Do MEs cause CFS?

[Jonathan Edwards]

@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.

Eeyore has given a good answer. We discussed this on the IiME rituximab thread a year or so ago. I think my analogy was that B cells are only trainee Samurai warriors but I can't remember exactly. You can close down the training unit for a while without anybody noticing much.

 

[BurnA]

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.

I see. Hmmm. That sums up the magnitude of the situation. Do the 'clues' from the b cell work by Dr Cambridge help in the case you where you don't know what you are looking for? Do they point you in the right direction or can they lead you up blind alleys ?

In practical terms, how does it impact a patient ? Apart from understanding the disease which would be a massive leap forward, If an antibody was identified would it enable more specific treatment ? Presume all or more research energy would get focused into this area then ?

Let's say rtx and or cyclo demonstrate efficacy in the short to medium term, could we have a situation where we are treating a disease without fully understanding how ? Does that occur often / ever ?

Thanks as always.

 

[Jonathan Edwards]

I see. Hmmm. That sums up the magnitude of the situation. Do the 'clues' from the b cell work by Dr Cambridge help in the case you where you don't know what you are looking for? Do they point you in the right direction or can they lead you up blind alleys ?

In practical terms, how does it impact a patient ? Apart from understanding the disease which would be a massive leap forward, If an antibody was identified would it enable more specific treatment ? Presume all or more research energy would get focused into this area then ?

Let's say rtx and or cyclo demonstrate efficacy in the short to medium term, could we have a situation where we are treating a disease without fully understanding how ? Does that occur often / ever ?

Thanks as always.

Treating immunological disease without understanding quite how is the norm - although less so recently perhaps.

It is not clear that we have the vital clue yet but there are various observations popping up that might get confirmed and lead where we want to go.

 

[Eeyore]

I have read some suggestions that there might be autoantibodies to oxidized membrane lipids. Not sure if there is any truth to it or any solid evidence, but something like that might be true. Might also explain a response to exercise - increased oxidative stress might create more targets for the autoantibodies.

 

[Eeyore]

Personally I am extremely eager to find a definitive biomarker and mechanism. What we need more than anything is acceptance that the disease is real and physiological and thus can respond to investigation by the scientific method. We don't need more voodoo science or hand waving, and we don't need psychobabble - we need hard science. If we can bring the great minds of the world to bear on this problem, it will not be so intractable. Unfortunately, to date, researchers have been few and far between and have toiled in obscurity, been under (or un) funded, and risked their careers and reputations.

Fortunately, if rituximab and cyclophosphamide work markedly better than placebo, and it is observed that respected scientifically minded physicians are treating us with serious drugs with the potential for serious side effects, that could really bring about a shift in the thinking of the medical profession.

I expect the rituximab phase 3 trial will be very successful, and if so, it will be the first trial of anywhere near that quality to show real therapeutic benefit to ME patients. FDA approval of rituximab for ME could follow relatively quickly if the study is solid enough, even without a mechanism identified. We could see treatment of ME patients in large numbers. Unfortunately, rituximab is extremely expensive and insurance companies will fight it hard. There are a lot of ME patients out there and nothing else really works. It might start the process of investigating other serious immunosuppressive drugs, as it's likely that some at least would work.

The other parts of the Norway trials also have substantial potential to help elucidate mechanism as well. So there is a lot of potential here, and we're probably less than 2 yrs from it being complete now.

 

[MeSci]

Treating immunological disease without understanding quite how is the norm - although less so recently perhaps.

It is not clear that we have the vital clue yet but there are various observations popping up that might get confirmed and lead where we want to go.

I think that many treatment effects have an unknown basis. Drugs for example tend to have several effects - not just the effect for which they were developed - and new effects keep being found for existing drugs. For that reason, drugs are continually being 're-purposed', which tends to be a lot quicker than developing a new drugs from scratch.

I don't know why changing my diet and adding some supplements has fixed/greatly improved several debilitating symptoms that prescribed and OTC treatments failed to alleviate for decades. Some people assume that the reason why antihistamines can reduce nausea, relax muscles and cause sedation is because they reduce histamine - because they are called antihistamines! But they are also anticholinergic.

