ME/CFS is a mast cell disorder (hypothesis)

[lansbergen]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906674/
Ligand recognition during thymic development and γδ T cell function specification

Christina Meyer,a Xun Zeng,a,b and Yueh-hsiu Chiena,

Abstract

γδ T cells develop in the thymus before entering the periphery. Recent work suggests that thymic development does little to constrain γδ T cell antigen specificities, but instead determines their effector fate. When triggered through the T cell receptor, ligand-naïve γδ T cells produce IL-17, ligand-experienced cells make IFN-γ and those that are strongly self-reactive make IL-4. Importantly, γδ T cells are able to make cytokines immediately upon TCR engagement. These characteristics allow γδ T cells to initiate an acute inflammatory response to pathogens and to host antigens revealed by injury. These advances warrant a fresh look at how γδ T cells may function in the immune system.

 

[alex3619]

Two things are coming up so far treatment wise, with regard to gut integrity and gamma delta T cells, that I am not sure have been mentioned before except in an earlier comment of mine. The first is alkaline phosphatase, which is often thought of by medical practitioners as bad if elevated, is necessary for gut repair. The second is apple skin polyphenols can enhance gut repair. I am still trying to finish reading this thesis:

http://igitur-archive.library.uu.nl/dissertations/2009-1113-200110/bolschoenmakers.pdf

There is so much information to review, but so far I can explain why NK cells are down (and possibly why the bright/dim ratio is off); some of the biochemstry that might underly PEM/PENE; MCS; increased allergies; Th2 bias, and so on. Of course its not clear that just because there is an explanation that it is a correct one. So many explanations exist, most of them will be proven wrong in time.

One of the primary functions of GDTC in the gut is to suppress mast cells and enhance food tolerance. That alone is reason for me to continue reading up on them.

Bye, Alex

 

[alex3619]

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/B_and_Tcells.html#Gamma_Delta

Curiously, many of the antigens to which γδ T cells respond are found not only on certain types of invaders (e.g., Mycobacterium tuberculosis, the agent of tuberculosis) but also on host cells that are under attack by pathogens.

Hi lansbergen, this makes sense. They would be attracted to components of our old cells that are under attack especially if the cell is destroyed. They are also involved in suppressing immune response, not just initiating it, so they again would need to recognize our own cells. Bye, Alex

 

[nanonug]

alkaline phosphatase [...] is necessary for gut repair

This is very interesting. My alkaline phosphatase levels are always lowish.

The second is apple skin polyphenols can enhance gut repair. I am still trying to finish reading this thesis [...] One of the primary functions of GDTC in the gut is to suppress mast cells and enhance food tolerance

Please, keep us posted! Thanks!

 

[lansbergen]

The first is alkaline phosphatase, which is often thought of by medical practitioners as bad if elevated, is necessary for gut repair.

Did you see this?

http://www.ncbi.nlm.nih.gov/pubmed/15548378







Induction of alkaline phosphatase in the inflamed intestine: a novel pharmacological target for inflammatory bowel disease.

Sánchez de Medina F, Martínez-Augustin O, González R, Ballester I, Nieto A, Gálvez J, Zarzuelo A.


Department of Pharmacology, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. fasanchez@ugr.es


Abstract

This study demonstrates the upregulation of alkaline phosphatase and the mechanisms involved in experimental colitis. All models of ileal and colonic inflammation examined, which were characterized by significant oxidative stress and neutrophil infiltration, resulted in an increase in alkaline phosphatase activity which was attributable to both epithelial cells and cells of the lamina propria, mainly leukocytes. The increase in alkaline phosphatase sensitivity to the inhibitors levamisole and homoarginine, together with changes in the apparent molecular size and in the sialization of the enzyme, indicated a change in the isoform expressed. An increase in tissue non-specific alkaline phosphatase expression was observed by Western blotting. Treatment with the bone/kidney alkaline phosphatase inhibitor levamisole or a monoclonal antibody resulted in significant protection from colonic inflammation. Taken together, these results indicate that the kidney isoform is a marker of intestinal inflammation and that it might even constitute a target for pharmacological intervention.

