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Rituximab Whacks NK Cells in ME/CFS Says Aussie Group

Cort

Phoenix Rising Founder
Boy is this interesting

Gradisnuk-Staines group in Australia is reporting the Rituximab is whacking the already whacked out NK cells in ME/CFS patients. It appears that the group tracked NK cell functioning in patients given the drug and found that it significantly worsened.

At one time it was thought that Rituximab might be aiding NK cell functioning I believe.

https://app.secure.griffith.edu.au/news/2018/03/27/drug-hoped-to-treat-cfs-causes-impaired-immune-function-griffith-study-says/

Reports that a drug used to treat autoimmune diseases and cancer could also treat Chronic Fatigue Syndrome (CFS) have been refuted by a new Griffith University study.

To be published in BMC Pharmacology and Toxicology, the study by Griffith’s National Centre for Neuroimmunology and Emerging Diseases(NCNED) concluded that the use of Rituximab in CFS patients could incur problems with their immune cells and is not beneficial as a potential treatment.

The Natural Killer (NK) cells have vital functions in fighting viruses, bacteria and tumours.

“We found that these functions were significantly impaired when exposed to Rituximab in CFS patients,” says Scientific Co-Director of NCNED, Professor Sonya Marshall-Gradisnik.

It makes the big study results all the more interesting. Did some people actually get worse? There was little evidence of that before but this was a much bigger trial.

I wonder if it's possible that while NK cells are impaired but that impairment doesn't necessarily influence. I say that because I've known people who's NK cell functioning has zoomed up who saw no change in their symptoms.

The Griffiths group has focused a lot of energy on NK cells.

The results of the Rituximab trial should be out any time I believe. It's possible that the drug did help a significant subset of patients but not enough for the results to be statistically significant.
 

Gingergrrl

Senior Member
Messages
16,171
@Cort Thanks for posting this interesting study and I quoted a couple parts from the article that I had questions about. I was also confused when it stated that Rituximab can impair the immune system (or potentially make someone immuno-compromised) b/c isn't that the mechanism of how it works (killing off the B-cells) so it seems like this piece of info would already be an established fact?

Also, is Griffith University the main research center in Australia or am I confusing them with someone else? I assume this research is considered solid like Fluge & Mella's (or would that be incorrect)? I didn't realize that there was an Australian Rituximab study even going on and don't know how I missed it!

The Gold Coast NCNED team has discovered the illness is related to problems in the ion channels that allow calcium into the body’s cells. Calcium is required by almost every cell in the human body and is vital in helping the immune system destroy a virus or infection. The team has proven that patients with CFS/ME have lower levels of calcium coming into their cells, that their cells store less calcium and that this is the basis of their illness.

This was the most interesting quote to me on a personal level since I have a calcium (ion) channelopathy and am positive for the N-type CA+ Channel autoantibody. I truly have no idea if this will ultimately be a biomarker for ME/CFS or if it will turn out to be a new disease that science has not yet named. But I find it fascinating that Griffith University feels they have proven that patients with ME/CFS have this issue. Did they explain how they proved it? This makes me more confused what my diagnosis will ultimately be.

“These results are important as NK cells are already known to have impaired function in CFS patients, suggesting certain doses of Rituximab may not be beneficial for the treatment of this condition.”

When they said "certain doses of Rituximab", do you know what dose was used in their study? Was it 1000 mg for every patient (like in Fluge & Mella's study) or did they use the autoimmune protocol based on body surface area (which for me gave me a dose of 600 mg). I don't know if it would actually change anything but was curious nonetheless!

I have very low NK cell functioning (in 2014, which was three years before I started Rituximab) but it never seemed to play any clinical role in my illness and I'm not sure if it will ever turn out to be a biomarker of anything. My MCAS doctor said NK functioning is low in his patients and when I saw a mold doctor (in 2015) she also said that it is low in her patients.

Neither felt it was really of any significance and my main doctor (who is an ME/CFS specialist) rarely even tests for it anymore and also told me that it doesn't seem to make any clinical difference (and he said that it usually just remains low). That is from my memory/paraphrasing and NOT a direct quote from him!

