TGF-beta: complex interplay regulator between gut microbiota and immune system

[Jesse2233]

Might cyclophosphamide serve to interrupt and potentially reset this cycle by killing off B and T cells?

Edit: I hope Prof Edwards' hypothesis gets communicated to Montoya, Davis et al

 

[Jonathan Edwards]

Might cyclophosphamide serve to interrupt and potentially reset this cycle by killing off B and T cells?

Cyclophosphamide does not seem to be that good at resetting things except possibly in huge doses that require intensive care and cell rescue.

 

[Jesse2233]

Cyclophosphamide does not seem to be that good at resetting things except possibly in huge doses that require intensive care and cell rescue.

I take it that scenario would be something similar to HSCT?

 

[Snow Leopard]

What might be crucial about this is that it would all be largely invisible. Nothing need be found in the blood except maybe a little bit more TGF beta in some studies but not in others. Because the signalling is painted into the fabric of the tissues, not sent around like cytokines are in the blood. Finding TGF beta in tissues would not be easy but it is possible to immunisation for LTBP. Maybe there are some muscle biopsies around that could be stained for LTBP. Quantitation is hard but one might find a qualitative difference in distribution.

Is this the sort of thing you had in mind when you mentioned the thought of the "opposite of autoimmunity" a while back?

Do you have any other hypotheses along these lines?

 

[Murph]

A few thoughts on that gut/tgf-b paper.

1. It's exciting to find a pathway that can link the gut, the microbiota and the immune response *and* have evidence of disturbance in me/cfs.

2. The paper is badly written. Okay, yes, if I were an expert I'm sure it'd seem clear. But good writing allows non-experts a glimpse of what's being conveyed. Instead it is so thick with jargon, interminable sentences and epic-scale paragraphs, while being so short on sign-posting and topic sentences, that despite my motivation to engage with it I found it a massive challenge.

3. What I can grasp is that we are still in the gathering observations phase. We have lots of findings but no sense of which ones are more important than others. I get this a lot when I look at these biochemical signalling papers. 'Tgf-beta does everything' is actually not a helpful statement when you think about it. The terms central pathway, critical pathway and key pathway get chucked around like confetti. I guess everyone likes to think they've identified the protagonist rather than the accomplices.

4. If these small, multifacteted and hard to control signalling molecules *are* central to the ME/CFS etiology then I reckon the pathway to progress is more likely to go cure->understanding than understanding -> cure.
i.e. if we can figure out how rituximab (or cyclo or ampligen) helps, that's more likely to yield clues than just bobbing for apples in the cells of sufferers...

 

[62milestogojoe]

I would think one possibility is through the normalization of the gut microbiota.

Hi Adreno, vis a vis normalization of gut microbiota I undertook an experiment to do just that a couple of weeks ago. So far, results have been very positive. The experiment is on the blog section
http://forums.phoenixrising.me/inde...n-order-to-alleviate-severe-ibs-symtoms.2200/

 

[Hip]

The Ritchie Shoemaker protocol for mold toxin-induced illness involves down-regulating TGF beta-1 using low dose losartan (25 mg twice daily).

According to Dr Shoemaker, elevated TGF beta-1 destroys T-regs, and so lowers the T-regs to Th17 cell ratio, which may worsen autoimmunity. Ref: 1

 

[Jonathan Edwards]

According to Dr Shoemaker, elevated TGF beta-1 destroys T-regs, and so lowers the T-regs to Th17 cell ratio, which may worsen autoimmunity. Ref: 1

Clearly Dr Shoemaker knows nothing about autoimmunity!

 

[adreno]

According to Dr Shoemaker, elevated TGF beta-1 destroys T-regs, and so lowers the T-regs to Th17 cell ratio, which may worsen autoimmunity. Ref: 1

Absolute nonsense. TGF-beta promotes Tregs. Next time you might want to check your facts before promoting the ideas of some quack doctor.

 

[Hip]

Just in case I have misquoted Dr Shoemaker, his actual statement is this:

When we have the combo of high TGF beta-1 and low T regs what is happening is that the helpful, good guy T regs are being directed into tissue by TGF beta-1 where the wonderfully helpful T regs are converted (plasticized) into pathogenic T cells that make more TGF beta-1 (OH NO!) which sends more T regs to their death in tissue.

Source: here

So he appears to be saying that in the circumstances of high TGF beta-1 and low T-regs, this results in the T-regs being converted to pathogenic T cells.

Does that still appear to be incorrect? There are no references given in his article, so it is not clear where his statement comes from. However, I found this paper which says:

‘Yin-Yang’ functions of TGF-β and Tregs in immune regulation

For years, we have investigated the immune suppressive functions of TGF-β and Tregs under normal and immune-pathological conditions. Recently, our and other’s studies suggest that, in a cell type and environment-dependent fashion, TGF-β and Tregs might also positively regulate immune responses.

Thus, while TGF-β and Tregs are dominantly viewed as critical mediators for immune suppression, they in fact exert both ‘Yin’ (negative) and ‘Yang’ (positive) effects on the immune system.

 

[Valentijn]

Does that still appear to be incorrect? There are no references given in his article, so it is not clear where his statement comes from.

