Robin Whittle on Steve Kirsch's newsletter

[Robin Whittle]

(1 of 2) Please see the research articles concerning the vitamin D compounds and the immune system, cited and discussed at https://vitamindstopscovid.info/00-evi/ for the background to all that follows.

Sepsis would be rare if everyone had at least the 50 ng/mL (125 nmol/L = 1 part in 20,000,000 by mass) circulating 25-hydroxyvitamin D their immune systems need to function properly. 25-hydroxyvitamin D calcifediol (AKA "calcidiol") is produced, mainly in the liver, over several days, from ingested or UV-B -> skin produced vitamin D3 cholecalciferol. "Vitamin D" blood tests measure the level (concentration) of 25-hydroxyvitamin D in the bloodstream, where it has a half life of weeks to a month or two.

Neither of these compounds function as hormones (long distance signaling molecules in the bloodstream). They are not signaling molecules. Vitamin D3's primary role is to be hydroxylated at the 25th carbon to 25-hydroxyvitamin D. 25 hydroxyvitamin D's best known role is to supply the kidneys, so they can hydroxylate it at the 1st carbon to become 1,25-dihydroxyvitamin D calcitriol. This goes into circulation at a very low level, ca. 0.05 to 0.1 ng/mL, where it functions as a hormone, affecting the behaviour of multiple cell types all around the body which are involved in calcium-phosphate-bone metabolism. The kidney's rate of hydroxylation depends on the parathyroid hormone (the parathyroid senses the bloods concentration of calcium ions, which must be controlled within very narrow limits) and by FGF-23 (fibroblast growth factor), which functions as a hormone, which is emitted by osteocytes.

It is often said that "vitamin D" is a hormone, but only calcitriol can act as a hormone, and this is a different compound from vitamin D3 and 25-hydroxyvitamin D. All the other functions of calcitriol, which are not well known, even to immunologists, are non-hormonal - as an intracrine agent or paracrine agent. These roles involve signaling within a single cell, or to nearby cells.

Hardly known at all to medical professionals and researchers, calcitriol also functions as a signaling molecule within individual cells, including many types of immune cell. This is intracrine signaling, which enables the cell to respond to its individual circumstances. In order for this to work properly, 25-hydroxyvitamin D needs to diffuse into the cell from the bloodstream. It appears that this can only occur to the degree necessary for full operation of the intracrine signaling systems if the level in the blood is 50 ng/mL or more.

Intracrine signaling is a general principle. Here is how it works for 25-hydroxyvitamin D -> calcitriol intracrine signaling, in this example, in Th1 regulatory lymphocytes, as elucidated in 2021 by Chauss et al. https://www.nature.com/articles/s41590-021-01080-3. (A summary of this dense cell-biology article is at: https://aminotheory.com/cv19/icu/#2021-Chauss.) They incorrectly referred to this as "autocrine" signaling, in which the receptor for the signaling molecule is on the outside of the cell, but it is inside the cell, in the cytosol, which is properly known as intracrine signaling.

The cell detects a cell-type specific external or internal condition. In the case of Th1 cells, this is the presence, outside the cell, of a high level of a particular complement protein. (Complement is a set of proteins which are important in blood clotting.) This causes the cell to produce two molecules in its cytosol: the 1-hydroxylase enzyme and the so-called "vitamin D receptor" (VDR). The VDR molecule has a low affinity for vitamin D3 and 25-hydroxyvitamin D, but a very high affinity for calcitriol. It is best to think of it as the "calcitriol receptor".

Assuming there is sufficient 25-hydroxyvitamin D in the cytosol, with more diffusing in as the following process occurs, the enzyme hydroxylates these molecules to become calcitriol. Each molecule of calcitriol binds tightly to a VDR molecule and the bound complexes find their way (by diffusion, to the best of my knowledge) into the nucleus where they bind to another molecule, retinol-X. The triple complex then alters the transcription of genes in the cell's DNA into messenger RNA molecules. This is a subtle and complex process, and the outcome is different for each kind of cell. Dozens to hundreds of genes are up-regulated - more copies of these are made to mRNA molecules than before. Dozens to hundreds of genes are down-regulated, so there are fewer mRNA copies than before. The details of which genes these are vary from one cell type to the next, as does the initial condition wich started this intracrine signaling process. mRNA molecules diffuse from the nucleus to the cytosol, where they program ribosomes to produce protein. Each mRNA carries the instructions to make one type of protein. (The details are more complex, since the mRNA can be edited before getting to the ribosomes.)

Th1 cells emit cytokines - short distance signaling molecules which affect the behaviour or one or more types of immune cells. Their startup program is for the cell to emit more (in terms of their effects) of a pro-inflammatory cytokine than of an anti-inflammatory cytokine.

"Inflammatory", in this context, means that certain types of immune cells, such as eosinophils (the suicide bombers of the immune system) destroy all types of cell, ideally those of pathogens, but also, inevitably, our own cells. These inflammatory responses evolved primarily to deal with multicellular parasites such as intestinal worms, which are not affected by other immune responses, such as antibodies and macrophages.

When Th1 cells detect the high level of the complement protein, and have sufficient 25-hydroxyvitamin D to run their intracrine signaling system, they produce, inside the cell, sufficient calcitriol to change the cell's behaviour by turning off its pro-inflammatory startup program and switching the cell to its anti-inflammatory shutdown program, in which it produces, and so releases to surrounding cells, less of the pro-inflammatory cytokine and more of the anti-inflammatory cytokine.