Do MEs cause CFS?

[Jonathan Edwards]

Scarecrow has pointed out that my thyroid test poll (under Members Only section of Forums) may be slow in getting completed because some of the people I have picked have not logged on to PR for a while. I am going to go through and see if I can address this. I am gradually going through doing an @ for groups on the list, as in @Chris,
@cornwall13, @Critterina, @Dolphin, @Ecolimber and am getting replies but not all by any means. Thanks to those who have replied.

 

[MeSci]

So when building ideas about how the immune system works one has to take into account the routes involved. An interesting example is the popular puzzle as to why a mother does not reject a baby in the womb as a 'foreign graft'. The answer is that because the baby has a completely separate circulation the mother's immune cells cannot do any harm once in the baby's tissues - they are a bit like a bunch of unarmed pirates in Times Square, not much chance of taking over the USA!

But the mother can develop an immune reaction to the foetus's blood in some cases, can't it? Notably when there is rhesus disparity:

http://www.nhsinform.com/health-library/articles/r/rhesus-disease/causes

The reaction to bacteria is largely due to the innate response to the surface lipopolysaccharide. As indicated, the more of an adaptive immune response there is on top of that the less trouble the bacteria should cause because they will get phagocytosed before any danger signals can be sent out. So conceivably leaky gut could cause someone to be chronically unwell but an immune response would tend to make that LESS likely. And if rituximab reduced antibody levels (which it probably would not in fact but might) it would make things worse I think.

The difficulty for me with all these popular theories is that they do not attend to sufficient detail to get the right predictions. I think we need to put together theories that take into account the complexity of the system.

Best wishes

Sorry if you've answered this before, but do you think that this paper looks at the detail properly?

 

[Jonathan Edwards]

But the mother can develop an immune reaction to the foetus's blood in some cases, can't it? Notably when there is rhesus disparity:

Absolutely right, and that shows the complexity of it all. The mother can damage the foetus through cross-placental antibody but not by a graft rejection reaction, which would have to be cell mediated.

 

[Leopardtail]

Dear Bob,
I think it is important to consider the way the immune system works in detail. It is easy to assume that an immune response would produce inflammation. However, it is worth remembering that the normal function of an immune response is to make one immune - that is to say to show NO inflammation when the stimulus is present.

The immune response in the gut works in a completely different way from that in other tissues. The gut is normally exposed to kilograms of foreign material and its job is to completely ignore it in terms of inflammatory response. A milligram of foreign material in a tissue like kidney, however, would produce an inflammatory reaction. Within the gut there are masses of plasma cells making antibody. If these recognise rubbish in the gut lumen the result is not inflammation but better tidying away of any rubbish that gets into the gut lining. And if we build up antibodies to food and gut bacterial antigens those antibodies will also help to make sure that any material that does get into the blood stream from the gut is very rapidly recognised and phagocytosed - probably in the spleen. The spleen does not get inflamed either when it eats up rubbish like this because its job is to eat up rubbish without complaining.

So when building ideas about how the immune system works one has to take into account the routes involved. An interesting example is the popular puzzle as to why a mother does not reject a baby in the womb as a 'foreign graft'. The answer is that because the baby has a completely separate circulation the mother's immune cells cannot do any harm once in the baby's tissues - they are a bit like a bunch of unarmed pirates in Times Square, not much chance of taking over the USA!

Leaking of the gut certainly occurs in serious bowel disease where there is ischaemia or some other serious damage to gut lining. Bacteria also get into the bloodstream in small numbers when we clean our teeth. But I doubt that bacteria get into the bloodstream on a regular basis and cause any reaction in MEs. The reaction to bacteria is largely due to the innate response to the surface lipopolysaccharide. As indicated, the more of an adaptive immune response there is on top of that the less trouble the bacteria should cause because they will get phagocytosed before any danger signals can be sent out. So conceivably leaky gut could cause someone to be chronically unwell but an immune response would tend to make that LESS likely. And if rituximab reduced antibody levels (which it probably would not in fact but might) it would make things worse I think.

