Paging Tex - re mast cells

Post by **tex** » Sat Apr 12, 2014 10:47 am

Polly wrote:OK, shall we become lab partners and try to develop anti-ligand treatments? Of course, they wouldn't work for long, because the bacteria would soon develop new ones. Devious little critters, ain't they?

You're doing most of the work, but I'll be happy to tag along (on your lab coattail).

This observation (from the article you cited) appears to be key in understanding what's going on with vitamin D, VDRs, and the ability of bacteria to suppress the innate immune system. But note that this suppression of the innate immune system apparently happens strictly on a local basis, where the rubber meets the road — not within the heart of the immune system itself, but out on the firing line, at one of the immune system's most critical sentry points. I'm guessing that's why it's generally overlooked by most mainstream researchers who are investigating autoimmune-type syndromes. They're thinking traditionally, and looking for markers of the suppression of the immune system in conventional (big picture) terms, and it never occurs to them to view it as a strictly local event.

However, bacteria create ligands, which like 25-D, inactivate the VDR and, in turn, the innate immune response. This allows the microbes to proliferate. In response, the body increases production of 1,25-D from 25-D, leading to one of the hallmarks of chronic inflammatory disease: a low 25-D and a high 1,25-D.

This pattern is a result of the disease process rather than a cause. For a variety of reasons, neither increased consumption of vitamin D nor the body's synthesis of additional 1,25-D is ultimately effective at combatting infection. However, bacteria create ligands, which like 25-D, inactivate the VDR and, in turn, the innate immune response. This allows the microbes to proliferate. In response, the body increases production of 1,25-D from 25-D, leading to one of the hallmarks of chronic inflammatory disease: a low 25-D and a high 1,25-D.

This pattern is a result of the disease process rather than a cause. For a variety of reasons, neither increased consumption of vitamin D nor the body's synthesis of additional 1,25-D is ultimately effective at combatting infection.

The red emphasis is mine, of course. And the remark about the 2 different forms of vitamin D also clearly illustrates why doctors who choose to test for 1,25(OH)D, rather than 25(OH)D are missing the most important point about the entire process — the higher one's 1,25(OH)D level, the worse the threat of autoimmune development, because when that test result is elevated, it indicates that VDRs have been inactivated by rogue ligands, rather than activated by vitamin D {in the 1,25(OH)D form}.

And by the same token (and even more importantly), I'm going to postulate that when the 25(OH)D test result is low, that also implies that available VDRs have been depleted, and as a result, autoimmune disease may be imminent, unless drastic intervention is taken.

IOW, my point here is that the 25(OH)D test result doesn't just tell us what our blood vitamin D level might be — much more than that, it warns us when our VDR availability may be approaching a dangerously low level.

Love,
Tex

P. S. I'm bearing down on those tax forms now, and the end is in sight (I hope). LOL.

Gabes-Apg · Post by **Gabes-Apg** » Sat Apr 12, 2014 3:06 pm

Just a gabes pondering for our two amazing scientists.....

in line with the bacteria, the VDR's and immune reaction.

just like the damage that Gluten can cause to villi (and be the main source for foggy brain, joint aches etc) would/could Gluten damage have any participation in the cycle discussed above??

suzanne · Post by **suzanne** » Sat Apr 12, 2014 6:28 pm

Does some of this imply that the use of antihistamines is questionable? Suzanne

Post by **tex** » Sat Apr 12, 2014 8:05 pm

Suzanne wrote:Does some of this imply that the use of antihistamines is questionable? Suzanne

No, antihistamines are a legitimate treatment, whenever mast cells are inappropriately releasing histamine.

The main consideration in this discussion is centered on the fact that IBDs are characterized by low vitamin D receptor availability. When vitamin D receptors (VDRs) are unable to be properly activated by the active form of vitamin D {1,25(OH)D}, then the immune system loses it's ability to suppress the inappropriate activation of various inflammation modulators, such as histamine, cytokines, T cells, etc. And in that situation, antihistamines should be beneficial.

