3 main viruses linked to ME — enterovirus, EBV & HHV-6 — all infect B-cells: autoimmune import?

Hutan

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FWIW re intracellular infections
Rickettsia ..... Being obligate intracellular parasites, the Rickettsia survival depends on entry, growth, and replication within the cytoplasm of eukaryotic host cells (typically endothelial cells).
There was a reasonable Australian study
http://qjmed.oxfordjournals.org/content/qjmed/101/4/269.full.pdf
on rickettsial infection in people with 'chronic illness including fatigue'. It would be good to see a followup study of this in an ME/CFS population elsewhere.

Markers of exposure to spotted fever rickettsiae in patients with chronic illness, including fatigue, in two Australian populations
N. UNSWORTH1, S. GRAVES1, C. NGUYEN1, G. KEMP2, J. GRAHAM3 and J. STENOS1
From the 1Australian Rickettsial Reference Laboratory, Barwon Biomedical Research, Geelong, 2The Burke Road Medical Centre, Camberwell, and 3The School of Medicine, Flinders University, Adelaide, Australia
Results: Of the Melbourne patient cohort, 14/526 (3%) were real-time PCR positive for rickettsial DNA compared to none of the 400 control patients (P < 0.001). Of these 14 patients, Rickettsia honei strain ‘marmionii’ was detected in 5 and isolated from 2. Rickettsaemia was seasonal, with more in winter (8/145; P < 0.03) and less in spring (0/143; P < 0.03). Positive rickettsial serology titres of 51:256 were seen in 206 (39%) patients. Of the Adelaide patient cohort, 238/581 (41%) had positive rickettsial antibodies titres. Of the 34 control sera, 5 (15%) were serologically positive (P < 0.002). Both Melbourne and Adelaide patient cohorts had significantly higher seroposi- tivity than the Newcastle control cohort (3/399; P < 0.0001).

Conclusions: In patients with chronic illness, rick- ettsial DNA in peripheral blood and/or rickettsial seropositivity may represent exposure to rickettsiae or underlying rickettsial diseases. It is not known whether the presence of rickettsiae is causally related to the patients’ chronic illnesses, or reactivation of a latent rickettsial infection.
But Rickettsias in B cells??? Ebola, Ross River fever??
 

taniaaust1

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Another shortcoming is that it probably would not explain the cases of ME/CFS or ME/CFS-like diseases from other pathogens such as parvovirus B19, Chlamydia pneumoniae, Giardia lamblia or Coxiella burnetii, which I don't think infect B-cells, as far as I am aware; however, it may be that these pathogens facilitate an autoimmune response by other mechanisms.





I can't for the moment see how this speculative idea, even if it were correct, translates to treatment strategies.

It's more just looking at a possible reason why enterovirus, EBV and HHV-6 are the viruses most strongly linked to ME/CFS.
The Aussie study years ago found that ross river fever and something else (one mentioned it here before but I've forgot) lead to ME/CFS just as often as gettting mono (EBV) did... it was a rate of around 10% of cases lead to ME/CFS (the more severe the case the more it was likely it is to lead to ME/CFS). So obviously there is lots of different things which have the same outcome and lead to ME/CFS manifesting.

Ive not a clue if Ross River Virus (its a mosquito borne virus) affects B cells too.
 

taniaaust1

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Some more exceptions: I don't think Giardia lamblia is intracellular (it is a protozoan parasite), and Ross River virus I don't think can establish latency. But these exceptions are relatively rare triggers of ME/CFS.
Ross River Virus actually triggers off ME/CFS at the same rate as mono (EBV) does. A good Aussie study found this. The outcome is about 10% go on to develop ME/CFS.

