Unsuspected aspect of immune regulation revealed: Role of 'B cells'

[bambi]

And there is little or no evidence for Tregs being important in human autoimmunity as far as I know.

@Prof. with all do respect, but this is nonsense.

Take a pick from the abundant literature on Tregs and their role the play in autoimmunity, cancer or chronic infections.
First page from google Treg autoimmunity . The topic has relived a renaissance. Inducing Tregs is quiet a topic in transplantation and autoimmmunity right now.

Or maybe I can entice you to read an Article by Richard A. Peterson, GlaxoSmithKline, which gives a short historical overview and summarizes the role of T- regulatory cells in various diseases.

 

[Seven7]

@bambi

Have bee looking for the obvious pathogens, that is the key issue!!! No one looked for the not so obvious one and you would be surprised what can cause exactly the same immune foot print,exercise intolerante, Circadian sleep rythm disorder (non 24 that should interest you), post exertional deteriation, cluster outbreaks and prevalence (vertical transmission) and much more.

Do you have a list of the not so obvious? Please elaborate. I have done research on bacterias and Have not found one to fit the profile, but again THE list is sooo long, I have not been lucky to find the right combination.

 

[RYO]

We have been looking for an obvious pathogen cause for a long time, and have not found it. We have evidence that many pathogens can trigger the illness, most of which have three properties in common - they are intracellular pathogens that infect both the gut and B cells. There is a long history of post-polio and post-Q fever, and now we have things like post-SARS and possibly post-Lyme. Of course what "post-" actually is is debatable.

Further we have evidence of ongoing damage to the immune system and metabolism. While a pathogen might be a cause, there are at least three additional possible causes: autoimmunity, autoinflammatory, and mitochondrial dysfunction. We have evidence of all three.

None of this proves its not a pathogen, and my leading contender is enteroviruses, as these have the right lifecycles (not just the lytic lifecycle), incubation period and tissue affinity. Please note that the incubation period that is understood (around 7 days) may only be for the trigger and not the causative agent.

So there are four possible categories of causative agents, not counting risk factors/predispositions like genetics. It looks very much like genetic susceptibility is part of it. So the four possible causes are pathogens, auto-immunity, auto-inflammatory and mitochondrial.

Yet here is the real kicker. It might take more than one to trigger to cause it. These things might work in combination. It might also take more than one pathogen. It might also be that all these things cause it, but in combination all together. Different causes maybe be present in different subgroups.

Other possibilities requiring research include environmental toxins.

The only thing I do not include as causative is any psychogenic hypothesis. They have been proven wrong numerous times, and not once proven right.

We have very close to a diagnostic test in the 2-day CPET. Presuming the science keeps developing the way it has, for mild to moderate (and I think even severe and very severe with modification) we have either a diagnostic test (though we need a much better one) or something that at least proves severe physical disability.

There are some interesting concepts in mitochondrial pathology to consider.

"Heteroplasmy - each mitochondiron has several DNA molecules and each cell has several hundred mitochondira. In a normal state, all these mitochondrial DNAs are identical (homoplasmy). When a pathogenic mutation ensues, it is generally present in some but not all of these mitochondrial DNA copies (heteroplasmy).

Threshold effect - Given variable heteroplasmy, not all cells in a tissue are abnormal. As a consequence, a minimal number of mutated DNAs must be present before respiratory chain failure and cellular dysfunction occur. Clinical signs do not become apparent until enough cells are affected. This is known as the threshold effect.

The threshold varies between different body tissues but is lower in tissues mainly relying on oxidative phosphorylation for energy production, such as the brain, the retina, the skeletal muscles, and the heart. This explains why systemic mitochondrial defects often manifest clinically in these organs.

Mutation rate - Mitochondrial DNA has a high mutation rate due to the lack of histones and to damage from oxygen radical species. More than 200 mitochondrial DNA mutations have been reported."

