDR-RXR joined pair of two different receptors. The RXR is a receptor that fits retinoic acid
There are many different VDRE. These "elements" signal sections of the host cell DNA that are "upstream" of the genetic region being activated. Keeping in mind that every nucleated cell in our bodies contains our complete genome, it becomes clear that we need a way to activate the specific sections of those genes pertinent to the tasks at hand.
These tasks include regulating serum (blood) calcium levels, stimulating cellular differentiation and subsequent apoptosis (cell death), as well as modulating the production of cytokines (messenger proteins) that pass signals within the immune and some other systems.
The role of Vitamin D3 in Multiple Sclerosis
Multiple Sclerosis is a neurodegenerative disease of the CNS (the Central Nervous System.) Both the myelin sheathing around nerve tissue and the axons or tissue themselves which conduct nerve impulses undergo an attack primarily mounted by the immune system. Over time this attack leaves scars called lesions which interfere with the transmission of signals to and from the brain. This immune attack against the "self" is called autoimmunity.
Epidemiologists have long observed a geographical north south gradient in MS occurrence. Moving further from earth's equator, there are more MS cases per capita. And among populations with similar genetics, those living at very high elevations are statistically less likely to contract MS than those below who live beneath a thicker layer of U.V. diminishing air.
Coastal populations where diets are rich in fish containing D3 are also less likely to have MS than inlanders in those same regions without fish in their diets.
These findings and our reliance on sunlight to produce VD3 coupled with its increasingly well documented immune system modulation have led many in the medical and research communities to suspect that a deficit of VD3 is involved in the development of multiple sclerosis.
It is beyond the scope of this article to fully describe the interactions of VD3 and immune system elements. If it were even currently possible, doing so would probably require several volumes. Of necessity, the following is only a few pertinent lines from a very long play.
Here's a snapshot of an immune system interaction.
An infectious agent like a virus or bacterium invades the body stimulating a response by the compliment system, killer T- cell and macrophage attack.
The infectious agent has molecules on it's surface that the body uses to identify it. These are called antigens. Macrophage actually engulf and dissolve invaders, they remove the antigen molecules from the invaders surface and act as APC (Antigen Presenting Cells) presenting examples of the antigen surface in order to recruit T and or B lymphocytes which produce receptors that fit the challenging antigens shape as a means of identifying it.
Next come the production of two types of cells, effectors and helpers. The helpers are those that "remember" the invading antigen by multiplying and generating more cells with surface receptors that fit it. These cells circulate throughout the body watching for the invaders return appearance. If it reappears, these cells stimulate the clonal production of both helper cells like themselves and effector cells which actually attack the challenging antigen.
Various stages of that process are controlled by messenger proteins called cytokines. There are over 100 different often structurally unrelated cytokines which fall into several families such as Interleukins (IL), Interferons (IFN) and Tumour Necrosis Factors TNF). Cytokines often work by controlling the direction of genetic transcription leading to immune cell production.
Most cytokines are very short lived, only working over short distances. Generally this short existence means that a cytokine acts only on the cell that produced it. It's called an "autocrine" effect. Those cytokines acting on other cells exhibit a "paracrine" effect. Usually that means other cells in the immediate area of the cell producing the cytokine. You'll often see that immediate area called a "micro-environment"
This is where VD3 enters. VD3 transcriptionally regulates cytokine production leading to differentiation (lineage maturation) and mitosis (multiplication) of these immune cells in subtle sometimes complex ways.
For example; 1,25(OH)/2D3 blocks animal models of (autoimmune) diabetes without generalized immuno-suppression. On the other hand VD3 actually increases the immune response by macrophage against bacteria. In some studies serum levels of 1,25(OH)/2D3 coincide with survival rates among those infected by HIV.
MS is typically characterized as presenting an elevated ratio of Th1 to Th2 cells. VD3 at least partially corrects that imbalance
VD3 influences ratios between these T-helpers reducing the over-proliferation of T and B leukocytes. this is partially caused at the hematopoietic level. that is at the point of blood cell creation in the bone marrow as well as at the point of leukocyte maturation in the thymus.
Vitamin D receptors have been found in both T and B lymphocytes maturing in the medulla of the thymus.
while glucocortical steroids limit maturation of many of these lymphocytes through apoptosis, some of those resistant to glucocorticoids may be stopped by VD3s ability to signal teir differentiation along a pathway leading to apoptosis rather than maturity as cytotoxic cells.
Vitamin d receptors are also found in cells of the lymph nodes and tonsils where VD3 down-regulates effector cell expression.
By these mechanisms VD3 actually has a biphasic effect on the immune system. Rather than a simple downregulation of immune response it blunts generalised over-proliferation of both lymphocytes and monocytes while sharpening the immune system attack on specific targets.
Copyright Ed Hill,