You just dont come across many with this trigger though as RRV is not a virus which is world wide. Australia is one of only a few countries who have it and it only appears in our Australian tropics. Thou its a mosquito borne, its main hosts are wallabies and kangaroos.

https://en.wikipedia.org/wiki/Ross_River_fever

". The incidence of chronic fatigue is 12% at 6 months and 9% at 12 months, similar to Epstein-Barr virus and Q fever.[2] The only significant predictor of the likelihood of developing chronic symptoms is the severity of the acute illness itself. No other aspects of the patient's medical or psychiatric history have been found to be predictive. However, in those with the most persisting symptoms (12 months or more), comorbid rheumatologic conditions and/or depression are frequently observed .[2] "


http://sacfs.asn.au/download/Baltimore-CFS-Lay.pdf

In 2006, a landmark study of post-infectious fatigue syndrome that was conducted in Dubbo, Australia, was published. The team studied people with each of three different kinds of infections—Epstein-Barr virus infection, Ross River virus infection, and infection with a bacterium, Coxiella burnetii, the cause of a disease called Q fever.

The study showed that about 10% of patients in each of the three groups developed a post-infectious fatigue syndrome that met the Centers for Disease Control and Prevention (CDC) criteria for CFS.

At the Conference, the team reported in detail on this study. The chronic illness was most likely to develop in those patients who were sickest at the time of the initial infection: demographic, psychological and microbiological factors did not predict who would develop PIFS.

Although final results were not presented, the team reported that the activity of a handful of genes predicted who would become most severely ill with PIFS, and that genes were plausible candidates to explain the symptoms of PIFS. In particular, the team found variations in the genes for two immune system chemicals that affect inflammation (cytokines)—interferon-γ and interleukin-10.
so even with that once again things are seeming to come down to genes.
 
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Hip

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the thing that near everyone has EBV exposure. From wikipedia " In the United States, about half of all five-year-old children and about 90 percent of adults have evidence of previous infection
That's true, and HHV-6 is also very common in the general population. Coxsackievirus B / echovirus are pretty common too.

But I am not suggesting that B-cell infection alone might be the singular cause of ME/CFS, but rather that B-cell infection might be a possible causal factor involved in triggering an autoimmune response that then leads to ME/CFS. In this picture, ME/CFS is multifactorial, with B-cell infection playing a role.


Regarding Ross River virus: I don't think there is a great deal of research on this virus, so it's unclear whether it might infect B-cells or not. In any case, as mentioned earlier, if we assume ME/CFS is an autoimmune disease, then there may be more than one way that infections might instigate autoimmunity. B-cell infection is just one (highly speculative) mechanism.

I just thought there could be some significance to the fact that the three main viruses associated with ME/CFS — enterovirus, EBV and HHV-6 (plus hepatitis C virus, which produces an ME/CFS-like disease) — all infect B-cells. And I don't think there are many other viruses that do infect B-cells.


It should be mentioned, though, that HHV-8 can latently infect B-cells (ref: here), and this virus is not associated with ME/CFS.
 

taniaaust1

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FWIW re intracellular infections


There was a reasonable Australian study
http://qjmed.oxfordjournals.org/content/qjmed/101/4/269.full.pdf
on rickettsial infection in people with 'chronic illness including fatigue'. It would be good to see a followup study of this in an ME/CFS population elsewhere.

[Markers of exposure to spotted fever rickettsiae in patients with chronic illness, including fatigue, in two Australian populations
N. UNSWORTH1, S. GRAVES1, C. NGUYEN1, G. KEMP2, J. GRAHAM3 and J. STENOS1
From the 1Australian Rickettsial Reference Laboratory, Barwon Biomedical Research, Geelong, 2The Burke Road Medical Centre, Camberwell, and 3The School of Medicine, Flinders University, Adelaide, Australia
oh wow, thanks for that as though i knew my old ME/CFS specialist Dr John Graham (he's retired now due to a stroke) had done his own study on rickettsia and CFS, I never knew it had been published.

