Innate Immune Changes in the Peripheral Blood

[Kati]

hi, @Kati , I didn't mean to say (and don't think I said) we know ME causes these things. Just that they can have them and shouldn't be ignored. A lot of docs will ignore any finding in a CFS or complaining-of-"fatigue"/similar-with-no-"major medical"-diagnosis patient, whether or not it seems to be related to (or potentially exclusionary for) ME/CFS.

Low Vit D is prevalent in the population in general, particularly in the northern latitudes, but seems more common in chronically ill people, like MS and ME. Seems no one has figured out whether there is a relevance to the diseases themselves, except that they think sending TB patients to the country from London before the days of antibiotics, might have helped cure the TB for some patients due to sunshine/Vit D exposure (as London was very smoggy then). But can't find a benefit from Vitamin D supplementation (or moving south, IIRC) for MS (they looked).

I had low K+ before I ever knew what disease I had or was using any medicines/supplements (I now use some Rx which can deplete K+, which can't help), and at a time when diarrhea was not a significant problem, but my mom tends to have low K+, too. However, the reasons like this that you mentioned are sound ones to look for causes of metabolite problems.

While I had an ME doc tell me low K+ is prevalent among his patients, and I think there is some limited research indicating some metabolic reasons to suspect why this might be (I forgot the specifics, something about ion channels maybe), at this point we have more guesses about ME than answers. We would need well-powered studies controlling for variable such as those you mentioned, before we could make any kind of definite statement. And you're right, we don't have that.

My point about bone marrow transplant is just that people have different risk tolerance levels based on their personal circumstances. I did not in any way imply it was a light decision.

Again, I think we pretty much agree.

best wishes.

Yes we agree. It's still a big mystery.

Personal experiences will vary. There will be no refund

Myself I am keen for medical interventions and medical treatments. But that is my preference. If I was told I would be cured after a BMT, knowing the risks and the horrible month long of life threatening side effects of bone marrow depletion, I think I would still opt in.

 

[Jonathan Edwards]

Ahhhh... Interesting @Jonathan Edwards, I would love to hear more on your take on autoimmunity vs auto-inflammatory. What are the differences? Is auto-inflammatory being currently recognized in the medical world?

The difference is well defined, but in the 1970-1990 period people were a bit lazy about distinguishing. Autoimmunity is defined as an adaptive reaction against self - i.e. a 'learnt' reaction based on positive selection of B or T cell clones that specifically recognise a self antigen through antibody or T cell receptor. Originally we only knew about antibodies so in the 1950s it was defined as antibodies to self.

Things got confused because when T cells and their receptors were discovered it was assumed that autoimmunity must involve T cell reacting against self because it was thought that B cells only did what T cells told them to do. However, after 40 years of looking nobody has found any T cells against self, except possibly in Type 1 diabetes and in a rare genetic disorder called AIRE. But people thought that all inflammatory diseases with no obvious cause might be due to T cell autoimmunity - things like Crohn's disease.

Then more information about the innate immune system was discovered and it became clear that conditions like Crohn's disease and Familial Mediterranean Fever involved genetic errors in innate immune mechanisms. So to separate these conditions off from true antibody-associated autoimmunity it was suggested that these should just be called auto-inflammatory. Neither name is very sensible in fact but the distinction is now well established.

The only difficulty is that the distinction turns out not to be black and white for some conditions - and Crohn's and ulcerative colitis in particular (also sarcoidosis). These conditions seem to involve problems in the innate system at least some of the time but some of the time we find autoantibodies too - so there may be a mix and match overlap situation.

Multiple sclerosis is a very interesting oddity in that it involves inappropriate production of antibodies, but although we know they are being produced in the wrong place we are not sure they are necessarily autoantibodies. So it might not really fit either of the above categories. I have a strong suspicion that some MEs may similarly not fit into recognised categories. That is why I think it is a mistake to talk too broadly about these disease categories - the rules are different in every different disease.

 

[Jonathan Edwards]

I thought low cortisol was related to chronic illness in general, and I don't think of it being important in ME particularly.

In fact I nearly said that I was not sure cortisol was abnormal in ME. From what I have heard recently from Stuart Watson cortisol in ME is normal but HPA suppression responses may be abnormal, although results seem to be conflicting. Cortisol levels are generally normal in other diseases except Addison's and of course high in Cushing's.

 

[Jonathan Edwards]

Myself I am keen for medical interventions and medical treatments. But that is my preference. If I was told I would be cured after a BMT, knowing the risks and the horrible month long of life threatening side effects of bone marrow depletion, I think I would still opt in.

