Do MEs cause CFS?
- Thread starter Jonathan Edwards
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halcyon
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No, I never have.
BurnA
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Could you elaborate on the differences between immune dysregulation and autoimmune ( if you haven't already ) ?
Would there likely be major differences in diagnosis and treatment between the two ?
Jonathan Edwards
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Autoimmune means that there is a specific immune response to a self antigen. Historically this was discovered as an antibody response - antibodies to red cells found by Donath and Landsteiner around 1905. Then people discovered anti-nuclear antibodies and rheumatoid factor antibodies and thyroid antibodies and about 100 others. When T cells were discovered it was assumed that the T cells must be recognising self too, but the evidence for that has been remarkably thin. In most cases it looks as if it is just antibodies that are auto-.
So to qualify as an autoimmune disease it seems reasonable to stick to the original idea of finding auto-antibodies, although autoreactive T cells could qualify if there were any. In reactive arthritis and ankylosing spondylitis there is apparently a T cell response (little if any evidence of B cell or antibody response) that should not be going on, but nobody knows what it is recognising or even if anything specific is being recognised. Maybe the T cells are just overenthusiastic generally.
So in practice the difference in diagnosis rests on whether or not there are autoantibodies, or at least antibodies that look as if they are probably auto (MS is a case). Autoantibody-related disease can be treated with B cell targeting therapies but if the problem seems to be in T cells or macrophages then that would not make sense. The T cell mediated conditions like reactive arthritis tend to respond well to TNF inhibition but this probably does not have a long term effect.
I'd add a bit to that, at least in terms of how I use the terms. Autoimmune is, most correctly, just what Dr. Edwards states, although many others, including me, use it in a more sloppy manner to include things w/o antibodies such as reactive arthritis or ankylosing spondylitis, but these seem to be fundamentally different and would be treated differently.
B-cells make antibodies, so depletion of B-cells is logical generally when antibodies are involved. It's possible, however, that B-cell depletion might have other, more complex effects due to the interconnected network of cytokines that connect all immune cells. Still, B-cell depletion is most likely to make sense and to be effective in antibody mediated autoimmunity. Rituximab depletes B-cells (CD20 B-cells). It thus reduces antibody production. If you are making antibodies against your own tissue, getting rid of some of the B-cells that do that is to your benefit, obviously. My point is that while rituximab's effectiveness against ME (if shown in the phase III trial - which I think likely) is suggestive of an antibody mediated autoimmune process, it's not proof, and other mechanism are possible.
Lastly, I would include in "immune dysregulation" other immune disorders, innate or acquired, that lead to an abnormal immune function. For example, AIDS is a form of immune dysregulation, but it is not autoimmune or even autoinflammatory (like AS, ReA, etc.) An inborn genetic error could also be immune dysregulatory in nature - for example, SCID, or severe combined immune deficiency, is a genetic illness in which a person cannot produce antibodies. In addition to dysregulatory, which is a broad term, it's also immune deficiency (these people cannot make antibodies). One can argue that autoimmune must be a form of immune dysregulation, as proper regulation of the immune system would not allow autoimmunity.
There is some ambiguity in some of the terms as most people use them, but Dr. Edwards is generally very precise in referring to autoimmune disorders as being only those with a self antibody.
B-cells make antibodies, so depletion of B-cells is logical generally when antibodies are involved. It's possible, however, that B-cell depletion might have other, more complex effects due to the interconnected network of cytokines that connect all immune cells. Still, B-cell depletion is most likely to make sense and to be effective in antibody mediated autoimmunity. Rituximab depletes B-cells (CD20 B-cells). It thus reduces antibody production. If you are making antibodies against your own tissue, getting rid of some of the B-cells that do that is to your benefit, obviously. My point is that while rituximab's effectiveness against ME (if shown in the phase III trial - which I think likely) is suggestive of an antibody mediated autoimmune process, it's not proof, and other mechanism are possible.
Lastly, I would include in "immune dysregulation" other immune disorders, innate or acquired, that lead to an abnormal immune function. For example, AIDS is a form of immune dysregulation, but it is not autoimmune or even autoinflammatory (like AS, ReA, etc.) An inborn genetic error could also be immune dysregulatory in nature - for example, SCID, or severe combined immune deficiency, is a genetic illness in which a person cannot produce antibodies. In addition to dysregulatory, which is a broad term, it's also immune deficiency (these people cannot make antibodies). One can argue that autoimmune must be a form of immune dysregulation, as proper regulation of the immune system would not allow autoimmunity.