 

[alex3619]

Did you see this?

http://www.ncbi.nlm.nih.gov/pubmed/15548378







Induction of alkaline phosphatase in the inflamed intestine: a novel pharmacological target for inflammatory bowel disease.

Sánchez de Medina F, Martínez-Augustin O, González R, Ballester I, Nieto A, Gálvez J, Zarzuelo A.


Department of Pharmacology, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain. fasanchez@ugr.es


Abstract

This study demonstrates the upregulation of alkaline phosphatase and the mechanisms involved in experimental colitis. All models of ileal and colonic inflammation examined, which were characterized by significant oxidative stress and neutrophil infiltration, resulted in an increase in alkaline phosphatase activity which was attributable to both epithelial cells and cells of the lamina propria, mainly leukocytes. The increase in alkaline phosphatase sensitivity to the inhibitors levamisole and homoarginine, together with changes in the apparent molecular size and in the sialization of the enzyme, indicated a change in the isoform expressed. An increase in tissue non-specific alkaline phosphatase expression was observed by Western blotting. Treatment with the bone/kidney alkaline phosphatase inhibitor levamisole or a monoclonal antibody resulted in significant protection from colonic inflammation. Taken together, these results indicate that the kidney isoform is a marker of intestinal inflammation and that it might even constitute a target for pharmacological intervention.

Hi lansbergen, I have read hundreds of abstracts in the last few days, but not this one. This is an isoform - which means an alternate version. I wonder how this impacts on the research showing alkaline phosphatase, the original version, improves gut integrity. Taken together, I think it means that we can make two kinds of alkaline phosphatase, one helps inflammation and the other causes it. I wonder why we produce the damaging variety? Pathogen? Or is the other research or this research wrong?

Bye, Alex

PS It might also depend on the experimental model. The research I was reading is on mice I think, I wonder what they used here? If two animal types differ so much, I wonder who well this will translate to people?

 

[lansbergen]

Hi lansbergen, I have read hundreds of abstracts in the last few days, but not this one. This is an isoform - which means an alternate version. I wonder how this impacts on the research showing alkaline phosphatase, the original version, improves gut integrity. Taken together, I think it means that we can make two kinds of alkaline phosphatase, one helps inflammation and the other causes it. I wonder why we produce the damaging variety? Pathogen? Or is the other research or this research wrong?

Bye, Alex

PS It might also depend on the experimental model. The research I was reading is on mice I think, I wonder what they used here? If two animal types differ so much, I wonder who well this will translate to people?

I use levamisole for immunomodulation and I can not relate to the severe gut problems discussed on the forum. This could explain it.

Levamisole normally does not inhibit gut and placenta alkaline phosphatase but it inhibits kidney and others. Question is why the normal gut form changes to a kidney like isoform.

 

[alex3619]

Something counter intuitive just came up in chapter 7 of the thesis on gut immunity I am reading:
http://igitur-archive.library.uu.nl/dissertations/2009-1113-200110/bolschoenmakers.pdf

Omega-3 fats, which are generally anti-inflammatory, in combination with vitamin E, actually increase mast cell reactions in the gut. I will update more on this when I have read more.

Bye, Alex

PS Both omega-3 fats and vitamin E (though they used alpha tocopherol) increased mast cell response to allergens (in this case peanut allergy in mice was the model). One idea they discussed is that the increased fluidity of the mast cells may enhance degranulation.

I have been saying for years that omega-3 fats can be proinflammatory. This reseach supports this. They also found that omega-3s increased TNF alpha, although PGE2 did decrease. Decreased PGE2 may not necessarily lead to worse gut repair here though - some of the omega-3s might enhance gut repair, this needs empirical not theoretical evidence to be sure.

 

[MNC]

Omega-3 fats, which are generally anti-inflammatory, in combination with vitamin E, actually increase mast cell reactions in the gut. I will update more on this when I have read more.