These concepts form a nice "backdrop" from which we may be able to explain the multiple triggers that ultimately lead to symptom of CFS/ME.

Given my limited knowledge, I am not sure if it would be possible to "put humpy dumpy back together again".

 

[RYO]

Reasonable questions Alex, but I am not sure just how much we should deduce from this paper. At least as reported in the press release it seems underwhelming. The reality is that we have known that 'B cells do more than produce antibody' including talking to T cells since about 1980! The first monoclonal marker for B cells recognised MHCII, which is what cells use to talk to T cells. Only later was it found on other cells like dendritic cells. B cells have not been seen as important educators in the thymus but does this study help? It seems that in the normal mouse thymus there weren't enough B cells there to study so they had to make transgenic mice with too many B cells, including some in the thymus and they found that these cells talked to T cells there. Not sure what that tells us about even normal mice, let alone humans.

And it seems a bit daft to suggest giving 'non-toxic' BAFF before transplant when we know that acute rejection is mediated at least in part by antibodies and it is quite common to give rituximab (i.e. the opposite) before transplantation and it reduces acute rejection if I remember rightly.

The further irony is that this idea of B cells 'doing other things' has been trendy for a good while. The first time this was 'discovered' (i.e. rediscovered by people who had not read the literature) was about 1994. All the evidence we have on pathogenesis of autoimmunity in humans (animal models are not similar) suggests that B cells are bad news and taking away B cells seems to help. The only thing it may make worse is psoriasis and related disorders that are probably not really autoimmune, but T cell dependent. And there is little or no evidence for Tregs being important in human autoimmunity as far as I know.

In answer to the question about how rituximab helps - it must be because of taking away the B cells because people get better during the period with no B cells and a good proportion get worse again as soon as B cells come back. You never see people getting better when B cells come back.

And in response to another query, I don't think there is any possibility of rituximab removing bacteria. It works directly on B cells and only B cells.

The trouble I have with CFS / ME being a potential autoimmune disease is that in my experience autoimmune disorders usually leave a "tissue trail" to follow. Where is the evidence of tissue damage in CFS / ME?

Other than what I have read about abnormal cytokine levels, I certainly don't understand the specific immune dysfunction in CFS / ME. My immunologic work up so far has been normal. What is the "nuts and bolts" explanation of why rituximab helps certain CFS / ME patients?

 

[bambi]

@Inester7 , I cannot elaborate right now and here, it would go far beyond the scope of a little post. I am working on it and it will be published.

The science behind Tregs, CD markers in general, is well documented and anyone can study it for them self. In fact I would recommend to everyone to do that. It is an eye-opener! But it took me nearly two years of studying the respective immunology and reading hundreds of papers on the topic before I understood really.

(Sorry for the many typos yesterday, it was three in the night when I answered this thread and I am really bad at writing anyway.)

 

[Jonathan Edwards]

Dear Bambi,
With due respect to you as well, you are not being very persuasive. One of the remarkable things about PR to my mind is that it is a forum where serious scientific issues are raised and debated, often in a precise and intelligent manner that you virtually never find in the official scientific literature. Sadly, the high profile scientific literature is more of a fashion show of what people think is trendy than an intellectual excercise. PR is different. People care and ask awkward questions. I have learnt more about ME from reading PR than from any other source.

What makes this work is: 1. Giving specific examples and arguments. and 2. Not taking any notice of people what other people say just because they say they know or because someone else says so. You are not giving us either.

Alex's original long post looked very fair and well balanced to me. A particularly key point I think is that it would be foolish to look for one answer to all ME. The direct evidence for autoimmunity in a subset is very limited but has the strength of being interventional - an apparent benefit in half of cases in a controlled trial of rituximab. We have discussed this evidence at great length in the past and all the ifs and buts involved.