I think the bone marrow replacement scenario is a very relevant one. I always used to come back to it as the obvious 'going all out' approach for autoimmune problems. When we started mortality rate was around 1 in 7. I think it is now down to about 1 in 30 for autologous transplant but that is still a lot. Moreover, even the most aggressive regimens do not necessarily remove all plasma cells and that may be necessary to clean out the bad signals. So I hoped that we would nearly get there with rituximab, and for some diseases it worked well enough to be very useful, but was always waiting for new drugs that would make bone marrow replacement really safe. Unfortunately, although there has been a lot of progress, we are still not yet in a position to get rid of old marrow without using unpleasant things like cyclophosphamide. With monoclonal antibody drugs it ought to be possible soon to do the whole job very safely, but so far it has not materialised. I think it will in the next ten years but I worry that bureaucracy has slowed up the progress of this sort of research. Maybe the positive thing - although not for the human race as a whole - is that there is still a big motivation in oncology to find these new techniques to deal with the really difficult leukaemias and lymphomas. The research is being done, even if nobody is thinking of ME.

 

[MeSci]

Sounds a bit far fetched to me MeSci. I cannot see why a low cortisol would lead to autoimmunity to be honest.

I was thinking that, as high cortisol/exogenous corticosteroids depress aspects of the immune system, low cortisol could allow these to rebound/become overactive, thus (indirectly?) allowing autoimmunity to develop. Perhaps by allowing increased production of antibodies generally, which might increase the likelihood of autoantibodies developing?

 

[WillowJ]

I think it will in the next ten years but I worry that bureaucracy has slowed up the progress of this sort of research. Maybe the positive thing - although not for the human race as a whole - is that there is still a big motivation in oncology to find these new techniques to deal with the really difficult leukaemias and lymphomas. The research is being done, even if nobody is thinking of ME.

I might be able to wait 10 years (I don't think so all times, but right now I think this is in the realm of possibility), but not all our PWME friends can. It's probably not necessary to remind you of that, though.

But it shouldn't take that long for rituxan, right? Supposing it works as well as we hope? Though this is not expected to be an answer for everyone... I lost track; is there a back-up plan for the other 30-50%?

 

[A.B.]

But it shouldn't take that long for rituxan, right? Supposing it works as well as we hope? Though this is not expected to be an answer for everyone... I lost track; is there a back-up plan for the other 30-50%?

The XMRV story resulted in an increase in interest and funding, even when it turned out to be false. A positive Rituximab trial and positive replication should have an even greater effect.

 

[Jonathan Edwards]

I was thinking that, as high cortisol/exogenous corticosteroids depress aspects of the immune system, low cortisol could allow these to rebound/become overactive, thus (indirectly?) allowing autoimmunity to develop. Perhaps by allowing increased production of antibodies generally, which might increase the likelihood of autoantibodies developing?

I don't think cortisol levels affect B cell production rates - not as far as I know. I think it is probably a mistake to think of autoimmunity as 'too much immunity' or 'overactive immunity'. It is an abnormal state of immunity. The other thing is that the effects of excess steroid are not the opposite of the effects of too little steroid. Steroids will block pathways but that does not mean that absence of steroids will increase the pathways. I am afraid there are a lot of bogus concepts around in immunology about 'this goes up when that goes down' etc. - like 'TH1-TH2 balance' or 'cytokine balance'. As far as I can see these are fairytales. You do not think of driving a car in terms of accelerator/break balance because you know that these are not opposites - even if they often have opposite effects they are different sorts of mechanism and there is no 'balance' involved.

 

[MeSci]

In fact I nearly said that I was not sure cortisol was abnormal in ME. From what I have heard recently from Stuart Watson cortisol in ME is normal but HPA suppression responses may be abnormal, although results seem to be conflicting. Cortisol levels are generally normal in other diseases except Addison's and of course high in Cushing's.

We tend to have normal responses to exogenous ACTH as usually used, but there are some who say that a low-dose version of the test gives more accurate results.

There is a theory that our own ACTH levels are low, so that however well we respond to exogenous ACTH, we have either a low or abnormal cortisol secretion the rest of the time. A (maverick?) scientist called Wheatland proposed this, and it is discussed here and here.

A number of studies have found low or abnormal cortisol secretion in ME. What measure(s) did Stuart Watson go by?