 

[MeSci]

I have read some suggestions that there might be autoantibodies to oxidized membrane lipids. Not sure if there is any truth to it or any solid evidence, but something like that might be true. Might also explain a response to exercise - increased oxidative stress might create more targets for the autoantibodies.

Does that fit with the (variable) delays before PEM kicks in?

 

[Eeyore]

@MeSci - It could, perhaps - but it's really, really speculative at this point whether or not that might be true.

We know based on a number of studies that C4a is elevated after exercise in healthy people, and there are also studies showing elevated C4a in Lyme and ME patients, sometimes dramatically elevated. If we have autoantibodies that fix complement (IgG, IgM), then potentially, it could be a combination of those factors.

The question would be why, if we have some autoimmune disease, are we affected by just an unusual kind of post exertional malaise. I tried early on in my illness to explain this to so many docs, and they just couldn't get their heads around it. They all understood fatigue from cardiac failure, or liver failure. The latter is virtually always present, and the former is present on exertion - at the moment of exertion. However, doctors knew of nothing that caused delayed post exertional malaise. It simply made no sense to them and fit no disease they knew, so they dismissed it as unimportant.

It's possible that unique among autoimmune patients, the epitope recognized by an autoantibody is variably present depending on exercise because it is not a natural part of our bodies, but a modified antigen produced somehow through exercise. These could fit with Dr. Edwards idea of a less normal autoantibody (I forget the phrase he used).

The elevations in C4a would suggest to me that the classical (antibody mediated) complement pathway is active, as C4 is part of the C3 convertase in the classical and MBL pathways, but not the alternative pathway.

I think we'd have to ask questions about how much membrane lipids actually become oxidized during exercise. Is it enough that it could matter? Is there a localization of membrane lipid oxidation? If they did become significantly oxidized, and this generated an epitope that could be recognized by an autoantibody, then that could trigger the complement cascade. In this case, you'd expect CH50 (broad measure of classical complement activity) to be up. The MAC (membrane attack complex) would form, and the cell would be damaged or destroyed - this is a problem perhaps, as we don't see much evidence of any end organ damage in ME. Patients do not suffer liver or kidney failure, for example. However, there have been reports of increased apoptosis, and Dr. Hokama's work showed increased circulating cardiolipin. This is interesting because cardiolipin (found in the membranes of mitochondria, and hence, in the heart) could be evidence of cell death. Then there's the question of which cells are dying? Is there any preference for one tissue type or another? It's just really hard to know.

We don't really have the information to answer any of these questions, but it's an interesting, if very speculative, theory.

 

[Eeyore]

@MeSci -

I'd really love to see a very large study of ME patients type HLA's. Almost all autoimmune and autoinflammatory disease is associated with some variation in genes in the MHC on chromosome 6, including both the HLA's as well as some other key proteins in the complement system. I suspect there are major risk factors there. Unfortunately, 23andme isn't much use in typing HLA's. It can give you guesses on a few, but the only one it called for me actually turned out to be wrong when typed with more accurate methods!

Different HLA's have a tendency to make antibodies that match certain things. For example, rheumatoid arthritis is strongly associated with HLA-DR4 and SLE and MS have strong associations with HLA-DR3. This is true of autoinflammatory (non antibody mediated) diseases as well, and all the serognegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, etc.) are associated with HLA-B27. Psoriasis is associated with HLA-Cw6. The list goes on - name an autoimmune or autoinflammatory condition and it will have an HLA association. Without the right HLA's, your body won't make antibodies to certain self antigens (or will be much less likely to).

 

[BurnA]

ME seems to be different from most autoimmune disease in that it does look as if infection may be a trigger in some cases - particularly epidemic cases. That would be similar to reactive arthritis which is an immune dysregulation but not autoimmune. If infection can trigger then vaccine probably can. But we do not have any clear idea how the immune dysregulation of reactive arthritis arises from an infective trigger. It looks like some sort of persistent T cell activation but that is about all we know.

It seems a virus can preceed onset in many reported cases ( not necessarily epidemic ) - would this be just a coincidence if autoimmunity was to blame or would there be an explanation?
When you say infection or vaccine can trigger, do you mean this is the last straw in the chain of events on an already dysregulated immune system or could these be the actual cause of the dysregulation?