Near half of his 600 Adelaide ME/CFS patients showed up positive as having Rickettsia, I didnt though when he had my blood sent away for testing
 

Hip

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The following study found that rheumatoid arthritis (RA) patients with an EBV infection of their B-cells responded better to rituximab therapy compared to RA patients without such an infection:

Epstein-Barr virus in peripheral blood is associated with response to rituximab therapy in rheumatoid arthritis patients

This result perhaps suggests that the EBV B-cell infection might be playing a role in driving the RA autoimmunity, so that when the rituximab presumably wiped out the EBV B-cell infection, there was an improvement in RA symptoms.

So for RA at least, this study shows patients with EBV B-cell infection are more likely to respond well to rituximab therapy.



A similar study found that RA patients with EBV infection in the B-cells of their bone marrow responded better to rituximab than patients without such an infection:

Epstein-Barr virus in bone marrow of rheumatoid arthritis patients predicts response to rituximab treatment

In bone marrow infections, EBV exists mainly in the B-cells of the bone marrow. Ref: 1

Tellingly, this study also found that in the 11 month period after their first rituximab treatment, most RA patients who initially tested positive for an EBV bone marrow infection did not need any more follow-up rituximab treatments, as the benefits of rituximab persisted (and the first rituximab treatment cleared the EBV infection).

Whereas most RA patients without an EBV bone marrow infection required additional rituximab treatments in that 11 month time period, because for them the benefits of rituximab more quickly wore off.

So this perhaps suggests that:

(1) EBV infection of B-cells might be driving autoimmune processes.

(2) In patients with EBV B-cell infections, rituximab treatment may be working in two ways: by deleting the B-cells that are making autoantibodies; and also by wiping out the EBV infection in the B-cells that may also be driving autoimmunity. Or as @Gingergrrl earlier put it, perhaps rituximab "kills two birds with one stone."

(3) In those RA patients with EBV B-cell infections, the positive effects of a single course of rituximab (which wipes out the EBV infection as well as killing the B-cells) last longer than in RA patients without such infections. This possibly suggests that an EBV B-cell infection might be a fundamental causal factor in the autoimmune processes, because by wiping out this infection, you are getting ameliorations in RA symptoms that are long-lasting compared to when you just wipe out the autoantibody-producing B-cells. Perhaps the EBV eventually reinfects the B-cells, but it may take a long time to do that, so that may be why the positive effects of a single course of rituximab last longer in RA patients with EBV B-cell infection.



So What's the Import for ME/CFS? Can We Use This to Treat ME/CFS?

Let's assume for the moment the hypothesis at the beginning of this thread, that a critical factor in the development of ME/CFS is chronic B-cell infection (at least in enterovirus, EBV and HHV-6-associated ME/CFS).

So then we would want to try to eliminate the infection from the B-cells, in the hope that this might ameliorate ME/CFS symptoms. Rituximab therapy would seem to be one way to achieve this, but what about other approaches, such as antiviral treatments to wipe out the B-cell infection?


According to this study, with long term daily use of the antiviral Valtrex (valacyclovir), you could slowly eliminate most of the EBV infection in B-cells:
We estimate that it would take 6 years of 500 mg of valacyclovir once each day to eradicate 99% of EBV from the B-cell compartment and 11.3 years to eliminate the virus completely from the body if persons were not reinfected during this time.
The study indicates that you can eradicate EBV faster if you use higher doses of the antiviral. Famvir is the usual alternative to Valtrex, for those who experience side effects from the latter (Valtrex sometimes causes anxiety side effects, for example).

Note that there are 3 latency states of EBV: latency I, latency II and latency III, with different viral proteins being expressed in each latency state.

Epstein-Barr Virus Latency States in B-cells:​
Within B cells, all three latency programs are possible. EBV latency within B cells usually progresses from Latency III to Latency II to Latency I.

Each stage of latency uniquely influences B cell behavior. Upon infecting a resting naive B cell, EBV enters Latency III. The set of proteins and RNAs produced in Latency III transforms the B cell into a proliferating blast (also known as B cell activation).