I would be very interested to hear of any evidence for Tregs being involved in human autoimmunity. I spent 30 years working on autoimmune disease and came to the conclusion that by and large nobody really knew anything much about mechanisms in humans, except that antibodies were involved. Vast amounts are published in the literature based on irrelevant animal models and hypotheses that are in fashion but lack any solid basis at all. It is all a reflection of the fact that in order to get grant money you have to work on things that are trendy so you have to pretend you believe in what everyone else believes in - or indeed actually believe in it. As has been said on another thread the medical profession are rather easily infected by memes.

Give us some clear evidence and we can discuss it. One paper would be a good start. Otherwise nullius in verba I am afraid.

 

[alex3619]

@RYO, heteroplasmy (a new word for me) might be the norm. I suspect, I don't know for sure, that it is heritable. This is because eggs have (I think, I am again not sure) more than one mitochondria. We inherit mitochondria from our mothers. One way to show mitochondrial disease might be through a family history. Does apparent inheritance follow a pattern of inheritance through women but not men? That is, do children of men with the disease not show it, but children of women with the disease do? There can be other reasons for this of course, particularly in a very small sample. What is needed is for this to be investigated in a huge number of families.

Of course it might be simpler to just test the mitochondria.

In my current view, mitochondrial replication is the key to treating heteroplasmic conditions. Defective mitochondria might replicate more slowly, whereas healthier mitochondria might be more responsive to replicative triggers, including DHEA etc. So it is in theory reversible, under this model, but in practice this might be hard to do, particularly when we still do not know so much.

 

[alex3619]

@bambi

Have bee looking for the obvious pathogens, that is the key issue!!! No one looked for the not so obvious one and you would be surprised what can cause exactly the same immune foot print,exercise intolerante, Circadian sleep rythm disorder (non 24 that should interest you), post exertional deteriation, cluster outbreaks and prevalence (vertical transmission) and much more.

Do you have a list of the not so obvious? Please elaborate. I have done research on bacterias and Have not found one to fit the profile, but again THE list is sooo long, I have not been lucky to find the right combination.

There is an additional corollary to this point. We have ignored the obvious because of dogma. Take enteroviruses as a case in point. When I was learning biology, then university biochemistry, it was taught that viruses follow the lytic lifecycle. That is they replicate like mad, lyse or destroy the cell, infect more cells, repeat. Yet now we know these viruses have two additional lifecycles. Further, we already knew that about some herpes viruses, but it was considered an anomaly or something, because these did not enter the discussion much. How many other pathogens have lifecycles or properties that we don't yet know about? How many of them are obvious pathogens that might cause ME, yet we have ignored them because it does not fit what we think we know?

A good answer is great. A good question is better. It can lead to even better answers.

 

[Marco]

The trouble I have with CFS / ME being a potential autoimmune disease is that in my experience autoimmune disorders usually leave a "tissue trail" to follow. Where is the evidence of tissue damage in CFS / ME?

Hi RYO

I linked to a presentation a few weeks ago on an autoimmune basis for chronic pain. Rather the watch the whole thing, one of the key concepts discussed was an autoimmune mechanism that doesn't result in tissue damage. One possible mechanism is autoantibodies to potassium channel complexes which disrupts neural function.

http://www.painresearchforum.org/news/19697-autoimmune-basis-chronic-pain

Not that this proves anything either way but it does leave the door open.

 

[RYO]

Hi RYO

I linked to a presentation a few weeks ago on an autoimmune basis for chronic pain. Rather the watch the whole thing, one of the key concepts discussed was an autoimmune mechanism that doesn't result in tissue damage. One possible mechanism is autoantibodies to potassium channel complexes which disrupts neural function.

http://www.painresearchforum.org/news/19697-autoimmune-basis-chronic-pain

Not that this proves anything either way but it does leave the door open.

The research you mentioned likely applies to patients with neuromyotonia. But I wonder whether others that mainly have pain as their symptom have elevated CK levels.