I tried Omega-3 in many forms and it always did me wrong. I always blamed it on my liver or gallbladder beig sick as all fats do me wrong, but certainly omega-3 is no different. Even boiled fish with omega-3 such as salmon doesn't do me very well.

 

[alex3619]

Hi lansbergen, about the kidney alkaline phosphatase isoform, I have an explanation. For those interested in the paper lansbergen cited, here is the link again: http://www.ncbi.nlm.nih.gov/pubmed/15548378

One of the things I am interested in is the the impact of lipopolysaccharide (LPS) on health. This is not quite how I would model it for ME or MCS, consider this a variation. If the gut becomes ulcerated for some reason (maybe even due to NSAIDs) then LPS will enter the blood stream. Some of that will wind up in the kidneys. Those with particularly susceptibility will then produce lots of kAP (my abbreviation for the kidney isoform, whereas iAP is the intestinal isoform). This neutralizes the LPS but will inevitably reach other parts of the body. In some individuals enough will do so that they disrupt the ulceration of the colon and prevent repair. This might also require genetic susceptibility.

Its also possible that it requires particular types of LPS. There are many. Different bacterial species produce different variations, and even different strains of the same bacteria can have different forms. It might be that it requires particular LPS to induce colitis. This might also explain the difference between ME, MCS and colitis in the GDTC model of ME and MCS I am working on. The mix of intestinal bacteria determine the mix of LPS forms.

All of this is hanging together. Investigations I was doing up to 19 years ago are now fitting together. This explains why most of us are Th2, why we have rapid sensitivity reactions to chemicals, and possibly even PEM though I have to investigate that further. Its also important the GDTC respond to lipids. Many of the chemicals that trigger MCS are organic or inorganic lipids, from petroleum to perfume compounds. Inevitably there will be cross talk between GDTC and mast cells. Mast cells, in the normal case, respond mainly to protein allergens.

Please be aware that though this might explain things, it doesn't mean its the right explanation, a point I hope to hammer home in my blog when I write this up. Fitting hypotheses to data is only one step in the science - hypothesis generation or model building.

Bye, Alex

PS I am starting to rethink the kidney isoform bit. This is also a bone isoform, and many bacteria like to target developing immune cells. The bone marrow might produce lots of bAP to protect itself.

A couple of more points. In conjuction with other recent immune models it explains why we get pathogen reactivation, including EBV. It also explains at least some of the nervous system lesions, though I do not think it yet fully explains brain fog or similar.

 

[alex3619]

I have found a list of substances that boost GDTC here:
http://jn.nutrition.org/content/138/1/1.full

Look at Table 1.

Please be aware that the idea of boosting GDTC capacity is experimental and hypothetical.

Does anyone have experience with statins or bisphosphonates, good or bad? That might help us figure it out.These two have opposite effect on GDTC capacity.

Bye, Alex

 

[MNC]

This testimonial is very interesting: http://forums.dinet.org/index.php?/topic/21174-mcas-confirmed/

 

[lansbergen]

PS The bone marrow might produce lots of bAP to protect itself..

Yes but if it comes from somewhere else my guess is bile duct.

 

[alex3619]

There is a major problem in extending my ideas of GDTC to MCS. While I can now show they react to amines (this is an immune reaction, not primarily neurological) I am still not able to show they react to volatile organic compounds of the range I think necessary. There is some evidence they react to phenolic compounds though. Some of the AIDS symptomology is also due to migration of these cells, and migration is intrinsic to my explanation. So if my model is right, a part of AIDS pathophysiology occurs in ME and MCS. I do not think its undestood what impact this has on AIDS patients - its appears to be an under researched area.

I still can't get good data on activating chemicals of a wide enough range to be sure about MCS though - darn!

Bye, Alex

PS In case I failed to mention it, GDTC are integral to wound healing, including gut healing. Indeed they are found at many lesions in many diseases - they try to prevent autoimmune damage and try to enhance repair mechanisms. This includes MS lesions in the brain.