Later, the virus restricts its gene expression and enters Latency II. The more limited set of proteins and RNAs produced in Latency II induces the B cell to differentiate into a memory B cell.

Finally, EBV restricts gene expression even further and enters Latency I. Expression of EBNA-1 allows the EBV genome to replicate when the memory B cell divides.

Source: Wikipedia


I just dug out an old 2011 article about the late Dr Lerner's long term antiviral treatment (using valacyclovir and/or valganciclovir) for ME/CFS. To quote the article:
Long term antiviral therapy was effective – very effective – in many of his patients. Many of them, while not completely cured, are able to work and lead normal lives again – an astounding finding in this field. Some are completely cured.
Because B-cells die off over time EBV is always in a race to keep infecting new cells before the cells it is present in die off. This means that if Valtrex can keep EBV reactivation down then as the infected B-cells die off the number of EBV infected cells should slowly decline over time.
Dr Lerner's paper: Subset-directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome.

So for EBV-associated ME/CFS, a main reservoir of EBV infection is in the B-cells, and perhaps this infection is causing ME/CFS by triggering autoimmune processes. Thus a long term EBV antiviral strategy might lead to major improvements in ME/CFS.
 
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Hip

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One further point: if EBV infection of the B-cells is driving autoimmunity in ME/CFS, and if this infection is eliminated with a series of rituximab infusions, then possibly regularly taking an antiviral (such as Valtrex or Famvir) each day forevermore after the infusion might prevent the virus from reinfecting the B-cells. This might then eliminate the need for any further rituximab infusions in the years to come, and prevent the return of ME/CFS symptoms.

If you took 500 mg of Valtrex each day, that would cost around $30 per month, which would work out a lot cheaper that doing additional rituximab infusions.
 

kangaSue

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@Hip ,I'm not too clever in interpreting these things but from these papers https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-015-0717-z and http://www.ncbi.nlm.nih.gov/pubmed/22394488, I think the suggestion is that finding antibodies to mutated citrullinated vimentin in RA identifies a group likely to respond to rituximab and also that that antibody is found in Hep C and EBV

If those with ME/CFS have the antibodies to mutated citrullinated vimentin too, it might identitify the sub-group likely to respond to rituxiximab at least.
 

Hip

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@kangaSue: that might be of general interest for those considering rituximab, but I am not sure if it relates to the focus of this thread (unless I am not understanding your meaning), which is how the viruses most commonly linked to ME/CFS (enterovirus, EBV and HHV-6) might precipitate the autoimmune processes thought to exist in ME/CFS.


The Fluge and Mella rituximab ME/CFS studies indicate that ME/CFS may well be an autoimmune condition, and also, several of the common comorbid disease found in ME/CFS are autoimmune, or suspected to be autoimmune, which again suggests there are autoimmune processes in ME/CFS.

But if ME/CFS is autoimmune, how does that fit in with the fact that ME/CFS is often triggered by viral infection?

Given that ME/CFS is often triggered by viral infection, it makes sense, to me at least, that we should be looking at possible mechanisms by which ME/CFS-associated viruses might instigate autoimmunity.

B-cell infection looks like one such possible mechanism worth looking into, especially because enterovirus, EBV and HHV-6 all appear able to infect B-cells, and lots of other viruses can't do that.
 
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kangaSue

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@Hip The common ground is still B-cell infection, I was pointing out that having antibodies to mutated citrullinated vimentin may be an extra screening layer of those likely to respond to rituximab but I doubt that this is something tested for in ME/CFS.