There is some ambiguity in some of the terms as most people use them, but Dr. Edwards is generally very precise in referring to autoimmune disorders as being only those with a self antibody.
BurnA
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Thanks, great responses.
If i might add another questoin or two...
If rituximab is effective could you speculate what other mechanism is possible ? Fluge and Mella discuss this briefly in the open- label study as follows :
Whatever the mechanism behind the rituximab effect, the patient described in our study with a
response but allergic reaction to rituximab, and later treated with
the humanized anti-CD20 antibody ofatumumab again achieving a clinical response, indicate
B-cell depletion as the factor responsible for response and not some other, unknown effect of
the antibody.
Also, for someone like me who knows nothing about the immune system... would a dysregulation ( as you describe ) be relatively easier to identify rather than an auto-aintibody, ? I presume studies to date would have looked at this type of dysregulation ?
And if the first auto-antibodies were discovered over 100 years ago why is it difficult to find them today ? Do advanced techniques help us here ? Could you attempt to describe what is involved in finding an autoantibody ?
The only mechanism that's been mentioned specifically that I know of is that EBV resides in B-cells, so depleting B-cells through apoptosis could kill off EBV - but I think this is unlikely for a number of reasons, primarily timing. Response to rituximab is on the order of months, which is what would be expected based on the half life of antibodies in the blood, whereas killing off ebv wouldn't take nearly as long.
The quote above seems to reference some non-cd20 specific aspect of rituximab (which to the best of my knowledge is unknown). The idea here is that if cd20 is the key, then anything that depletes cd20 b-cells would work - and they are saying that based on the info they have so far, that is the case.
Another mechanism that I could conceive of is that it's not a specific antibody response but rather a general one. ME patients don't seem to have "more" antibodies, but it may be that antibodies play a key role in some pathway, so depletion to abnormally low levels could block that pathway (e.g. classical complement activation). B-cells also play a role in antigen presentation (one of 3 types of cells that do - macrophages, dendritic cells, and b-cells).
There are likely many other possible mechanisms. I just give some above as examples - they are not necessarily theories I think are correct.
Neither is necessarily easier to identify. If anything, I think autoantibodies would be easier to identify. There is some evidence of autoantibodies in ME - I saw one paper which showed autoantibodies to the heat shock proteins - but this is not universal (it was about 2/3 of patients I think) and it may not even be relevant. During the unfolded protein response, heat shock proteins are produced in higher quantities, and they are present in the endoplasmic reticulum where proteins are folding, and where the ubiquitin proteasome system is active, therefore it would not be surprising to see them get presented as antigens on MHC class I molecules. It could also be due to increased autophagic flux that we might see enhanced antigen presentation on MHC class II molecules, as these peptides are derived from phagosomes (rather than the ubiquitin proteasome system). I think it may be more of an issue of heat shock proteins being elevated due to cellular stress and their upregulation.
Immune dysregulation encompasses an enormous array of possible ideas - and is nearly tantamount to saying "the immune system is sort of broken or working weird." For example, if there is indeed NK cell dysfunction in ME, which is widely reported, that is a form of immune dysregulation. Whether it is a cause or effect is unknown.
In very simple terms, you find autoantibodies by exposing human serum to tissue and seeing if there is antibody binding to the tissue. There exist various ways to do this - but this is the basic process. So in general, I'd say something as specific as autoantibodies would be easier to find than something as vague as "immune dysregulation." I often use the latter term to emphasize that ME may or may not be a state of immune deficiency simply because it is a state of immune abnormality. It might involve some partial immune deficiency - but we don't know that yet. There isn't really any evidence that we develop opportunistic infections like in HIV or are more likely to die of infections that affect the immunocompromised, so I think people need to be careful in jumping to the conclusion that we are immunosuppressed. If you had a patient whose main problem was immunosuppression, the last thing you'd intuitively do would be to give them an immunosuppressant drug like rituximab - and yet, rituximab works. Drugs designed to amplify immune response have not been nearly as successful.