It appears to me that VDR suppression is probably the reason why mast cell activation disorder (MCAD) exists in the first place. That would imply that if we can prevent VDR suppression, then mast cells would not inappropriately degranulate, and cause histamine problems for us (along with other inflammation modulators). And of course, if our system is not flooded with excess histamine, then we would no longer need antihistamines. One good thing about antihistamines is that they don't usually cause any adverse side effects, even when they're not needed (if they're taken when they're not needed, the worst that happens is usually drying out of nasal passages).

Tex

Post by **tex** » Sat Apr 12, 2014 8:11 pm

Gabes,

That's a very good question. It would surely amplify the problem, but I haven't yet figured out a way that it might initiate the process. I'll have to mull that over and try to visualize possible connections.

Tex

Zizzle · Post by **Zizzle** » Sat Apr 12, 2014 10:57 pm

My mind is blown by this thread. Here are my crazy questions:

1. Many people believe viruses are involved in autoimmune disease development. Could they also have an ability to damage or suprress VDRs? Or is it more likely dormant viruses are able to re-emerge after bacteria have done their work suppressing VDRs?

2. There are so many different AI diseases. Are we suggesting there is one microbe behind all of them, or that each disease has it's own microbe? Do genetics determine which AI disease we are predisposed to? Or does the location of the bacterial infection (gut-MC/UC/CD, joints-RA, CNS-MS, thyroid-Hashis, etc)? What about Lupus, which can attack all over, and which is commonly associated with toxic exposures? How do environmental toxicants play a role?

3. How does this play into the leaky gut theory of disease? Do inflammatory foods like gluten cause leaky gut, which allows these bacteria to travel out of the gut and into other body tissues, causing non-gut AI diseases?

4. Could Vit D3 supplementation be harmful if we take large quantities and they can't reach the receptors?

4. My daughter had a GI infection with an e.coli strain that produces shiga toxin. She's had mild D ever since. Could she still carry this strain, despite having a normal stool culture? I notice shigella is on the list of organisms with power over VDRs. What's the relationship between shigella and shiga-toxin producing e-coli? Could she slowly be losing control of her VDRs as a result of this and be headed to AI disease?

So may implications!! What is sorely needed is testing to accurately diagnose all these stealth infections!!

Polly · Post by **Polly** » Sun Apr 13, 2014 6:33 am

Gabes,

Good question! I will attempt to answer it.

But first, here is some background info:

Mechanisms of Action of Vitamin D

Most if not all actions of vitamin D are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR) (3). Upon entering the nucleus of a cell, 1,25-dihydroxyvitamin D associates with the VDR and promotes its association with the retinoic acid X receptor (RXR). In the presence of 1,25-dihydroxyvitamin D the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs) and initiates a cascade of molecular interactions that modulate the transcription of specific genes. More than 50 genes in tissues throughout the body are known to be regulated by 1,25-dihydroxyvitamin D (4). from the Linus Pauling Institute

OK, I know it looks like Greek, but here is how I interpret it. It appears that the VDR is located in the nucleus of certain cells (T-cells, macrophages, and other cells necessary for optimal immunity). In the presence of vitamin D (or more accurately, its metabolite after it leaves the liver) and another factor located in the cell nucleus called RXR, the VDR's job is to transcribe certain genes. Transcription is the process by which DNA strands are copied into RNA strands, which eventually become the new DNA strands. If microbes can prevent vitamin D from being utilized properly in this process, then genetic errors can occur and perpetuate every time the DNA is copied. Dr. Fine has always said that the gene that is responsible for MC is the same gene that is involved with gluten sensitivity (and I would suspect many of the other foods to which we are sensitive).

You will recall that it is not gluten itself that damages the villi - it is the antigen/antibody complex that is formed when the gluten antibody attacks the gluten protein. My take is that the reason we make antibodies in the first place to gluten (and other foods) as well as the "good" bacteria in our colon (the hallmark of MC) is because our VDRs are defective - they have been disabled because they can no longer use vitamin D effectively - and therefore errors in copying our genes are being made.

Of course, I could be all wet here! But what an interesting discussion this is!!!

Love,

Polly

Polly · Post by **Polly** » Sun Apr 13, 2014 7:19 am

Hi Z!

More good questions! I surely do not have the answers, but I'll take a stab with some opinions.