The difficulty for me with all these popular theories is that they do not attend to sufficient detail to get the right predictions. I think we need to put together theories that take into account the complexity of the system.

Best wishes

What do you think of the H2S hypothesis for the interaction of gut microbia and ME?

 

[Bob]

Dear Bob,
I think it is important to consider the way the immune system works in detail. It is easy to assume that an immune response would produce inflammation. However, it is worth remembering that the normal function of an immune response is to make one immune - that is to say to show NO inflammation when the stimulus is present.

The immune response in the gut works in a completely different way from that in other tissues. The gut is normally exposed to kilograms of foreign material and its job is to completely ignore it in terms of inflammatory response. A milligram of foreign material in a tissue like kidney, however, would produce an inflammatory reaction. Within the gut there are masses of plasma cells making antibody. If these recognise rubbish in the gut lumen the result is not inflammation but better tidying away of any rubbish that gets into the gut lining. And if we build up antibodies to food and gut bacterial antigens those antibodies will also help to make sure that any material that does get into the blood stream from the gut is very rapidly recognised and phagocytosed - probably in the spleen. The spleen does not get inflamed either when it eats up rubbish like this because its job is to eat up rubbish without complaining.

So when building ideas about how the immune system works one has to take into account the routes involved. An interesting example is the popular puzzle as to why a mother does not reject a baby in the womb as a 'foreign graft'. The answer is that because the baby has a completely separate circulation the mother's immune cells cannot do any harm once in the baby's tissues - they are a bit like a bunch of unarmed pirates in Times Square, not much chance of taking over the USA!

Leaking of the gut certainly occurs in serious bowel disease where there is ischaemia or some other serious damage to gut lining. Bacteria also get into the bloodstream in small numbers when we clean our teeth. But I doubt that bacteria get into the bloodstream on a regular basis and cause any reaction in MEs. The reaction to bacteria is largely due to the innate response to the surface lipopolysaccharide. As indicated, the more of an adaptive immune response there is on top of that the less trouble the bacteria should cause because they will get phagocytosed before any danger signals can be sent out. So conceivably leaky gut could cause someone to be chronically unwell but an immune response would tend to make that LESS likely. And if rituximab reduced antibody levels (which it probably would not in fact but might) it would make things worse I think.

The difficulty for me with all these popular theories is that they do not attend to sufficient detail to get the right predictions. I think we need to put together theories that take into account the complexity of the system.

Best wishes

Thank you, Jonathan.
I've not done a lot of research in the area of leaky guts etc., and it's an issue that I used to be quite sceptical about (it seemed like a rather vague theory, without a great deal of evidence behind it, and too lazy an explanation for a variety of illnesses and autoimmunity), but it's something that I'm becoming increasingly interested in because of personal experiences with my illness.
I think your response, above, explores what usually happens in the gut, when everything is running as it should do (i.e. in a healthy person.)
But I'm exploring the possibility of (localised or general) dysfunction of the cells lining the gut, whereby the contents of the gut might suddenly be treated as a foreign invader, for whatever reason. (Perhaps mild damage to the gut wall, or a dysfunction of the immune/protective processes within the gut? Or perhaps there could be an autoimmune issue that attacks the gut lining?)
When I once had some food debris lodged in a small 'pocket' in my gum, I felt as if I had a flu-like illness. i.e. all the signs of a general infection. The symptoms didn't subside until I visited my dentist, but when he flushed out the gum, I had instant relief from all of the symptoms.
I'm wondering if a similar type of thing has potential to happen in (a mildly damaged, or weakened) gut lining, and thus produce a chronic immune response.

 

[Jonathan Edwards]

Sorry if you've answered this before, but do you think that this paper looks at the detail properly?

I think I have seen this one before but anyway it's worth discussing. I spent yesterday at an advisory board for IiME and on Monday I go to the CMRC meeting in Bristol. I am excited by the idea that the ways we might explain MEs are gradually getting clearer but we need to think carefully about specifics and also to take a wide angled view. So many ideas have been knocking around for fifty years and got nowhere. My own views may have been seen as 'maverick' for a long time but I think you only get progress if you challenge the popular paradigms.