 

[WillowJ]

In fact I nearly said that I was not sure cortisol was abnormal in ME. From what I have heard recently from Stuart Watson cortisol in ME is normal but HPA suppression responses may be abnormal, although results seem to be conflicting. Cortisol levels are generally normal in other diseases except Addison's and of course high in Cushing's.

I don't really understand what "HPA suppression" is meant to mean aside from mildly low cortisol/ stuff related to cortisol (such as ACTH)?

Most of the papers/abstracts I see on that look a lot like this:
http://www.sciencedirect.com/science/article/pii/S0306453014000420

Or like this:
http://www.cdc.gov/media/transcripts/t060420.htm

A review page on PR agrees that findings are inconsistent:
http://phoenixrising.me/research-2/...gue-syndrome-mecfs-artifact-or-central-factor

 

[Jonathan Edwards]

We tend to have normal responses to exogenous ACTH as usually used, but there are some who say that a low-dose version of the test gives more accurate results.

There is a theory that our own ACTH levels are low, so that however well we respond to exogenous ACTH, we have either a low or abnormal cortisol secretion the rest of the time. A (maverick?) scientist called Wheatland proposed this, and it is discussed here and here.

A number of studies have found low or abnormal cortisol secretion in ME. What measure(s) did Stuart Watson go by?

I do not remember in detail - this was a presentation of recent findings. I assume they measured baseline steroid levels and did a dexamathesone suppression test (that is what I meant by suppression response WillowJ) or modern equivalent. They found the opposite to what was in the literature if I remember correctly.

 

[Gijs]

I understand that especially in the morning cortisol levels are abnormal low in ME patiënts. And measure cortisol over 24 hours in saliva too. But on the other hand it can be high at some moments..... but low cortisol a consistent finding if measure correctly.

 

[lansbergen]

@Jonathan Edwards
Do you know this paper and what do you make of it?
http://jid.oxfordjournals.org/content/177/2/451.full.pdf

 

[Jonathan Edwards]

@Jonathan Edwards
Do you know this paper and what do you make of it?
http://jid.oxfordjournals.org/content/177/2/451.full.pdf

I am not really sure what to make of it. They seem to have wanted to show something to do with Th1 and Th2 cells on the basis that these are supposed to be important in autoimmune disease. I have yet to see any evidence that the Th1/Th2 idea has anything to do with human disease. Rheumatoid was supposed to be Th1 until it became clear that the T cells are probably entirely normal and that it is antibody mediated after all (which if anything would be Th2).

The authors found something they were sort of expecting and something they were not expecting, which is fair enough. However, I am unclear where it would take us in terms of a mechanistic story. If it proved to be repeatable it might be a place to start to build up a story but it is 15 years old and I am not aware that anyone has found the same thing since.

 

[lansbergen]

I have not seen anybody try to repeat it.

Visser moved to Groningen and I think is doing other things.

 

[Kati]

I think the bone marrow replacement scenario is a very relevant one. I always used to come back to it as the obvious 'going all out' approach for autoimmune problems. When we started mortality rate was around 1 in 7. I think it is now down to about 1 in 30 for autologous transplant but that is still a lot. Moreover, even the most aggressive regimens do not necessarily remove all plasma cells and that may be necessary to clean out the bad signals. So I hoped that we would nearly get there with rituximab, and for some diseases it worked well enough to be very useful, but was always waiting for new drugs that would make bone marrow replacement really safe. Unfortunately, although there has been a lot of progress, we are still not yet in a position to get rid of old marrow without using unpleasant things like cyclophosphamide. With monoclonal antibody drugs it ought to be possible soon to do the whole job very safely, but so far it has not materialised. I think it will in the next ten years but I worry that bureaucracy has slowed up the progress of this sort of research. Maybe the positive thing - although not for the human race as a whole - is that there is still a big motivation in oncology to find these new techniques to deal with the really difficult leukaemias and lymphomas. The research is being done, even if nobody is thinking of ME.

For stem cell transplant, the conditioning regimen (ie the chemo used prior to BMT) varies from disease to disease. Multiple Myeloma has its own, large B-cell lymphoma has its own, mantle cell lymphoma has its own. It could be tricky to decide what to use for us patients with ME, and why since we're still in the dark as of what exactly is going on.

In the case of MS, here are articles about trials of BMT in Ottawa for MS patients.

http://www.cbc.ca/news/canada/ottawa/ottawa-doctors-optimistic-about-new-ms-treatment-1.1368173
http://www.ohri.ca/newsroom/11092004.asp

70% cure rate is a good number.