I wouldn't bother trying to make sense of Shoemaker. His own "research" is of extraordinarily poor quality, so I wouldn't trust his interpretations or claims regarding other research either. I think he's in the Yasko camp of saying whatever it takes to sell a product.

 

[Hip]

His own "research" is of extraordinarily poor quality

That's a strong statement to make. How did you come to that conclusion? Are you saying this for all his published studies?

 

[Valentijn]

That's a strong statement to make. How did you come to that conclusion? Are you saying this for all his published studies?

His HLA studies are complete garbage. Either he doesn't understand science, or he's willing to concoct bullshit to support his treatments/services.

 

[Jonathan Edwards]

Just in case I have misquoted Dr Shoemaker, his actual statement is this:


So he appears to be saying that in the circumstances of high TGF beta-1 and low T-regs, this results in the T-regs being converted to pathogenic T cells.

Does that still appear to be incorrect? There are no references given in his article, so it is not clear where his statement comes from. However, I found this paper which says:

Nobody ever found pathogenic T cells in autoimmunity so I don't know what he is on about. He is giving a garbled misinterpretation of garbled trendy immunobabble.

 

[Chrisb]

The view seems to be that it's a load of cobblers.

 

[Hip]

Nobody ever found pathogenic T cells in autoimmunity so I don't know what he is on about.

Aren't pathogenic T-cells found infiltrating muscle tissues in the autoimmune conditions of polymyositis and dermatomyositis?

 

[Hutan]

Absolute nonsense. TGF-beta promotes Tregs.

So he appears to be saying that in the circumstances of high TGF beta-1 and low T-regs, this results in the T-regs being converted to pathogenic T cells.

I thought people with ME typically have high numbers of Tregs? It would be interesting to know about the Tregs of the people in that Montoya study.

What I took from that interesting ‘Yin-Yang’ functions of TGF-β and Tregs in immune regulation' paper is that the body is bloody complex. With various subsets of both TGF-β and T-regs and the added complication of the possibility of inactivation, it's likely that simple quantification at the broad category level is missing a whole lot of the story.

 

[adreno]

I thought people with ME typically have high numbers of Tregs?

Yes. This would fit with high TGF-beta.

What I took from that interesting ‘Yin-Yang’ functions of TGF-β and Tregs in immune regulation' paper is that the body is bloody complex.

Yes, immunology is extremely complex. There is this schematic of the effects of TGF-beta in the paper. Probably a simplified explanation of things, but might give a general idea under normal circumstances:

 

[Jonathan Edwards]

Aren't pathogenic T-cells found infiltrating muscle tissues in the autoimmune conditions of polymyositis and dermatomyositis?

Not as far as I know. Jo Cambridge spent about five years studying T cells in myositis and she is of the same opinion as I. There are T cells in the muscle that should not be there but that is true of a cut finger or a burn. T cells are normal inflammatory surveillance cells. There is no good evidence that there is actually anything wrong with the T cells themselves in terms of what they recognise in myositis as far as I am aware.

 

[Blue Hef]

It is easy to get carried away with confirmation bias as biochemistry is multipurposed and "a theory that explains everything, explains nothing" (the trap of non-specificity).

There is certainly potential for peripheral changes, not merely "fooling the brain", given the links between TGF-Beta and the metabolic findings of Fluge & Mella:

"Reverse crosstalk of TGFβ and PPARβ/δ signaling identified by transcriptional profiling."
https://www.ncbi.nlm.nih.gov/pubmed/20846954

"Transforming growth factor-beta1 is a molecular target for the peroxisome proliferator-activated receptor delta."
https://www.ncbi.nlm.nih.gov/pubmed/18007025

"PPARdelta promotes wound healing by up-regulating TGF-beta1-dependent or -independent expression of extracellular matrix proteins."
https://www.ncbi.nlm.nih.gov/pubmed/19538467

The decreased NK Cell activity findings could be explained by elevated TGF-Beta:
"TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway."
https://www.ncbi.nlm.nih.gov/pubmed/26884601

"Reverse crosstalk of TGFb and PPARb/d signaling identified by transcriptional profiling"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017614/

"Transforming Growth Factor Beta, Bioenergetics and Mitochondria in Renal Disease"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444292/
(discusses relationships between energy sensing pathways and TGF-Beta cross regulation)

"TGF-β – an excellent servant but a bad master" (about development of neoplasms)
https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-10-183

"TGF-β: A New Role for an Old AktTOR"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789270/

"PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation"
https://www.nature.com/articles/ncomms8212

Everyone's favourite hypotheses confirmed.
I don't pretend to understand the feedback loops which would result from all the findings discussed above...

Hilarious @Snow Leopard. I've been a fan of the mTor overactivation theory for a while now and it was indeed confirmation bias when I realized how involved PPAR delta is with mTor and Tgf-b. Personally I have a feeling that upregulated PPAR delta is causing a sort of hyperlipidemia which is leading to cellular distress such as ER stress and impaired autophagy, and our mitochondria suffer. Metabolic shifts can influence T and B cells too and cause autoimmunity. The question for me is what is upstream of PPAR delta? mTorC1 perhaps?