We have some data about how different substances are affecting the system, but we don't yet have a cohesive theory for what's going on. I believe Dr. Edwards does favor the idea that there is an as yet undiscovered autoantibody present, which would explain the action of rituximab. It may be true - or it may be true in some subgroups but not others. While the Fluge and Mella trials have been extremely statistically significant, they have not shown 100% effectiveness in ME (more like 60-70%). So at least some ME patients are not responding. Are they misdiagnosed? Are there subgroups? Is the rituximab simply not depleting their B-cells enough? We don't know the answers to these questions yet. I favor the idea that there are subgroups.
The quote above seems to reference some non-cd20 specific aspect of rituximab (which to the best of my knowledge is unknown). The idea here is that if cd20 is the key, then anything that depletes cd20 b-cells would work - and they are saying that based on the info they have so far, that is the case.
Another mechanism that I could conceive of is that it's not a specific antibody response but rather a general one. ME patients don't seem to have "more" antibodies, but it may be that antibodies play a key role in some pathway, so depletion to abnormally low levels could block that pathway (e.g. classical complement activation). B-cells also play a role in antigen presentation (one of 3 types of cells that do - macrophages, dendritic cells, and b-cells).
There are likely many other possible mechanisms. I just give some above as examples - they are not necessarily theories I think are correct.
Neither is necessarily easier to identify. If anything, I think autoantibodies would be easier to identify. There is some evidence of autoantibodies in ME - I saw one paper which showed autoantibodies to the heat shock proteins - but this is not universal (it was about 2/3 of patients I think) and it may not even be relevant. During the unfolded protein response, heat shock proteins are produced in higher quantities, and they are present in the endoplasmic reticulum where proteins are folding, and where the ubiquitin proteasome system is active, therefore it would not be surprising to see them get presented as antigens on MHC class I molecules. It could also be due to increased autophagic flux that we might see enhanced antigen presentation on MHC class II molecules, as these peptides are derived from phagosomes (rather than the ubiquitin proteasome system). I think it may be more of an issue of heat shock proteins being elevated due to cellular stress and their upregulation.
Immune dysregulation encompasses an enormous array of possible ideas - and is nearly tantamount to saying "the immune system is sort of broken or working weird." For example, if there is indeed NK cell dysfunction in ME, which is widely reported, that is a form of immune dysregulation. Whether it is a cause or effect is unknown.
In very simple terms, you find autoantibodies by exposing human serum to tissue and seeing if there is antibody binding to the tissue. There exist various ways to do this - but this is the basic process. So in general, I'd say something as specific as autoantibodies would be easier to find than something as vague as "immune dysregulation." I often use the latter term to emphasize that ME may or may not be a state of immune deficiency simply because it is a state of immune abnormality. It might involve some partial immune deficiency - but we don't know that yet. There isn't really any evidence that we develop opportunistic infections like in HIV or are more likely to die of infections that affect the immunocompromised, so I think people need to be careful in jumping to the conclusion that we are immunosuppressed. If you had a patient whose main problem was immunosuppression, the last thing you'd intuitively do would be to give them an immunosuppressant drug like rituximab - and yet, rituximab works. Drugs designed to amplify immune response have not been nearly as successful.
We have some data about how different substances are affecting the system, but we don't yet have a cohesive theory for what's going on. I believe Dr. Edwards does favor the idea that there is an as yet undiscovered autoantibody present, which would explain the action of rituximab. It may be true - or it may be true in some subgroups but not others. While the Fluge and Mella trials have been extremely statistically significant, they have not shown 100% effectiveness in ME (more like 60-70%). So at least some ME patients are not responding. Are they misdiagnosed? Are there subgroups? Is the rituximab simply not depleting their B-cells enough? We don't know the answers to these questions yet. I favor the idea that there are subgroups.
Jonathan Edwards
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I would add that almost all autoantibodies have been discovered by mistake. Rheumatoid factors were discovered when human serum was put on to sheep red cells coated with rabbit immunoglobulin - probably as part of research into blood transfusion reactions. I don't think it would be obvious that the cause of arthritis would be found messing about with other animals blood in this way!!
BurnA
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Ha! Does this mean we have to wait for some other freak occurence or are there better techniques nowadays ?
Jonathan Edwards
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There are better techniques for looking for ordinary sorts of autoantibodies but what if we need to look for not so ordinary sorts of antibodies - as could be the case?
gregh286
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Ldn appears to boost nk count but offers little.to b cell depletion. Data is thin however.
http://www.users.on.net/~julian.robinson/cfs/naltrexone-graphs.htm
http://www.users.on.net/~julian.robinson/cfs/naltrexone-graphs.htm
@gregh286 -
There are many diseases that can be treated through different mechanisms. For example, allergy shots boost IgG to antigens shielding it from IgE. Antihistamines block the effects of histamine, which results from degranulation of mast cells. Different treatments, different mechanisms, but both work.
