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

[kangaSue]

@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!

I recall Jonathon Edwards mentioning somewhere that muscarinic or adrenergic antibodies were likely just markers of autoimmunity rather than being pathogenic. There are some papers around on an autoimmune cause of POTS which found these same antibodies in people without having ME/CFS too.

 

[Gingergrrl]

@kangaSue if they are markers of autoimmunity, wouldn't that make them pathogenic? I do remember the POTS antibodies in the absence of ME/CFS, thanks for reminding me.

 

[Hip]

could someone have muscarinic or adrenergic antibodies and respond to RTX without having ME/CFS

I guess it's possible, if those antibodies are causing problems (if they are pathogenic). But I don't really know much about what tests there are (if any) that determine in advance whether someone responds to rituximab. There aren't any such tests for ME/CFS, because that's one of the things the UK rituximab research wants to look at: to work out how to identify in advance which ME/CFS patients might benefit from rituximab.

if they are markers of autoimmunity, wouldn't that make them pathogenic?

The complexity here is that autoantibodies can be functional or non-functional. Usually when you detect autoantibodies, you don't know if they are functional or not. My understanding is that only functional autoantibodies can be pathogenic.

For example, a muscarinic receptor autoantibody will attach to that receptor, but if it does not affect the receptor (does not activate, block or modulate the receptor) once attached, then it is non-functional, and does not interfere with the receptor's functioning.

But in another person, their muscarinic receptor autoantibodies may both attach to the receptor, and activate it, in which case, this is a functional autoantibody, than may well have pathogenic effects, because it can interfere with the receptor and thus the body's proper functioning.

 

[unto]

my experience is that you just (I think) the contact with my body fluids (mainly saliva) or with liquids of people who have contracted me to convey the ME.
So or in my saliva are present both the factors (x and y) or that ME is caused by a single pathogen and is not multifactorial .....
About 15 years after the beginning (2004) did the tests to see if I had autoimmunity
but they were all negative, then as regards my case ME is not multifactorial autoimmune it .....
Then there were people I knew 20 years after the onset of the disease and have ME contract frequenting my house.
In conclusion ME is not genetic and is not an infection ended ..... but unfortunately persistent

 

[Gingergrrl]

There aren't any such tests for ME/CFS, because that's one of the things the UK rituximab research wants to look at: to work out how to identify in advance which ME/CFS patients might benefit from rituximab.

Is this research still going to occur in the UK? If so, that would be amazing! The last I had heard was that it might not happen but I am not fully up to date on this stuff.

The complexity here is that autoantibodies can be functional or non-functional. Usually when you detect autoantibodies, you don't know if they are functional or not. My understanding is that only functional autoantibodies can be pathogenic.

For example, a muscarinic receptor autoantibody will attach to that receptor, but if it does not affect the receptor (does not activate, block or modulate the receptor) once attached, then it is non-functional, and does not interfere with the receptor's functioning.

But in another person, their muscarinic receptor autoantibodies may both attach to the receptor, and activate it, in which case, this is a functional autoantibody, than may well have pathogenic effects, because it can interfere with the receptor and thus the body's proper functioning.

Thank you for that explanation, which I absolutely did not grasp the distinction before, and it was very helpful. So someone could have an auto-antibody but if it did not activate, block or somehow modulate the receptor then it is sort of inactive or non-functional vs. if it did those things, then it becomes pathogenic. Is this right?

Is there a way to measure auto-antibodies to know if they are non-functional versus pathogenic or is it only by the combination of having both the auto-antibody AND the symptoms?

 

[kangaSue]

@kangaSue if they are markers of autoimmunity, wouldn't that make them pathogenic? I do remember the POTS antibodies in the absence of ME/CFS, thanks for reminding me.

I'm not clear on the workings of it all but I think it's only channelopathies that are the pathogenic ones, i.e., antibodies that affect function of direct ion channels. Ligand-gated and voltage-gated ion channels seem to be common offenders so calcium, potassium, sodium, chloride and nicotonic acetylcholine ion channel antibodies.

Muscarinic and adrenergic antibodies use a secondary messenger function through G protein coupled receptors to affect ion channel functioning.