That, and EBV infection may initiate production of autoantibodies and development of autoimmune diseases.
http://www.ncbi.nlm.nih.gov/pubmed/23844744
https://www.sciencedaily.com/releases/2015/06/150611144244.htm

It's actually from an Idiopathic Gastroparesis perspective that interests me here as it has a viral onset cause in a lot of cases so we can have chronic GI dysfunction but without the fatigue element and Enterovirus is one of the suspected viral causes.
http://forums.phoenixrising.me/inde...-etiology-of-gastroparesis.45508/#post-741702
 

Gingergrrl

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(2) In patients with EBV B-cell infections, rituximab treatment may be working in two ways: by deleting the B-cells that are making autoantibodies; and also by wiping out the EBV infection in the B-cells that may also be driving autoimmunity. Or as @Gingergrrl earlier put it, perhaps rituximab "kills two birds with one stone."
Thanks for summarizing my thoughts on this @Hip and I think it's the first time I've ever been quoted in a scientific context in 2+ years on PR!
 

unto

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in more than 30 years of ME (beginning 1985) I saw several persons (family members, relatives, friends)
show symptoms of ME; some of these people, in turn, transmitted the disease to their partners and friends .....
it is possible to explain this situation (which I consider quite widespread in the population of people with ME) with those ideas in this discussion?
thank you.
 

Hip

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it is possible to explain this situation (which I consider quite widespread in the population of people with ME) with those ideas in this discussion?
Yes, it is possible. Let's assume that to trigger B-cell autoimmunity and ME/CFS, it requires the presence two factors: a B-cell infection, and another (unknown) factor, which we can call factor X.

Then for those people who are already exposed to factor X, or already have factor X in their body, when they later catch a virus like enterovirus, EBV or HHV-6 that infects B-cells, they will get ME/CFS. But for people who are not exposed to factor X, they will not get ME/CFS when they catch one of these viruses, because it requires both factors in tandem to precipitate ME/CFS. That's the general idea behind diseases of a multifactorial etiology.

So for example, factor X might be environmental mold toxin (mycotoxin) exposure, or a chronic mold infection in the body that creates mycotoxins. Mycotoxins have been linked to ME/CFS. Then ME/CFS may be triggered when you catch a B-cell infecting virus like EBV while at the same time being exposed to mycotoxins.

This is an example of the sort of multifactorial etiology of ME/CFS I am talking about. I am not saying this is the case; it's just an hypothetical example. Interestingly enough, though, a quick Google check reveals that B-cells are highly sensitive to mycotoxins.
 
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Gingergrrl

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So for example, factor X might be environmental mold toxin (mycotoxin) exposure, or a chronic mold infection in the body that creates mycotoxins. Mycotoxins have been linked to ME/CFS. Then ME/CFS may be triggered when you catch a B-cell infecting virus like EBV while at the same time being exposed to mycotoxins.
Very interesting and this is quite literally what happened to me. I had mono/EBV and then a few months later moved into a rental with severely high toxic levels of mycotoxins which I believe was the final trigger or "factor X" as you said.
 

Tammy

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I don't know enough about autoimmunity to comment any further; but I noticed that the 3 main viruses linked to ME/CFS (as well as HCV) all are able to infect B-cells, so thought this might be of some significance from the perspective of ME/CFS being a possible autoimmune disease.

Assuming ME/CFS is autoimmune, and given that we know ME/CFS is often triggered by viral infections, we clearly need to consider possible mechanisms by which these viruses might set the scene for instigating autoimmunity. I am suggesting that B-cell infection might be a mechanism worth looking into.
I thought the premise with autoimmune disease is that the body is attacking itself. I don't think the body attacks itself...........it attacks a pathogen. I do believe though that you are on to something with the herpetic viruses being main culprit behind CFS/ME
 

Hip

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I thought the premise with autoimmune disease is that the body is attacking itself. I don't think the body attacks itself
There is evidence for autoimmune attack on the body in ME/CFS: see this list of autoantibodies found in ME/CFS patients. Plus of course the Fluge and Mella ME/CFS rituximab research suggests ME/CFS is autoimmune.
 