1. I would bet that viruses could be involved too. Most of what I've been reading lately uses the term "microbes", which would include viruses. Viruses are much more difficult to work with in the lab, so that may explain why we haven't heard more about them.

2. I don't think AI disease is microbe-specific (or dependent upon location of an infection). It appears that they have found a number of microbes that can disable the VDR. I would agree that one's inherited genes play the major role in determining AI disease . But we also know that infections, toxins, etc. can alter genes and contribute to AI disease. It is now seems to me that much of the AI problem lies in the cell nucleus where errors occur in DNA replication (IOW, genetics).

3. Not sure. I would doubt that bacteria traveling out of the gut to distant sites is a problem. Again, I think it is errors at the gene level that are responsible for most, if not all AI disease. The type of AI disease probably depends upon your underlying genome (for example, we know that folks here with the double DQ HLA gene pattern are more likely to have multiple food sensitivities) as well as those other factors like infection/toxins, and yes, even stress. Don't forget about the Harvard study that has shown that regular meditation/relaxation can actually alter gene expression. This study always blows my mind. They actually analyzed the full genome of each participant before and after some weeks of meditation and found that genes associated with certain conditions could actually be "turned off". So even the mind-body connection seems to occur at the gene level.

4. Don't know. It may be possible (perhaps certain folks with a genetic propensity to vitamin D toxicity?). Tex' earlier comments about the level of vitamin D vs. the level of its metabolite are interesting.

5. Don't know.

Your final comment about "stealth infections" reminds me of our former discussion here about Mycobacterium paratuberculosis/Jonne's disease. Talk about a stealth microbe! It can lie dormant for years, eliminate its cell membrane, do everything possible to escape detection!

Love,

Polly

Zizzle · Post by **Zizzle** » Sun Apr 13, 2014 7:55 am

Interesting. What would ANti-Nuclear Antibody testing tell us about what's going on in our cell nuclei? Could +ANA be proof of this attack on the VDRs?

Post by **tex** » Sun Apr 13, 2014 9:54 am

Call me retarded, but I think we're looking at this bass-ackwards. This viewpoint is probably going to be interpreted as convoluted at best, and confusing at worst, but here's what I think:

Pathogens don't typically cause autoimmune-type reactions (by definition — an autoimmune-type reaction is a reaction against self, not a reaction against an exogenous pathogen.

We've been focusing on what happens when a pathogen manages to deactivate the VDRs. But let's look at the other side of the coin. What happens when no pathogenic threat exists?

IMO, we shouldn't lose sight of these facts:

1. Vitamin D in the form of 1,25(OH)D activates the VDRs to turn on certain genes, whenever a pathogenic threat is detected. This action allows the immune system to effectively (hopefully) combat the pathogenic threat, and eventually eliminate the problem.

2. Vitamin D in the form of 25(OH)D calms the immune system (by deactivating the VDRs to turn of those genes). So when the threat is past, vitamin D deactivates the VDRs, which effectively commands the immune system to "stand down" (stop all aggressive behavior). This action is the primary mechanism by which the immune system prevents autoimmune-type reactions (IMO).

But obviously, this implies that if we have a vitamin D deficiency, then once the VDRs are activated, and the defensive genes are turned on, then the body has no effective way to prevent an autoimmune-type syndrome from developing (when no pathogenic activity exists), because there's no way to deactivate the VDRs (unless some bacterial strain turns them off with an effective ligand). Am I right? But this obviously complicates the picture by introducing the possibility that bacteria producing such ligands might be misconstrued as beneficial. Is this possibility mind-boggling, or what?

This suggests that a vitamin D deficiency could make us dependent on (probably) pathogenic bacteria, to deactivate our immune system to prevent an autoimmune-type reaction from developing. So does this also imply that if we are experiencing an autoimmune-type reaction, then that is prima facie evidence that we are free of any bacteria that are able to produce ligands capable of deactivating the VDRs?

In the most likely scenario (IMO):

A pathogenic threat occurs. Most likely, it will be squelched by the immune system. But what happens then? If plenty of vitamin D is available, then the immune system is turned off, and everything is copasetic. If vitamin D is in short supply, some of the VDRs will not be deactivated, and the inflammatory response continues. The severity of the residual response depends on the percentage of VDRs that are not properly deactivated.