 

[BeWell]

I'm new to the forum. I've tested positive for several immediate and delayed food allergies as well as environomental. I'm diagnosed with CFS/fibro. Are you having any success with antihistimines? Or is Neuropak superior? I've been treated with anti-virals for EBV, Parvo,etc...a short of course anti-virals wiped me out of energy, spiked pain and lost extraordinary weight. I'd like to see if I can better prepare my immune system going this route, first, before trying another round of antivirals. And with the Ketotifen research in mind...I''m looking for antihistimines that might have a positive effect as well as stimulate appetite. A tall order. But, there is lots of knowledge here. And, I apprecipate your thoughts and patience as I try to become educated on the MAST cell component (link) to my condition.
Thank you!

 

[camas]

I'm new to the forum. I've tested positive for several immediate and delayed food allergies as well as environomental. I'm diagnosed with CFS/fibro. Are you having any success with antihistimines? Or is Neuropak superior? .

Welcome, BeWell. Some of us are testing NeuroProtek and antihistamines. You'll find more discussion about it on this thread.

http://forums.phoenixrising.me/index.php?threads/allergy-mast-cell-treatments.19045/

 

[nanonug]

I'm diagnosed with CFS/fibro. Are you having any success with antihistimines? Or is Neuropak superior?

You need a cocktail, a single drug won't do it, in my opinion. Currently, I am taking fluoxetine, ranitidine and NeuroProtek. I am waiting for a doctors appointment to obtain a prescription for cromolyn sodium, which is a mast cell stabilizer at least in cases of IgE induced activation.

 

[fozzaw]

Allergies and chemical sensitivities are not the same thing. The gut immunology of all these is a balance of different factors. While mast cells are indeed implicated, they work in conjunction with other parts of the immune system. A huge allergy suppression factor in the gut is from gamma delta T cells. There is evidence that we have something wrong with them too. I am investigating the literature and hope to write a blog on this soon. It may be that the mast cells are fine, but the systems which suppress them are not working. Bye, Alex

I never claimed that allergies and chemical sensitivities are the same thing. I'm aware that they aren't the same thing. I have both problems.

 

[fozzaw]

Something I posted yesterday on a facebook forum after a miserable week of allergies:

When I run low on manganese, my histamine becomes sky high and react to everything (esp moldy rooms), with eczema and neurological symptoms. This is despite SAM-e, grape seed extract, and quercetin. Allegra/fenofexadine is good in a pinch but I think its toxic over the long term. SAM-e helps too but the mannitol is bad for the gut plus it is expensive for only a few hours of mild relief. Too much P5P makes it worse (CBS), too much methylfolate too. I've had to raise manganese over time as I've increased moly for copper issues, I currently do better at 30mg, tried reducing it to 22mg for a week and the allergies were terrible. I'm still trying to find ways of increasing SAM-e and GSH production but haven't found anything reliable/workable yet. Well, lipo-C helped a lot for GSH sparing and it was reliable but it's a huge pain in the ass to make good quality lipo-C.​

Further notes:

• According to the BRENDA enzyme database, CBS is downregulated by Mn3+.
• Elevating already high cysteine is known to make allergies worse (Cutler), and I've experienced that in multiple ways. Seems consistent with CBS issues.
• Manganese is oxidized/reduced by the body between different valences: http://pharmacy.mc.uky.edu/faculty/...ransformation/biotransformation-manganese.htm
• Pfeiffer wrote that higher doses of supplemental zinc might prevent the accumulation of Mn despite supplementation of 50 mg MnCl/day http://www.orthomed.org/resources/papers/pffschz.htm
• I currently take Mn-Picolinate, but will be switching to gluconate, and I don't assume that they are equivalent in bioavailability, so I may have to adjust my dose.
• I'm not sure why methylfolate makes things worse. In addition to making my allergies worse, it gives me tight muscles/headache (tiny doses of creatine does that too). I have no problem with mb12 so it might not be a simple too-much-methyl-group issue. I have slow MAT if that explains anything.

 

[Sherlock]

make good quality lipo-C.

is it possible to make liposomal quercetin?