The results of the Rituximab trial should be out any time I believe. It's possible that the drug did help a significant subset of patients but not enough for the results to be statistically significant.

Do you mean of this new study from Griffith University or the full results of the Fluge & Mella study? I also believe that there is a subset of patients who were helped (even if this subset turns out to be a misdiagnosed group, or a group with the calcium channelopathy, or another autoimmune disease).

I know Rituximab remains a controversial topic (I'm not sure why but some of the posts get heated on this topic!) but I think it is important and am glad you posted this study. Thank you!
 
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Cort

Phoenix Rising Founder
@Cort Thanks for posting this interesting study and I quoted a couple parts from the article that I had questions about. I was also confused when it stated that Rituximab can impair the immune system (or potentially make someone immuno-compromised) b/c isn't that the mechanism of how it works (killing off the B-cells) so it seems like this piece of info would already be an established fact?

Also, is Griffith University the main research center in Australia or am I confusing them with someone else? I assume this research is considered solid like Fluge & Mella's (or would that be incorrect)? I didn't realize that there was an Australian Rituximab study even going on and don't know how I missed it!

This was the most interesting quote to me on a personal level since I have a calcium (ion) channelopathy and am positive for the N-type CA+ Channel autoantibody. I truly have no idea if this will ultimately be a biomarker for ME/CFS or if it will turn out to be a new disease that science has not yet named. But I find it fascinating that Griffith University feels they have proven that patients with ME/CFS have this issue. Did they explain how they proved it? This makes me more confused what my diagnosis will ultimately be.

When they said "certain doses of Rituximab", do you know what dose was used in their study? Was it 1000 mg for every patient (like in Fluge & Mella's study) or did they use the autoimmune protocol based on body surface area (which for me gave me a dose of 600 mg). I don't know if it would actually change anything but was curious nonetheless!

I have very low NK cell functioning (in 2014, which was three years before I started Rituximab) but it never seemed to play any clinical role in my illness and I'm not sure if it will ever turn out to be a biomarker of anything. My MCAS doctor said NK functioning is low in his patients and when I saw a mold doctor (in 2015) she also said that it is low in her patients.

Neither felt it was really of any significance and my main doctor (who is an ME/CFS specialist) rarely even tests for it anymore and also told me that it doesn't seem to make any clinical difference (and he said that it usually just remains low). That is from my memory/paraphrasing and NOT a direct quote from him!

Do you mean of this new study from Griffith University or the full results of the Fluge & Mella study? I also believe that there is a subset of patients who were helped (even if this subset turns out to be a misdiagnosed group, or a group with the calcium channelopathy, or another autoimmune disease).

I know Rituximab remains a controversial topic (I'm not sure why but some of the posts get heated on this topic!) but I think it is important and am glad you posted this study. Thank you!

I don't think the study is out yet.

There are other research groups in Australia (Armstrong and McGregor come to mind) but Marshall-Gradisnuk's at Griffiths I think it is - is easily the biggest one. They're doing more work on NK cells than anyone and have demonstrated calciium ion channgl problems in them. From what I can tell they think calcium channel problems may be "it" in ME/CFS.

I must say they do some of the most densely technical papers I've ever seen.

https://www.ncbi.nlm.nih.gov/pubmed/27727448

In fact they were the first to ever identify that some calcium channels existed on NK cells.

https://www.ncbi.nlm.nih.gov/pubmed/27245705

This study suggested that RItuximab helped the immune system in those who responded to it.
In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.


https://www.ncbi.nlm.nih.gov/pubmed/26399744
 

Gingergrrl

Senior Member
Messages
16,171
I don't think the study is out yet.

Thanks and I was not sure.

but Marshall-Gradisnuk's at Griffiths I think it is - is easily the biggest one.

That's what I thought but was also not sure!

From what I can tell they think calcium channel problems may be "it" in ME/CFS.

Wow, that is so interesting to me based on having that exact issue. Do you know how they determined this (or is it in the future study to be published)... which I most likely would not understand even if I read it!