JES

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I thought the premise with autoimmune disease is that the body is attacking itself. I don't think the body attacks itself...........it attacks a pathogen. I do believe though that you are on to something with the herpetic viruses being main culprit behind CFS/ME
Up to a point that is true. However, if the initial attack to kill the pathogen is unsuccessful, then there is a risk that the immune response goes haywire. In order to kill the pathogen, the immune system has to launch a more power attack, which doesn't distinguish between the virus and your own tissues anymore. The only goal for the immune system becomes to eliminate the virus, even at the cost of destroying some of your own cells.

This is in simple terms what autoimmunity is about, and I believe most autoimmune diseases are a result of initially having a weak or dysfunctional immune response to a virus/pathogen, so immunodeficiency and autoimmunity are closely tied together. The idea of treating autoimmune diseases with immune suppressants is not really targeting the root cause, it doesn't surprise me at all that treating MS for instance with immune suppressants tends to be unsuccessful.
 

Gingergrrl

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@Hip, we were discussing this in another thread, and I know it has been discussed in the past, but I was curious of your opinion re: this test:

http://www.celltrend.de/newsreader/...yndrome-myalgic-encephalomyelitis-cfs-me.html

which is conducted in Germany. Would this test correlate to any of the issues that you are proposing in this thread and from your experience, have you heard of anyone outside of Germany having this test ordered by their doctor? Would the results of this test (if you happen to know?) differ from testing for Myasthenia Gravis or MuSK antibodies?

Your chart that you link to in post #36 lists so many different kinds of muscarinic and cholinergic receptors and I get lost figuring out which are which!

Also, would someone who tests positive on this test be a better candidate for Rituximab? (in your opinion of course!) I am wondering if trying to get this test in the US, or have my blood sent to Germany, for this test would be of value. Am still not certain if ME/CFS is my diagnosis but I match with all of the stuff you are discussing in this thread (prior EBV infection, current auto-antibodies, dysautonomia, etc).

Thanks in advance.
 

Hip

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However, if the initial attack to kill the pathogen is unsuccessful, then there is a risk that the immune response goes haywire. In order to kill the pathogen, the immune system has to launch a more power attack, which doesn't distinguish between the virus and your own tissues anymore.
Not that I know much about it, but I have never seen any research on autoimmunity that indicates autoimmune diseases are caused by the immune system simply fighting more fiercely against a pathogen, and triggering autoimmunity as a result of collateral damage, even if this idea might be an appealing one.


Although a weak intracellular immune response does appear to increase the chances of getting an autoimmune disease, in the sense that high STAT-3 activation raises the risk of autoimmunity (ref: 1).

High STAT-3 activation weakens intracellular immunity by putting the breaks on interferon type I responses, which drive intracellular immunity. The more STAT-3 is activated, the weaker the intracellular immune response.

This study found that if reduce STAT-3 activation (thus increasing intracellular immunity), this ameliorates experimental autoimmune uveitis. So STAT-3 seems like an important player in the development of autoimmunity.

Interestingly enough, nicotine activates STAT-3, and in this way nicotine weakens intracellular immunity, so that could explain why smoking is a major risk factor for triggering the autoimmune condition of rheumatoid arthritis.

In this post I was experimenting with trying to reduce STAT-3 activation as a means to ameliorate ME/CFS.



would someone who tests positive on this test be a better candidate for Rituximab?
In theory you would think yes, but with these things, the proof is in the pudding, meaning that if someone conducted a study that demonstrated that ME/CFS patients with adrenergic and muscarinic autoantibodies responded better to rituximab, then you could say yes, we know such people are better candidates. But I am have not seen any such studies.

In Fluge and Mella's latest ME/CFS study, they did measure adrenergic, muscarinic and other autoantibodies, and I think they found that in some rituximab responders, levels of these autoantibodies dropped after treatment.

But I don't think the study connected the pre-treatment levels of these autoantibodies to responses to rituximab treatment.
 

Gingergrrl

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@Hip could someone have muscarinic or adrenergic antibodies and respond to RTX without having ME/CFS or would these things be one and the same? Am not sure if I am phrasing this question to mean what I am trying to ask!