 

[user9876]

I think the bone marrow replacement scenario is a very relevant one. I always used to come back to it as the obvious 'going all out' approach for autoimmune problems. When we started mortality rate was around 1 in 7. I think it is now down to about 1 in 30 for autologous transplant but that is still a lot. Moreover, even the most aggressive regimens do not necessarily remove all plasma cells and that may be necessary to clean out the bad signals. So I hoped that we would nearly get there with rituximab, and for some diseases it worked well enough to be very useful, but was always waiting for new drugs that would make bone marrow replacement really safe. Unfortunately, although there has been a lot of progress, we are still not yet in a position to get rid of old marrow without using unpleasant things like cyclophosphamide. With monoclonal antibody drugs it ought to be possible soon to do the whole job very safely, but so far it has not materialised. I think it will in the next ten years but I worry that bureaucracy has slowed up the progress of this sort of research. Maybe the positive thing - although not for the human race as a whole - is that there is still a big motivation in oncology to find these new techniques to deal with the really difficult leukaemias and lymphomas. The research is being done, even if nobody is thinking of ME.

Its not just the mortality rate but there are problems with chronic graft vs host disease which can be quite hideous although there are new treatments.

@Kati I think the side effects are more than a month long since you can be kept on anti rejection drugs for much longer and under considerable risk and basically not allowed out in public. Then there is the lifetime on antibiotics.

Would you actually need a transplant. With Leukemia treatments they start with a chemo therapy that just kills off the bone marrow but letting it regrow. Would that be enough? If a BMT were used with a autoimmune patient could they donate their own stem cell thus eliminating the chance of GVHD?

 

[Kati]

Its not just the mortality rate but there are problems with chronic graft vs host disease which can be quite hideous although there are new treatments.

@Kati I think the side effects are more than a month long since you can be kept on anti rejection drugs for much longer and under considerable risk and basically not allowed out in public. Then there is the lifetime on antibiotics.

Would you actually need a transplant. With Leukemia treatments they start with a chemo therapy that just kills off the bone marrow but letting it regrow. Would that be enough? If a BMT were used with a autoimmune patient could they donate their own stem cell thus eliminating the chance of GVHD?

@user9876 first there are 2 types of transplants:

1) autologous (your own stem cells are harvested and kept in a freezer with DMSO until needed). since these stem cells are your own, you don't need anti-rejection meds.

2) allogenic (unrelated, sometimes sibling donor) where the mortality risks are much higher, and anti-rejections meds will be needed for the rest of your days. A close match such as sibling donor improves the chances of survival.

bone marrow depletion starts 5-7 days before transplant day and may include 3-4 different high doses chemotherapy agents and some patients will also receive total body irradiation (especially those who have residual disease in lymphoma)
In either case, patients do not receive lifelong antibiotics. The 3-4 weeks after the transplant days are usually most dangerous, because the patient has lost all immunity. Neutrophils drop down to 0. The bone marrow does not make new red blood cells and platelets. The mucous membrane is raw (and I mean raw) from mouth to bowels at the other end. Fungal and bacterial infections, diarrhea (and sometimes c-diff) and other complications are to be expected and they can be fatal if not taken care of properly. All acquired immunity from childhood disease and from prior vaccines is gone.

One the stem cells have been reinfused, it takes about 3weeks to start working and produce blood cells including white blood cells to fight infection.

For allogenic transplant, the few months after the transplant are when the 'graft vs host' or rejection symptoms appear. The donor stem cells start attacking various organs.

I suspect autologous BMT would be sufficient for us but what do I know.

I hope I have portrayed a realistic explanation of the bone marrow transplant process. I just want to say it is not to be taken lightly.

 

[Jonathan Edwards]

I am sure we are only talking about autologous transplantation. That is what has been used in autoimmunity so far. It isn't really transplantation as I guess people realise. More saving some stem cells, clearing out the old marrow and trying to get new marrow to grow as quickly as possible. The pity is that even with current regimens you do not seem to get permanent cure in things like RA although you probably do in some lupus cases. That may be because plasma cells do not divide much so are not hit by cytotoxics that target dividing cells.

 

[Bob]

I am sure we are only talking about autologous transplantation. That is what has been used in autoimmunity so far. It isn't really transplantation as I guess people realise. More saving some stem cells, clearing out the old marrow and trying to get new marrow to grow as quickly as possible. The pity is that even with current regimens you do not seem to get permanent cure in things like RA although you probably do in some lupus cases. That may be because plasma cells do not divide much so are not hit by cytotoxics that target dividing cells.

Has bone marrow transplant actually been trialled in RA and lupus then?