I must say they do some of the most densely technical papers I've ever seen.

Then I definitely will not be reading it LOL

This study suggested that RItuximab helped the immune system in those who responded to it.

Wow, this is so interesting and must somehow relate to my experience with Rituximab (I have done four infusions so far with 5th in early May). My immune system in hyperdrive and I have not had a cold, flu, fever in 5+ years.

I expected to be immunocompromised from Ritux but still have not gotten a cold, flu or traditional illness. I spent every day for 3 months at hospital (and then skilled nursing facility) while my mom was dying of cancer and every single member of my family got sick in that time period (6 people), plus massive flu epidemic at hospital, yet I did not catch anything in spite of Ritux. It's not that I want to get sick vs. it appears that I am incapable of it (which might not be a good thing vs. it is just weird to me).

In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.

I have very elevated autoantibodies of those mentioned in your quote above, in addition to the CA+ autoantibody, and so far I have been a responder to Ritux.

I know Dr. Schiebenbogen's group in Germany has studied this in addition to this group in Australia and I wish someone in the US would study it but no one seems to be interested!
 

Murph

:)
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1,792
Amazing. I am with Ginger on a couple of questions here.

1. When did they do a rituximab trial? Or, perhaps, did another research group share samples with them? It doesn't appear to be in vitro.
2. We know ritux hurts the immune system. That's the point! Prof Staines says it "may not be beneficial" for patients and I'm not sure you can go much further than that when you've not done a trial testing the overall benefit. The word *refuted* in the first sentence of the press release is a terrible choice.

Third and final point. I am very interested in the calcium channel work these guys are doing. seems tightly intertwined with the purinergic signalling theory. But it seems not many other groups are working alongside them. I do idly wonder if this is who McGregor was having a dig at last week when he made some comments on a panel about researchers who don't collaborate!?!
 

JES

Senior Member
Messages
1,318
Rituximab works by killing B-cells, which are a central part of the immune system. So to me it's not surprising at all to hear that wiping them off would in some ways impair the immune system, because (from my limited understanding) those B-cells are not existing for no reason. Probably there is a trade-off, if for example an uncontrolled EBV infection or some other factor makes those B-cells malfunction, then the individual is probably better off without them. But if the problem is elsewhere than in the B-cells, then I would assume Rituximab could make patients worse.
 

Ema

Senior Member
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Location
Midwest USA
I totally believe that calcium channels are implicated, but I'm not sold on the idea that iCa is low in MECFS. The hallmark of MCAS in particular is HIGH intracellular calcium, not low. I've seen that exact statement written somewhere in a research paper.

Calcium channels are pretty important in the proper functioning of just about everything in the body. Calcium is one of those ions that is supposed to be higher in concentration (by about 10,000x) outside of the cell in the blood and extracellular fluid. This concentration gradient is vital for the proper functioning of muscles, glial cells and neurotransmission.

Basically high intracellular calcium can cause most all the symptoms of MECFS. Fatigue, muscle recovery problems, neuroendocrine issues, mast cell issues, POTS...etc etc.

Calcium also affects mitochondrial function with high intracellular calcium levels causing conformational changes which make the mitochondria stop functioning well. This consequently leads to mitochondrial dysfunction but it isn't a genetic mitochondrial disorder...it's caused by the increased intracellular calcium.

Does anyone know for sure that the the calcium channel antibodies antagonize the associated receptors? It seems at least theoretically possible that they could agonize the receptor as well, but I admit all the talk of agonists, antagonists, and inverse agonists makes my head spin a bit. I do know that not all antibodies automatically block channels though for sure from that POTS paper a while back.

I would dearly love to resolve this in my mind as it's been bugging me for ages with their research.
 

Gingergrrl

Senior Member
Messages
16,171
1. When did they do a rituximab trial? Or, perhaps, did another research group share samples with them? It doesn't appear to be in vitro.

I was curious too @Murph. Does anyone know?

2. We know ritux hurts the immune system. That's the point!

That was my understanding.

I am very interested in the calcium channel work these guys are doing. seems tightly intertwined with the purinergic signalling theory.