I assume it's not easy to detect persistent t cell activation ? I think I've read that cyclo has an effect on T cells, could this in any way explain why it might prove to be effective?

 

[BurnA]

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.

Is there any evidence or lack of evidence that T cells are involved in me/cfs? Do you have any suspicions because I know there are too many unknowns

 

[Snow Leopard]

Some researchers are convinced there is a link between pathogens and autoimmunity.
http://www.sciencedirect.com/science/article/pii/S1074761315003039

A certain member of this forum is probably not so impressed given that it is:
- an induced animal model (yes, they are using IRBP T cell receptor transgenic mice and are claiming this represents real disease!)
- it involves handwaving about molecular mimicry
- it involves 'autoreactive T-cells'
- Francis Collins (from the NIH) got excited enough to post about it on twitter (only a handful of articles a month - he must know one of the researchers)

Oh and an editorial:
http://www.nature.com/nri/journal/vaop/ncurrent/full/nri3911.html

Autoimmune uveitis is major cause of human blindness and is thought to be driven by retina-specific T cells. As the eye is an immune-privileged site, it has been unclear how T cells become activated to respond to retinal antigens.

Additional edit, I may as well ask:
@Jonathan Edwards do you believe there are other possibilities in Uveitis? Given that MHC molecule expression is suppressed, along with inhibition of complement activation? A B-cell driven response, instead of autoreactive T-cells perhaps?

 

[unto]

hi dr. Jonathan Edwards,I apologize for grammatical errors but with google translate from ItalianI wanted to give my opinion / contribution on ME;I am sick since 1985, the start was similar to the flu, sore throat, moderate,fever 37.2 malaise ...., then slowly came all the other classic symptoms.My experience with the ME is that it can be a viral diseasecontagious (as history shows), this contagiousness is durable in fact I noticed the symptomseven in people who have known and visited after 20 years from the onset of MEin my body.I think: 1) that this virus? or family of viruses has been further adapted to the human body, it tends to give minor reactions, 2) that patients who do not "remember" a beginning-like INFLU is why they traded for parainfluenza, 3) the term CFS is to be abolished, because it was given by mistake to clear epidemics of ME.4) Finally, there is an issue to consider psychosocial very important,the sick ME, although it is conscious of having an infectious disease (I believe the majority) can not admit it ...... mainly for "guilt" and "shame";those who study the ME should also consider the reaction of the sick

 

[leokitten]

@MeSci - It could, perhaps - but it's really, really speculative at this point whether or not that might be true.

We know based on a number of studies that C4a is elevated after exercise in healthy people, and there are also studies showing elevated C4a in Lyme and ME patients, sometimes dramatically elevated. If we have autoantibodies that fix complement (IgG, IgM), then potentially, it could be a combination of those factors.

The question would be why, if we have some autoimmune disease, are we affected by just an unusual kind of post exertional malaise. I tried early on in my illness to explain this to so many docs, and they just couldn't get their heads around it. They all understood fatigue from cardiac failure, or liver failure. The latter is virtually always present, and the former is present on exertion - at the moment of exertion. However, doctors knew of nothing that caused delayed post exertional malaise. It simply made no sense to them and fit no disease they knew, so they dismissed it as unimportant.

It's possible that unique among autoimmune patients, the epitope recognized by an autoantibody is variably present depending on exercise because it is not a natural part of our bodies, but a modified antigen produced somehow through exercise. These could fit with Dr. Edwards idea of a less normal autoantibody (I forget the phrase he used).

The elevations in C4a would suggest to me that the classical (antibody mediated) complement pathway is active, as C4 is part of the C3 convertase in the classical and MBL pathways, but not the alternative pathway.

I think we'd have to ask questions about how much membrane lipids actually become oxidized during exercise. Is it enough that it could matter? Is there a localization of membrane lipid oxidation? If they did become significantly oxidized, and this generated an epitope that could be recognized by an autoantibody, then that could trigger the complement cascade. In this case, you'd expect CH50 (broad measure of classical complement activity) to be up. The MAC (membrane attack complex) would form, and the cell would be damaged or destroyed - this is a problem perhaps, as we don't see much evidence of any end organ damage in ME. Patients do not suffer liver or kidney failure, for example. However, there have been reports of increased apoptosis, and Dr. Hokama's work showed increased circulating cardiolipin. This is interesting because cardiolipin (found in the membranes of mitochondria, and hence, in the heart) could be evidence of cell death. Then there's the question of which cells are dying? Is there any preference for one tissue type or another? It's just really hard to know.