My problem with the leaky gut paper here is that the same old mistake comes in right at the beginning. They say:

'It is generally accepted that the interplay between environmental factors and specific susceptibility genes underlies the aberrant immune response responsible for the onset of autoimmune diseases. Fewer than 10% of those individuals with an increased genetic susceptibility actually develop clinical disease. This suggests a strong environmental trigger in the preautoimmune process.'

Wrong. Understanding of genetics in autoimmunity really starts with Paul Stastny finding that HLA-DR4 predisposes to RA in about 1974. I remember hearing him talk around 1980 and he emphasised that apart from the genetic factor the mathematics of the epidemiology indicated that the remainder of causation was NOT environmental but random. And now we understand what that randomness could be since all antibodies are made by a random sequence generator. So the authors of the gut paper have no reason to look for another factor in the gut. There might be one but their starting assumption is wrong.

The also talk about foreign antigens inducing responses to self antigens - the old molecular mimicry idea. But the problem is that this has never been an explanation. For 99.999% of proteins molecular mimicry does not occur, so if it did occur once in a blue moon we would need a theory of why it occurred on that occasion. And there never has been such a theory. There is a much more plausible theory specifically for coeliac disease that they do not seem to mention. The autoantigen is not LIKE the foreign stimulus here, it is something that the foreign stimulus binds to.

I see no reason why gut permeability should not be relevant in some situations but, to answer your question precisely, there isn't actually any argument in this paper to suggest that it fulfils the role the authors erroneously invent for it. It is woolly argument I think. Unfortunately most papers like this are advertisements for ideas that people want to get grants for. The result is that what the general public perceive as cutting edge immunology is just a lot of rather tired recycled ideas that get flagged up to try to persuade grant committees to renew people's salaries. But there is cutting edge immunology out there - it just tends to go below the radar until it has a big payoff in terms of diagnosis or treatment.

 

[Jonathan Edwards]

I think your response, above, explores what usually happens in the gut, when everything is running as it should do (i.e. in a healthy person.)
But I'm exploring the possibility of (localised or general) dysfunction of the cells lining the gut, whereby the contents of the gut might suddenly be treated as a foreign invader, for whatever reason. (Perhaps mild damage to the gut wall, or a dysfunction of the immune/protective processes within the gut? Or perhaps there could be an autoimmune issue that attacks the gut lining?)
When I once had some food debris lodged in a small 'pocket' in my gum, I felt as if I had a flu-like illness. i.e. all the signs of a general infection. The symptoms didn't subside until I visited my dentist, but when he flushed out the gum, I had instant relief from all of the symptoms.
I'm wondering if a similar type of thing has potential to happen in (a mildly damaged, or weakened) gut lining, and thus produce a chronic immune response.

I think the problem here is being too anthropomorphic. The contents of the gut are always 'treated as a foreign invader' in as much as that makes sense. That is why the gut has vast stores of plasma cells in its lining. But in another sense the immune system does not treat anything as 'self' or 'foreign', it just follows biochemical rules and the basic rules remain the same for ever. If the system starts generating antibodies to a self protein that must be because there is a bug in the rule book somewhere that now and again comes to light. But it is always in the rule book.

The problem with food debris lodged in a gum pocket illustrates the fact that the immune response in the mouth is totally dependent on exactly where the antigen is. We put foreign antigens in our mouths all day long and have no problem. But if foreign antigens get into places where they are not allowed - like gum pockets and tooth roots all hell is let loose. A tiny focus of non-specific junk tucked down under a gum where pressure can build up will send you into a high fever and put your CRP up to sky high, just like a few crystal in a joint in gout.

The gut situation will be very complicated. Deleder flagged up the giardia study. A number of tropical and not so tropical organisms can damage small intestinal lining producing an effect a bit like coeliac damage. It used to be called tropical sprue. You can get it from giardia or amoebae. The damage may be assocaited with changes in architecture of the lymphoid (Peyer's) patches and mechanical effects may contribute to grumbling pain. I have had the problem for ten years now since I first went to India. But that does not necessarily mean that any lymphocytes in the gut are reacting to the original organism or indeed anything in the gut.