What does "purinergic signalling theory" mean (if it is humanly possible to explain in terms that I could understand which there may not be :D).

But it seems not many other groups are working alongside them.

I wish everyone could pool their research and work together but I know it will never happen :aghhh:

Probably there is a trade-off, if for example an uncontrolled EBV infection or some other factor makes those B-cells malfunction, then the individual is probably better off without them. But if the problem is elsewhere than in the B-cells, then I would assume Rituximab could make patients worse.

I think in the responder group there is a trade-off like you said... whether it is controlling an EBV infection or killing B-cells that are creating pathogenic autoantibodies. Then in the ideal scenario, the new B-cells grow back healthy. But if the problem is not in the B-cells, I agree it would have no effect or potentially make the person worse (especially if they are already immunocompromised for another reason).
 

Gingergrrl

Senior Member
Messages
16,171
I totally believe that calcium channels are implicated, but I'm not sold on the idea that iCa is low in MECFS. The hallmark of MCAS in particular is HIGH intracellular calcium, not low. I've seen that exact statement written somewhere in a research paper.

Does iCa mean "intracellular calcium"? I agree with you that calcium channels are implicated but from what I have been told in my case, the autoantibody blocks CA+ going into the cells making the intracellular calcium low. I was told by Stanford, and then two other Neuros, that I should not take any meds that further block the CA+ channel, and two of the three Neuros even included Magnesium in that group (but one did not). I wish I knew the answer, too.

Basically high intracellular calcium can cause most all the symptoms of MECFS. Fatigue, muscle recovery problems, neuroendocrine issues, mast cell issues, POTS...etc etc.

Even though I remain unclear if ME/CFS is my diagnosis, I have the CA+ channel autoantibody and prior to treatment I had severe muscle fatigue/weakness, severe mast cell issues, and POTS. The first two issues are resolved but I still have POTS. It is better on most days but it's still here. And at the time that I was told the autoantibody blocks the CA+ Channel, this had nothing to do with Rituximab in my case, b/c I was told this in early to mid 2016 and I did not start Ritux until mid 2017.

Does anyone know for sure that the the calcium channel antibodies antagonize the associated receptors?

I know nothing for sure and this is what I was told by the Neuro at Stanford and then two other Neuros. None of them offered me a single treatment but this is what they told me.

I would dearly love to resolve this in my mind as it's been bugging me for ages with their research.

It bugs me, too. I avoid any med that even remotely has calcium channel blocking properties b/c of what these three Neuros told me but I do take a small dose of Magnesium Malate at night or I get cramps in my calves/legs that wake me up at night.
 

Murph

:)
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1,792
What does "purinergic signalling theory" mean (if it is humanly possible to explain in terms that I could understand which there may not be :D).

We all know you are very clever! One of the ways this manifests is in asking questions in a particularly humble way that encourages people to reply! :p

Purinergic signalling is just cells signalling using ATP (and related molecules). ATP is the very same molecule that cells use for energy.

Naviaux's theories of ME/CFS and autism are all about purinergic singalling. It is a well-known part of the cell danger response that he suspects is stuck on chronically. Suramin is antipurinergic, which is why he's excited about that.

In Naviaux's paper Metabolic features of Chronic fatigue Syndrome, he measured many many metabolites. the one that was basically furthest out of whack was Adenosine. Adenosine is the A in ATP and it's what you get after ATP is processed by the body. The fact it was so out of line is not solid evidence of problems with purinergic signalling, but it sure is heavy circumstantial evidence.

here's a chart I made ages ago of that data. from left to right the groups are female patients, female controls male patients, male controls. You can see the controls have way more adenosine.

adenosine.png
 
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Learner1

Senior Member
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So, from Wikipedia:
Both adenine and guanine are derived from the nucleotide inosine monophosphate (IMP), which in turn is synthesized from a pre-existing ribose phosphate through a complex pathway using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as the coenzyme tetrahydrofolate.
So, is it because we're short of ribose, glycine glutamine and aspartic acid and/or tetrahydrofolate?