 

[bambi]

Dear Bambi,
With due respect to you as well, you are not being very persuasive. One of the remarkable things about PR to my mind is that it is a forum where serious scientific issues are raised and debated, often in a precise and intelligent manner that you virtually never find in the official scientific literature. Sadly, the high profile scientific literature is more of a fashion show of what people think is trendy than an intellectual excercise. PR is different. People care and ask awkward questions. I have learnt more about ME from reading PR than from any other source.

What makes this work is: 1. Giving specific examples and arguments. and 2. Not taking any notice of people what other people say just because they say they know or because someone else says so. You are not giving us either.

Alex's original long post looked very fair and well balanced to me. A particularly key point I think is that it would be foolish to look for one answer to all ME. The direct evidence for autoimmunity in a subset is very limited but has the strength of being interventional - an apparent benefit in half of cases in a controlled trial of rituximab. We have discussed this evidence at great length in the past and all the ifs and buts involved.

I would be very interested to hear of any evidence for Tregs being involved in human autoimmunity. I spent 30 years working on autoimmune disease and came to the conclusion that by and large nobody really knew anything much about mechanisms in humans, except that antibodies were involved. Vast amounts are published in the literature based on irrelevant animal models and hypotheses that are in fashion but lack any solid basis at all. It is all a reflection of the fact that in order to get grant money you have to work on things that are trendy so you have to pretend you believe in what everyone else believes in - or indeed actually believe in it. As has been said on another thread the medical profession are rather easily infected by memes.

Give us some clear evidence and we can discuss it. One paper would be a good start. Otherwise nullius in verba I am afraid.

Dear Prof. Edwards,

I appreciate your willingness to come here and talk to us and you have been nothing but kind.
If I have stepped on your toes, than I apologize.

But in regard to your answer about forums and the discussions here, I have to tell you that I have been around a bit longer than you and seen and heard it all for over a decades. My patience for lengthy discourse, which lead nowhere, has run out.

And although I respect your expertise in regard to RA and autoimmunity, and certainly would not arguer with you on B cells, I can certainly stand my ground on Treg cells and ME.

I in turn have not seen any convincing data from you on how you will conduct your trial with Rituximab.
Some concrete information from you would help to clear a view very important issues. For example: which patient cohort will you actually select, on what criteria will you base your selection and which bio markers will you use to select cohort. Which immune markers will you use to accompany your trial.

And I think the abundant scientific literature on Tregs and their role in various clinical setting is more than clear. I have given you a paper which gives a good overview on Tregs.

Maybe this will do for a starter http://moms4science.wordpress.com

 

[bambi]

p.s.

I am not interested in arguing a case, nor do I feel the need to convince anyone. My priority is to find out what I and our children suffer from, get biomarkers established to get our children once and for all out of the clutches of the psych-lobby and establish treatments which could work for us, especially for children with ME.

 

[Marco]

The research you mentioned likely applies to patients with neuromyotonia. But I wonder whether others that mainly have pain as their symptom have elevated CK levels.

Not sure I understand the question but the paper I linked to was intended only as an example of 'non-destructive' autoimmunity which may be linked to various channelopathies - with channelopathy being a notion which has previously been proposed as a potentially key mechanism in ME/CFS (as per this PR article) :

http://phoenixrising.me/research-2/...annelopathy-in-chronic-fatigue-syndrome-mecfs

 

[RYO]

Not sure I understand the question but the paper I linked to was intended only as an example of 'non-destructive' autoimmunity which may be linked to various channelopathies - with channelopathy being a notion which has previously been proposed as a potentially key mechanism in ME/CFS (as per this PR article) :

http://phoenixrising.me/research-2/...annelopathy-in-chronic-fatigue-syndrome-mecfs

Thanks for the link. I have heard of channelopathies in the past. It sounds plausible. I have always been sensitive to alcohol but now I strickly avoid. Any treatments available?

 

[bambi]

You might want to watch a presentation of the world leading expert Dr. Maria Grazia Roncarolo on Treg cells .
She does studies on Tregs, specifically the induced Tregs, in patients with autoimmune diseases and transplantation.