Basically what I am saying is that changes in the gut might well be caught up in whatever is going on in several forms of ME but simple ideas of autoimmune reactions or even a specific immune reaction to gut bacteria would I think be too easy. Where we understand disease mechanisms they tend to be remarkably subtle. And despite Ockham's razor there often seems to be more than one reason going on at the same time!

 

[Jonathan Edwards]

What do you think of the H2S hypothesis for the interaction of gut microbia and ME?

The only thing I can find on that on the net is a PR thread and some dampening comments by Charles Shepherd! It looks like nonsense to me. I am not sure how H2S would cause oxidative stress since it is an extremely powerful reducing agent etc. etc.

 

[Leopardtail]

The only thing I can find on that on the net is a PR thread and some dampening comments by Charles Shepherd! It looks like nonsense to me. I am not sure how H2S would cause oxidative stress since it is an extremely powerful reducing agent etc. etc.

Was not sure what to make of it... but rather think you just cleared that one up..

 

[Bob]

I think the problem here is being too anthropomorphic. The contents of the gut are always 'treated as a foreign invader' in as much as that makes sense. That is why the gut has vast stores of plasma cells in its lining. But in another sense the immune system does not treat anything as 'self' or 'foreign', it just follows biochemical rules and the basic rules remain the same for ever. If the system starts generating antibodies to a self protein that must be because there is a bug in the rule book somewhere that now and again comes to light. But it is always in the rule book.

The problem with food debris lodged in a gum pocket illustrates the fact that the immune response in the mouth is totally dependent on exactly where the antigen is. We put foreign antigens in our mouths all day long and have no problem. But if foreign antigens get into places where they are not allowed - like gum pockets and tooth roots all hell is let loose. A tiny focus of non-specific junk tucked down under a gum where pressure can build up will send you into a high fever and put your CRP up to sky high, just like a few crystal in a joint in gout.

The gut situation will be very complicated. Deleder flagged up the giardia study. A number of tropical and not so tropical organisms can damage small intestinal lining producing an effect a bit like coeliac damage. It used to be called tropical sprue. You can get it from giardia or amoebae. The damage may be assocaited with changes in architecture of the lymphoid (Peyer's) patches and mechanical effects may contribute to grumbling pain. I have had the problem for ten years now since I first went to India. But that does not necessarily mean that any lymphocytes in the gut are reacting to the original organism or indeed anything in the gut.

Basically what I am saying is that changes in the gut might well be caught up in whatever is going on in several forms of ME but simple ideas of autoimmune reactions or even a specific immune reaction to gut bacteria would I think be too easy. Where we understand disease mechanisms they tend to be remarkably subtle. And despite Ockham's razor there often seems to be more than one reason going on at the same time!

I'm sorry to hear that you've had gut problems for so long. You're in good company, with many of us here, if that's any consolation.

Yes, my thoughts about the gut are preliminary and very simplistic. I'm just exploring general ideas about ME, to see if they might resonate with you at all. Thank you for responding.

Thinking through the leaky gut theory further, I can't see how it would fit with post-exertional relapses anyway. The post-exertional response always takes me back to the idea of auto-immunity affecting cellular function (e.g. mitochondria etc.)

 

[Bob]

Hello, @Bob. Interesting question. Check this out:

https://translate.google.no/translate?sl=auto&tl=en&js=y&prev=_t&hl=no&ie=UTF-8&u=http://totoneimbehl.wordpress.com/tag/pilotstudie-pa-rituximab-og-ibs/&edit-text=

Interesting, thanks Deleder.

@Jonathan Edwards, have you seen this research proposal from Fluge, Mella and colleagues? You might find it interesting.