Whether or not LDN works or not I have no idea. It did absolutely nothing for me when my doc tried it. I felt nothing. I might as well have been swallowing tic tacs (although at least those give you fresh breath). Maybe it works for others. Either way, b-cell depletion is not the only way to treat this disease - it's just what we've found works the best so far.
Even in RA, there are many other treatments used besides rituximab. Probably the most common first line treatment is NSAIDS (advil, naproxen, etc.). This is generally followed by DMARDS (disease modifying anti-rheumatic drugs), such as sulfasalazine and methotrexate. These have some serious toxicity issues, especially with the liver. They work in a number of ways, including folate synthesis (probably less important than originally thought) and, to some degree, selective depletion of B-cells. IMO - methotrexate is only used because it's cheaper than other options. It's less effective and less safe than other options, but it does work. After DMARDS, you're into biologics, which include, primarily, the tnf-alpha (receptor) blockers (infliximab, etanercept, etc.) Anakinra works - that blocks IL-1. Rituximab works as well, by depleting B-cells.
The point - there's more than one way to skin a cat. Many aspects of disease can be addressed in different ways.
There are many diseases that can be treated through different mechanisms. For example, allergy shots boost IgG to antigens shielding it from IgE. Antihistamines block the effects of histamine, which results from degranulation of mast cells. Different treatments, different mechanisms, but both work.
Whether or not LDN works or not I have no idea. It did absolutely nothing for me when my doc tried it. I felt nothing. I might as well have been swallowing tic tacs (although at least those give you fresh breath). Maybe it works for others. Either way, b-cell depletion is not the only way to treat this disease - it's just what we've found works the best so far.
Even in RA, there are many other treatments used besides rituximab. Probably the most common first line treatment is NSAIDS (advil, naproxen, etc.). This is generally followed by DMARDS (disease modifying anti-rheumatic drugs), such as sulfasalazine and methotrexate. These have some serious toxicity issues, especially with the liver. They work in a number of ways, including folate synthesis (probably less important than originally thought) and, to some degree, selective depletion of B-cells. IMO - methotrexate is only used because it's cheaper than other options. It's less effective and less safe than other options, but it does work. After DMARDS, you're into biologics, which include, primarily, the tnf-alpha (receptor) blockers (infliximab, etanercept, etc.) Anakinra works - that blocks IL-1. Rituximab works as well, by depleting B-cells.
The point - there's more than one way to skin a cat. Many aspects of disease can be addressed in different ways.
BurnA
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You mean there are not so ordinary antibodies ?? Are they only considered not so ordinary because they haven't been found yet ? If they are not so ordinary will you recognise them if you see them ? I'm beginning to get the picture....
voner
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@Eeyore, @Jonathan Edwards,
thank you for your elucidating replies. They have been invaluable to me. Such a wonderful education .
wondering if you could help me with explaining one thing that always bugs me when I hear B cell depletion story....
why doesn't the depletion of the B cells cause a more dramatic effect to the immune system and why don't these people catch more diseases? Are there other parts of the immune system that come in and take over the B cells roles?
it just always seems to my naïve thinking that patients would be a very immunocompromise position and be susceptible to all sorts of diseases, but that's obviously not true.
thank you for your elucidating replies. They have been invaluable to me. Such a wonderful education .
wondering if you could help me with explaining one thing that always bugs me when I hear B cell depletion story....
why doesn't the depletion of the B cells cause a more dramatic effect to the immune system and why don't these people catch more diseases? Are there other parts of the immune system that come in and take over the B cells roles?
it just always seems to my naïve thinking that patients would be a very immunocompromise position and be susceptible to all sorts of diseases, but that's obviously not true.
Depletion of B-cells is immunosuppressive and DOES increase the risk of developing a number of infectious diseases. Relapses of latent viruses are more common. New infections are more common, and can be more serious. However, antibodies have a long half life in the blood - a few months - and the ones that are already produced are unaffected and provide immunity to a degree.