We don't really have the information to answer any of these questions, but it's an interesting, if very speculative, theory.

ME patients can experience the same or even greater levels of PEM and symptom exacerbation from mental exertion as with physical, so it makes one wonder that the underlying mechanism might not be anything only driven or affected by exercise.

 

[lansbergen]

ME patients can experience the same or even greater levels of PEM and symptom exacerbation from mental exertion as with physical, so it makes one wonder that the underlying mechanism might not be anything only driven or affected by exercise.

In my opion it is anything that demands cells to work faster.

 

[Marco]

ME patients can experience the same or even greater levels of PEM and symptom exacerbation from mental exertion as with physical, so it makes one wonder that the underlying mechanism might not be anything only driven or affected by exercise.

I think I may have Identified a potential candidate immune signal in something called high mobility group box 1 (HMGB1) protein which works as a pretty ubiquitous danger signal.

After some digging around I found that HMGB1 plays a proximal role in priming and activating microglia in response to various pathogen and damage 'insults' including acute (psychological) stress. In addition it may play a role in signalling (and aggravating?) weakness and fatigue in inflammed skeletal muscle, correlates with fatigue in SLE and symptom levels in fibromyalgia, is acutely induced by exercise, is associated with cognitive problems following surgery or sepsis and is associated with autonomic dysfunction in various conditions.

 

[Valentijn]

ME patients can experience the same or even greater levels of PEM and symptom exacerbation from mental exertion as with physical, so it makes one wonder that the underlying mechanism might not be anything only driven or affected by exercise.

My experience is different. I do get crashes from cognitive activity, but those crashes are primarily cognitive in nature. I don't get full body aches from it, or swollen lymph nodes, whereas I do get those symptoms from physically-triggered crashes.

 

[Marco]

My experience is different. I do get crashes from cognitive activity, but those crashes are primarily cognitive in nature. I don't get full body aches from it, or swollen lymph nodes, whereas I do get those symptoms from physically-triggered crashes.

PEM following either physical or mental exertion is pretty much the same for me including aching limbs. I don't tend to get swollen lymph nodes with either but even if I did the same signalling mechanisms may be involved :

Emerging roles for HMGB1 protein in immunity, inflammation, and cancer

HMGB1 triggers inflammation, attracting other cells, inducing tissue repair, recruiting stem cells, and promoting their proliferation. HMGB1 also activates dendritic cells and promotes their functional maturation and their response to lymph node chemokines. Therefore, HMGB1 acts in an autocrine/paracrine fashion and sustains long-term repair and defense programs. HMGB1 secretion is critical for the immunity system because dendritic cells, when reaching the lymph nodes, secrete HMGB1, sustaining the proliferation of antigen-specific T-cells, to prevent their activation-dependent apoptosis, and to promote their polarization toward a T-helper 1 phenotype.46

https://www.dovepress.com/emerging-...and-cancer-peer-reviewed-fulltext-article-ITT

 

[Mij]

ME patients can experience the same or even greater levels of PEM and symptom exacerbation from mental exertion as with physical, so it makes one wonder that the underlying mechanism might not be anything only driven or affected by exercise.

My understanding is that the brain uses up more energy than any other organ. When I over use my brain, even when socializing it affects my gait. My equilibrium goes and I start to stagger when I walk. I also get sore calves. I don't know if this is true PEM though since the symptoms occur soon after. Either way, it's still debilitating.

 

[Sidereal]

My understanding is that the brain uses up more energy than any other organ. When I over use my brain, even when socializing it affects my gait. My equilibrium goes and I start to stagger when I walk. I also get sore calves. I don't know if this is true PEM though since the symptoms occur soon after. Either way, it's still debilitating.

Same here, it's a really debilitating & isolating symptom. I can't really socialise because the exertion of trying to keep my brain engaged with conversation will cause me to start slurring my words and get dizzy, confused and ataxic. I'm ok with brief one-on-one conversation or phone calls but anything more than that is exhausting and overwhelming to the senses.