Norwegian Research: CD20 depletion with rituximab in patients with post-infectious irritable bowel syndrome - a pilot study
https://translate.google.no/translate?sl=auto&tl=en&js=y&prev=_t&hl=no&ie=UTF-8&u=http://totoneimbehl.wordpress.com/tag/pilotstudie-pa-rituximab-og-ibs/&edit-text=

Extracts:

Project Description: This entry gives an overview of a pilot study aimed at including nine patients with persistent symptoms of irritable bowel syndrome (IBS) after being infected with intestinal parasite Giardia in Bergen in 2004...

Project Manager project

Irritable bowel is frequent and affects about 20% of the population. The condition is often seen after an acute intestinal infection. In autumn 2004, one in Bergen an outbreak of the parasiteGiardia lamblia. Ca 5000 from Bergen became infected and got them serious gastrointestinal ailments. After successful treatment of the parasite, was after 8 years still many from Bergen persistent ailments of the bowel.

In an ongoing study we have investigated the immune system in these patients. CD20 (B cells) in intestinal biopsy was elevated in IBS patients. The use of immune modulating CD20 depletion with Rituximab may be a viable alternative to treat patients with irritable bowel syndrome.

From the Department of Oncology was published in October 2011 promising treatment with Rituximab an immunomodulatory drug that showed good effect on chronic fatigue syndrome. In collaboration with the Cancer department will do a pilot study to see whether CD20 depletion with rituximab will have an effect on IBS patients with abdominal pain.

Main findings in the study of the post-infectious IBS and chronic giardiasis patients with reduced CD4 T-cell numbers in the lamina propria, while all Giardia exposed groups have elevated B cell numbers in the lamina propria. The findings suggest that there is a prolonged immune activation in duodenal mucosa after undergoing Giardia infection.

An important finding was that CD20 (B cells) in the lamina propria crypts were elevated in both chronic giardiasis group and post-ifeksiøs IBS group compared to healthy controls. And that group of post-infectious IBS group were examined one year later had persistent CD20 numbers and these patients had persistent abdominal pain.

 

[MeSci]

Understanding of genetics in autoimmunity really starts with Paul Stastny finding that HLA-DR4 predisposes to RA in about 1974. I remember hearing him talk around 1980 and he emphasised that apart from the genetic factor the mathematics of the epidemiology indicated that the remainder of causation was NOT environmental but random. And now we understand what that randomness could be since all antibodies are made by a random sequence generator. So the authors of the gut paper have no reason to look for another factor in the gut. There might be one but their starting assumption is wrong.

Thanks for your reply, @Jonathan Edwards.

I get your point about antibodies being generated at random, but are they are not also destroyed in a non-random way or less-random way, weeding out the ones that are deemed to be inappropriate? My brain is rather fuzzy at the moment (how unusual!) but I think there is at least one aspect of selective destruction of autoantibodies or their precursors or cells producing them - I can't remember the details.

Is this the process that goes wrong - a lack of appropriate destruction rather than an excess of creation? I think you may have explained this in your main rituximab thread, but it is lost somewhere in my brain or may have fallen out!

 

[MeSci]

Thinking through the leaky gut theory further, I can't see how it would fit with post-exertional relapses anyway. The post-exertional response always takes me back to the idea of auto-immunity affecting cellular function (e.g. mitochondria etc.)

There are papers reporting that exertion causes leaky gut, e.g. this one.

 

[Bob]

There are papers reporting that exertion causes leaky gut, e.g. this one.

Thanks MeSci. However, I'm not sure if that paper, in itself, can explain severe relapses after minimal exertion such as a short walk.

 

[Jonathan Edwards]

Thanks for your reply, @Jonathan Edwards.
Is this the process that goes wrong - a lack of appropriate destruction rather than an excess of creation? I think you may have explained this in your main rituximab thread, but it is lost somewhere in my brain or may have fallen out!