There are many arms of the immune system that do different things, and yes, there can be partial compensation for deficiency in one arm by the other arms. However, the end result is that there is a less robust immune response and patients must be followed closely for adverse effects. Dr. Edwards has used these drugs as a physician - I obviously have not, as I am not a physician - so he could probably give a more realistic assessment of the magnitude of the immune suppression and what it means in practical terms.
Your thinking is right - patients become immune suppressed and susceptible to diseases with greater frequency and severity. It's a trade off. It's the reason we don't use these drugs lightly. They are not completely benign drugs.
Right now we have only rather blunt instruments of immune suppression. We cannot target a specific part of the adaptive immune response (e.g. in RA, we cannot target only the autoantibodies). We can only reduce all of them or none of them. It's conceivable we might be able to deplete a subclass of immunoglobulins in the future, which might be helpful, but we can't yet. One could also consider using a decoy molecule perhaps to competitively inhibit antibody binding to some self antigen, but that might just upregulate antibody production and cause more problems. These are future, speculative ideas - we can't do it yet.
Patients who get organ transplants can live decades with them. In those cases, we use other immunosuppressants (mostly tacrolimus and cyclosporine, some myophenolate mofetil, azathioprine - maybe steroids early on or in difficult cases). The patient will continue to be at increased risk of infection, and infections will be more dangerous - but not doing it means the patient will die in many cases, so you choose the lesser of evils.
In a way, it's heartening to see someone taking ME seriously enough to give us real treatments like rituximab. By giving a serious drug with serious potential side effects, there is an implicit recognition of the severity of our disease. NSAIDS are first line in many rheumatological diseases because they are (relatively) benign medications - you give drugs like rituximab, steroids, and other biologics when the safer stuff isn't working anymore, and the condition is severe.
There are many arms of the immune system that do different things, and yes, there can be partial compensation for deficiency in one arm by the other arms. However, the end result is that there is a less robust immune response and patients must be followed closely for adverse effects. Dr. Edwards has used these drugs as a physician - I obviously have not, as I am not a physician - so he could probably give a more realistic assessment of the magnitude of the immune suppression and what it means in practical terms.
Your thinking is right - patients become immune suppressed and susceptible to diseases with greater frequency and severity. It's a trade off. It's the reason we don't use these drugs lightly. They are not completely benign drugs.
Right now we have only rather blunt instruments of immune suppression. We cannot target a specific part of the adaptive immune response (e.g. in RA, we cannot target only the autoantibodies). We can only reduce all of them or none of them. It's conceivable we might be able to deplete a subclass of immunoglobulins in the future, which might be helpful, but we can't yet. One could also consider using a decoy molecule perhaps to competitively inhibit antibody binding to some self antigen, but that might just upregulate antibody production and cause more problems. These are future, speculative ideas - we can't do it yet.
Patients who get organ transplants can live decades with them. In those cases, we use other immunosuppressants (mostly tacrolimus and cyclosporine, some myophenolate mofetil, azathioprine - maybe steroids early on or in difficult cases). The patient will continue to be at increased risk of infection, and infections will be more dangerous - but not doing it means the patient will die in many cases, so you choose the lesser of evils.
In a way, it's heartening to see someone taking ME seriously enough to give us real treatments like rituximab. By giving a serious drug with serious potential side effects, there is an implicit recognition of the severity of our disease. NSAIDS are first line in many rheumatological diseases because they are (relatively) benign medications - you give drugs like rituximab, steroids, and other biologics when the safer stuff isn't working anymore, and the condition is severe.
I should add that this is part of why I do not favor a viral etiology for ME. Suppression of the immune system if the primary problem is infectious is the last thing you'd want to do - and it would be very dangerous and make patients worse. This is, however, not what we are observing. Patients are not dying of herpesvirus infections or enteroviral infections when we suppress their immune systems. They are feeling better.
This favors an autoimmune, autoinflammatory, or immune dysregulatory etiology for ME.
This favors an autoimmune, autoinflammatory, or immune dysregulatory etiology for ME.
Jonathan Edwards
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The antibodies in MS might be thought of as not so ordinary in that they are made in the wrong place but we do not know if they are auto-. In RA there are also not so ordinary auto-antibodies in that they do not target self because it is self but because they recognise proteins that have arginine converted to citrulline -whether self or non self. So there are a hundred and one ways of having antibodies that do not quite obey the rules and it is not always easy to guess what the seventy-third way is even if you know the seventy-second.
In other words they knew they were looking for the Higgs boson but we don't know what we might be looking for.