This is a random observation and I'm not sure if it applies.. I have hyperadrenergic POTS and was recently put on amlodipine, a calcium channel blocker. My vslvium usually runs slowish. It gave me extreme fatigue, so bad I instinctively stopped. Then my labs came back with alarm level lows on hematocrit, hemoglobin and platelets. A month later after stopping amlodipine, my lab values return to normal. I wonder if the calcium channel blocker has anything to do with the above discussion. Does it? Thank you.
 

Wonkmonk

Senior Member
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Rituximab works by killing B-cells, which are a central part of the immune system. So to me it's not surprising at all to hear that wiping them off would in some ways impair the immune system, because (from my limited understanding) those B-cells are not existing for no reason. Probably there is a trade-off, if for example an uncontrolled EBV infection or some other factor makes those B-cells malfunction, then the individual is probably better off without them. But if the problem is elsewhere than in the B-cells, then I would assume Rituximab could make patients worse.
My immune system in hyperdrive and I have not had a cold, flu, fever in 5+ years.

I am wondering: Could there be different segments of patients with regard to the activity of the immune system? I have seen reports of:

(1) Patients who have lots of problems with allergies/autoimmunity and normal or mildly elevated herpesvirus antibodies who never catch a cold (e.g. @Gingergrrl)

(2) People without any autoimmunity but with high autoantibodies against herpesvirus who never catch a cold (e.g. myself)

(3) People who always feel sick (e.g. Mr. Olaf Bodden)

In patient Group 1, one could hypothesize that their immune system is overactive because it's partly in self-destruct mode. These patients might improve with Rituximab. Antivirals don't help.

In Group 2, the immune system is overactive, because these patients are constantly fighting a chronic infection that for some reason can't be cleared. Their symptoms may be caused in part by the pathogen and in part by the immune response. But the immune system is still strong enough to defend mucous membranes, lymph nodes etc. That's why these patients don't have the usual flu-like symptoms. Rituximab would be counter-productive, because the underlying infection would get worse. The right antivirals could help fight or control the infection.

In Group 3, the immune system has collapsed and a virus or combination of pathogens is constantly wreaking havoc. Immune function is for some reason unable to clear the pathogens from mucous membranes, lymph nodes etc. which leads to constant flu-like symptoms. Rituximab would be counter-productive, because it would further weaken an already compromised immune system. Antivirals could help, but the prognosis would probably be worse than in group 2 because the immune system is less capable to help control the infection.

In Group 1, the challenge would be to find broader or better targeted immunosuppressive drugs in addition to or instead of Rituximab and to help control the autoimmunity (e.g. with IVIG).

In Group 2, the challenge would be to find the right antiviral and explore the conditions how to make the antivirals more effective and treatment success more sustainable.

In Group 3, one would have to find out why the immune system has collapsed and how proper immune function can be restored.

From this perspective, there could be an explanation why Mr. Olaf Bodden has got so much worse after Rituximab. The drug has weakened his already weak immune system further. It would also be an explanation why the Charité has had no success in a small-scale Rituximab trial (of 10 patients 2 got worse, incl. Mr Bodden and 8 had no benefit). They are selecting their patients on the basis of weak immune function. I applied to be accepted as a patient at the Charité. One question was if I was feeling sick constantly or having more colds and illnesses as usual. I stated that to the contrary I never get sick and I was told that for this reason I won't be accepted, because the Charité focuses on immunocompromised patients.

So they are selecting the subgroup among CFS patients who like Mr. Bodden are in the group with the weakened immune system. From this perspective, it is not surprising that Rituximab wasn't the right drug for that group of patients.

So maybe - as Dr Mella said in his lecture posted elsewhere - it is really all about patient selection and despite the negative recent trial, there is a group of patients that benefits from Rituximab and it has just not been identified.

EDIT: There may be a Group 4 whose problem is Epstein-Barr-Virus, and only Epstein-Barr-Virus. This group might also respond to Rituximab, because it kills EBV's reservoir cells. The challenge would be to identify that group.
 
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Learner1

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Jarred Younger found an infection group and an autoimmune group in his research.