That seems to me a very good way of putting it. There is no possibility that I can think of within what we know of antibody production that anyone would ever be more likely to create an autoimmune B cell. What must be the explanation is that we all create autoimmune B cells but only in very few situations is there a failure to weed them out. You might reasonably ask why a weeding out control system should fail on these very few occasions. The answer as I see it is that once a B cell is born with instructions to make a particular antibody it can engage either controlling negative feedback signals or positive feedback vicious cycle-inducing signals. The positive feedback ensures that as soon as a useful B cell is born it is immediately told to multiply and produce a rapid antibody response. If by chance the B cell's own antibody interferes with the feedback mechanism to shift it from negative to positive then you have an explosion of autoantibody production.

 

[aimossy]

@Bob have you just come across this very recently form deleder2k? I wonder if it is being published soon or already is... Thank you for this info.
@deleder2k or anyone know any more about this?

Norwegian Research: CD20 depletion with rituximab in patients with post-infectious irritable bowel syndrome - a pilot study
https://translate.google.no/translate?sl=auto&tl=en&js=y&prev=_t&hl=no&ie=UTF-8&u=http://totoneimbehl.wordpress.com/tag/pilotstudie-pa-rituximab-og-ibs/&edit-text=

 

[Bob]

That seems to me a very good way of putting it. There is no possibility that I can think of within what we know of antibody production that anyone would ever be more likely to create an autoimmune B cell. What must be the explanation is that we all create autoimmune B cells but only in very few situations is there a failure to weed them out. You might reasonably ask why a weeding out control system should fail on these very few occasions. The answer as I see it is that once a B cell is born with instructions to make a particular antibody it can engage either controlling negative feedback signals or positive feedback vicious cycle-inducing signals. The positive feedback ensures that as soon as a useful B cell is born it is immediately told to multiply and produce a rapid antibody response. If by chance the B cell's own antibody interferes with the feedback mechanism to shift it from negative to positive then you have an explosion of autoantibody production.

I'm probably asking some basic stuff that you've explained before, but do you think that many autoimmune conditions involve a proliferation of b-cells due to b-cells creating antibodies to themselves, or would that be an unusual scenario?

Also (sorry, I know you've explained this before, but I've lost the info), in relation to your explanation of the destructive process for antibodies, how does the immune system decide whether an antibody is useful or not? i.e. how does the immune system distinguish useful self-proteins from harmful foreign proteins when newly created antibodies attach themselves to proteins?

Apologies for asking you to repeat info that you've explained before.

 

[Bob]

@Bob have you just come across this very recently form deleder2k? I wonder if it is being published soon or already is... Thank you for this info.
@deleder2k or anyone know any more about this?

Norwegian Research: CD20 depletion with rituximab in patients with post-infectious irritable bowel syndrome - a pilot study
https://translate.google.no/translate?sl=auto&tl=en&js=y&prev=_t&hl=no&ie=UTF-8&u=http://totoneimbehl.wordpress.com/tag/pilotstudie-pa-rituximab-og-ibs/&edit-text=

Yes, I haven't seen it before today, but it seems to be quite old. I think the document says the research proposal is from 2012. Deleder might know more about it.

 

[aimossy]

Thanks @Bob I read in there - that the study was set to finish Dec 2013. So if it was going to be published it can take ages for that to happen. It is interesting about the biopsies of the duodenum as well and the B cells..

 

[MeSci]

Thanks MeSci. However, I'm not sure if that paper, in itself, can explain severe relapses after minimal exertion such as a short walk.

Not on its own, no. But if we produce excessively-high levels of inflammatory cytokines in response to mild exertion, for which I think there is evidence, then combine that with this from the linked paper:

The leakiness of tight junctions is increased by cytokines...and, as shown in the present study, by high-intensity running exercise.

So - defective aerobic ATP production may lead to excessive production of inflammatory cytokines, which in turn leads to increased gut permeability. Then, also from the linked paper:

Compromised barrier function may produce an inflammatory response and initiate a cytokine cascade

So the cytokines make the gut wall leakier, which produces even more of the cytokines, increasing inflammation, etc. (That is if all or most of the cytokines involved are pro-inflammatory rather than anti-inflammatory.)

I'm sure there are many other factors involved, but that could explain a pathological inflammatory consequence of exertion. What do you think, @Jonathan Edwards?