Does that not concisely define the most likely etiology of autoimmunity?

Tex

gluten · Post by **gluten** » Sun Apr 13, 2014 10:23 am

Hi, Great information. IMO, If you look at the over forty different types of muscular dystrophies, each one could be caused by a different bacteria or virus. A genetic researcher from Boston has stated " that we are all born with approx. ten DNA defects." When our biochemistry matches the DNA defect it triggers the defect. One researcher for FSHD in Worcester Mass has been looking at an extremely rare case of FSHD. Identical twins, both with the DNA for FSHD, one has no symptoms and the other has muscle weakness and is progressing. Another is a family of five children four have the FSHD defect and only two are effected. It is highly possible that a change in the microbiota is responsible for this happening. Jon

Post by **tex** » Sun Apr 13, 2014 11:50 am

Jon,

I wonder if the 25(OH)D level of those subjects has been carefully monitored on a regular (long-term) basis. It might provide some valuable insight into the probability of disease activation.

Tex

Polly · Post by **Polly** » Sun Apr 13, 2014 2:22 pm

Good thinking, Tex. It boggles the mind, doesn't it?

Apparently a lot of work is going on just now in this area. Check this out:

Autoimmune diseases and over-active T cells (which are deactivated by vitamin D) – March 2014
The vitamin D receptor turns off chronically activated T cells.[/color]
Ann N Y Acad Sci. 2014 Mar 26. doi: 10.1111/nyas.12408. [Epub ahead of print]
Cantorna MT1, Waddell A.
1Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, Pennsylvania; Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, Pennsylvania.

T cell proliferation and T helper (TH ) cells that make IL-17 (TH 17 cells) and IFN-γ (TH 1 cells) have been shown to be inhibited by 1,25(OH)2 D3 . Previous work has shown that immune-mediated diseases, where TH 1 and TH 17 cells are pathogenic, are ameliorated with 1,25(OH)2 D3 treatment.

Paradoxically, infectious diseases that require TH 1 and TH 17 responses for host resistance are unaffected by 1,25(OH)2 D3 treatment.

Resting T cells are not responsive to vitamin D because they do not express the vitamin D receptor (VDR) until late after activation. T cells activated following an infection help clear the infection, and since the antigen is eliminated, vitamin D is not needed to dampen the immune response.

Conversely, in immune-mediated disease, there is chronic T cell activation, and in this scenario, vitamin D and 1,25(OH)2 D3 are critical for inhibiting T cell proliferation and cytokine production. Vitamin D is a late regulator of T cell function and acts to turn off T cells. This paper will review these data.

© 2014 New York Academy of Sciences.
KEYWORDS: CD8 T cells, TH17, inflammatory bowel diseases, vitamin D

Does this shed any light? (VDRs are located in the nuclei of T-cells....and other cells)

You are correct that pathogens don't really cause AI (reactions against self) Unless we consider our gut bacteria to be "self". Gluten and other food substances certainly aren't self.

I enjoyed your thinking about the microbes being beneficial in helping to prevent the development of AI disease. Isn't the relationship between man and microbes considered to be "commensual"? It would make sense I think.

Love,

Polly

Gabes-Apg · Post by **Gabes-Apg** » Sun Apr 13, 2014 2:48 pm

another Gabes Pondering... (thanks for considering the previous one!)

Thinking about the commonalities of MC 'starting' with things like medications, hormone (HRT)
are they part of the 'combo' when the VDR are hoodwinked, that kick starts MC?

the combo being some or all of; Genes, Lifestyle, bacteria flares, over use of antiobiotics, Certain medications, HRT, Vit D deficiency, allergy/histamine issues most of life.

Post by **tex** » Sun Apr 13, 2014 9:51 pm

Polly wrote:Does this shed any light? (VDRs are located in the nuclei of T-cells....and other cells)

Definitely. I didn't realize they were located in the nucleus, but it would obviously make sense that they would be located in the control center (where all the DNA material is situated). So clearly their role is vital to the operation of the cell.

Thanks.

Love,
Tex