Confused by this, as I had an underactive immune system with multiple infections including EBV, low NK cells and immunoglobulins G and M as well as multiple autoimmune problems. I asked him if it was possible have both. He told me yes, definitely, he just hadn't mentioned it yet.

@Wonkmonk I'm confused again, am I, and the many people like me out there, in group 1, 3, or 4? Or all 3? And what would be the treatment?
 

Wonkmonk

Senior Member
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Germany
@Wonkmonk I'm confused again, am I, and the many people like me out there, in group 1, 3, or 4? Or all 3? And what would be the treatment?

These groups - if they exist, which again I stress is my personal speculation - probably couldn't be separated exactly from each other, so some people who are in group 2,3 and 4 might also have some autoimmune issues, especially if those started before their CFS started, so that may be sort of a "legacy autoimmunity" not connected to the CFS.

In your case, I think you had very good success with Valcyte, so that probably puts you in Group 3. Given the treatment success you had, the treatment would probably be to keep doing what you are doing.

Dr Montoya said in his lecture posted in the other thread that NK cell function returns after a few years of Valcyte, so antivirals might work for some patients in Group 3.

I did not find evidence that Mr Bodden ever tried antivirals, but looking at the range of treatments he has had, including even Rituximab, I'd be surprised if he didn't try Valcyte as well, and it obviously didn't help.
 

Learner1

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The infections many of us have, especially EBV, are notorious for causing autoimmunity, and some of us are more prone to autoimmunity genetically.

There seem to be a number of other patients here who developed autoimmune POTS and/or MCAS as a result of infections. (My ME/CFS specialist says half of his patients have autoimmune MCAS, not genetic mast cell disease.)
 

Gingergrrl

Senior Member
Messages
16,171
We all know you are very clever! One of the ways this manifests is in asking questions in a particularly humble way that encourages people to reply! :p
Purinergic signalling is just cells signalling using ATP (and related molecules). ATP is the very same molecule that cells use for energy.

Thanks @Murph and I actually am not that clever re: all of these scientific terms (as much as I wish I was)! I still can't quite figure out what the word "purinergic" means (although it probably doesn't matter)!

Naviaux's theories of ME/CFS and autism are all about purinergic singalling. It is a well-known part of the cell danger response that he suspects is stuck on chronically. Suramin is antipurinergic, which is why he's excited about that.

I never really understood how Naviaux's theories re: autism and Suramin related to autoimmunity and Rituximab (or do they truly not relate whatsoever and have nothing to do with each other)?

My vslvium usually runs slowish.

@Learner1 Was the word above "calcium" and if so, what did you mean that your calcium runs slowish? Did you mean that you test low for Calcium on blood tests (similar to how someone could test low for Potassium or Magnesium) or were you talking about the CA+ ion/autoantibody? I just wanted to make sure I understood.

A month later after stopping amlodipine, my lab values return to normal. I wonder if the calcium channel blocker has anything to do with the above discussion. Does it? Thank you.

I don't know the answer to this but would be curious if someone else does! My only attempt at a Calcium Channel blocker was one single dose of Diltiazem (in 2014) for POTS but it dropped my blood pressure incredibly low and caused me to throw up and I almost fainted. My Cardio at the time told me never to take it again and put me back on the low-dose beta blocker (Atenolol) for POTS which I still take today. No one knew that I tested positive for the CA+ channel autoantibody until the beginning of 2016 (and I truly do not know when it first became positive).

Everything started off viral for me with severe mono/EBV in 2012, and then a second virus in Jan 2013, which was either a new virus or the re-activation of the EBV. Within two weeks of the second virus, I developed severe POTS. I tested positive for EBV on IgM and Early Antigen at very high levels for 3+ YEARS post Mono. I suspect, which I will reply to in my next post re: @Wonkmonk's theories, that in 2015, it all shifted into autoimmunity for me.
 

Gingergrrl

Senior Member
Messages
16,171
I am wondering: Could there be different segments of patients with regard to the activity of the immune system? I have seen reports of:

In my opinion, which is very similar to yours, there are at least two groups in regard to activity of the immune system (and for lack of better terminology, I'd call them under-active, overactive, and mixed).

(1) Patients who have lots of problems with allergies/ autoimmunity and normal or mildly elevated herpesvirus antibodies who never catch a cold (e.g. @Gingergrrl)

This describes my situation well except that I had extremely high antibodies to EBV (IgM+ and EA+) for 3-4 yrs post Mono (2012). They finally went down in 2015 (pre IVIG & Ritux) but I have not tested them recently b/c my doctor said that antibody tests will not be accurate for me as I have done 1.5 years of IVIG (and am still doing it at present). Eventually once I stop IVIG completely and several months have passed, it may be possible to do antibody tests again but I am not certain of this. PCR tests, however, would still be accurate for me.

In patient Group 1, one could hypothesize that their immune system is overactive because it's partly in self-destruct mode. These patients might improve with Rituximab. Antivirals don't help.

This is what my main doctor said and that my immune system remains in hyper-drive where it immediately attacks any pathogen it comes into contact with. But the downside is the autoimmunity and it continues to attack my own body.

In Group 1, the challenge would be to find broader or better targeted immunosuppressive drugs in addition to or instead of Rituximab and to help control the autoimmunity (e.g. with IVIG).

I guess this is why IVIG has worked so well for me, especially re: putting the MCAS and allergic reactions into remission. Last night I ate pizza and chocolate chip cookies with my daughter & niece, with no MCAS meds, and no longer have any concerns about allergic reactions. Even with a Benadryl injection 30 min prior to ingesting food plus eight other MCAS meds, this would have killed me in 2015.

I applied to be accepted as a patient at the Charité. One question was if I was feeling sick constantly or having more colds and illnesses as usual. I stated that to the contrary I never get sick and I was told that for this reason I won't be accepted, because the Charité focuses on immunocompromised patients.

That is really a shame that they only accepted patients who had constant colds or illnesses. My understanding of ME/CFS (from this board and am not talking about myself) is that about half the patients fit that description but the other half literally lost the ability to get a cold or traditional illness.

So they are selecting the subgroup among CFS patients who like Mr. Bodden are in the group with the weakened immune system. From this perspective, it is not surprising that Rituximab wasn't the right drug for that group of patients.

I agree.

So maybe - as Dr Mella said in his lecture posted elsewhere - it is really all about patient selection and despite the negative recent trial, there is a group of patients that benefits from Rituximab and it has just not been identified.

I agree with this as well but I know that this opinion is in the extreme minority.

Jarred Younger found an infection group and an autoimmune group in his research.

Agree with this, too.

The infections many of us have, especially EBV, are notorious for causing autoimmunity, and some of us are more prone to autoimmunity genetically.

Agree, too, and I believe in my case (as do my two doctors) that the EBV shifted into autoimmunity. I had the additional factor of several years of exposure to toxic mold in a former rental and I feel that the combo of viral infection and mycotoxin exposure caused the shift into autoimmunity (in my case).

There seem to be a number of other patients here who developed autoimmune POTS and/or MCAS as a result of infections. (My ME/CFS specialist says half of his patients have autoimmune MCAS, not genetic mast cell disease.)

I agree with this statement although my MCAS doctor uses different words (which might just be semantics). He feels that Mastocytosis is always 100% of the time the primary disease and is life-long (I think what you are describing as genetic) vs. MCAS is a secondary disease and can be life-long or it can go into remission with treatments like IVIG (which happened in my case). My MCAS doctor does not describe MCAS as an autoimmune disease (and it has no identifiable autoantibodies) but it is definitely a shift in the immune system toward hyperactivity/chaos.

Both my main doc and MCAS doctor feel that I have "Autoimmune POTS" though, and I believe that the entire concept of Autoimmune Dysautonomia will some day be better understood by science.

Alot of drs get nk function and nk numbers tests mixed up. Nk function test isnt a common test like the nk numbers is.

I agree although in my case, it truly was NK functioning that was tested and being referred to by the doctors I mentioned. My NK numbers were always normal (and never low) but my NK functioning was extremely low.