 

[Hip]

Is this research still going to occur in the UK?

I am not sure of the status of that UK research. I know there were some question marks about whether it would go ahead or not.

So someone could have an auto-antibody but if it did not activate, block or somehow modulate the receptor then it is sort of inactive or non-functional vs. if it did those things, then it becomes pathogenic. Is this right?

That's my understanding.

But note that the autoimmune diseases in which autoantibodies bind to receptors on cells are just one type of autoimmune reaction. The various different types of allergy/autoimmune reactions are called hypersensitivity reactions, and there are five types of hypersensitivity reaction (or 4 types if you are in the US).

The type of autoimmunity where autoantibodies attach to receptors is classed as a type V hypersensitivity reaction.

So POTS may be a type V hypersensitivity reaction, and possibly ME/CFS too. By contrast, rheumatoid arthritis is a type III hypersensitivity reaction, where autoantibodies attach to soluble antigens that I believe are just floating along in body fluids, rather than the autoantibodies binding onto receptors or binding to other components fixed to cells as occurs in type V and type II respectively.

Rheumatoid arthritis is also classed as a type IV hypersensitivity, as is Hashimoto's thyroiditis.

Type I hypersensitivity is only found in allergy; type I does not correspond to any autoimmune condition.

Is there a way to measure auto-antibodies to know if they are non-functional versus pathogenic or is it only by the combination of having both the auto-antibody AND the symptoms?

Not really sure on that one.

 

[Lolinda]

My vitamin D is borderline deficient too, can't recall the number offhand but I don't tolerate vit Dsupplements.

@kangaSue & @Gingergrrl , I have just the same: vit D "just disappears" from my body. Did a test this summer: every day 10 min sunshine + every weekseveral times 100g mackerel, but no vit D supplementation. Was not enough: I went from my sufficient supplemented levels to deficiency: 31 nmol/L (normal: >50. you guys in the US use a gramm based measure instead of mol).

I wonder if the production is decreased or the usage is increased...?.
@kangaSue: what do you get is you take vitD?

Dr. Chia think it is the intracellular enterovirus infection IN the stomach (primary site) that is the cause of a subgroup of CFS sufferers.

Anyone thinking this can simply get tested. I did: it took 3 gastroenterologists until one was willing to do this simple test: take a lot of biopsy probes from the stomach and the duodenum and send them to Redlabs.be They test all cfs relevant viruses. They have a subsidy in the US, too. (Came back all fine.)

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

When I read this, I ask myself: Can we find out in ourselves? Now, when one sees a doctor, one gets an EBV panel,such as this one:

I had this positive result in January 2015. Then could resolve it by taking zink. But the big question is: how valid is a negative result on this panel? So, the researchers in the cited study measured EBV copies in the bone marrow. Did they do that because a negative result on the Igg IgM panel is not valid...?

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

Did you try or do you plan to try?

 

[frederic83]

@Lolinda

Can you tell us which virus exactly you were tested via the biopsies ?

 

[Hip]

Did you try or do you plan to try?

This is only a highly speculative idea, based on the idea that EBV infection of the B-cells might be driving autoimmunity. But how autoimmunity arises is not known at present.

 

[frederic83]

But how autoimmunity arises is not known at present.

Maybe of interest: http://forums.phoenixrising.me/inde...n-d-deficiency-and-steps-to-autoimmunit.47632

 

[kangaSue]

@kangaSue: what do you get if you take vitD?

@Lolinda The same as for a whole range of things, foods, drugs, supplements - really intense abdominal pain that I can't tell apart from the pain I get when my Chronic Mesentery Ischemia swings to an Acute Mesentery Ischemia (AMI) flare but without the drop in b.p. that happens with an AMI event.

 

[Lolinda]

Can you tell us which virus exactly you were tested via the biopsies ?

You see a tiny elevation at HHV7. I mailed the lab manager, she said that this is negligible. People have magnitudes higher values.

This is only a highly speculative idea, based on the idea that EBV infection of the B-cells might be driving autoimmunity

I like your speculative idea! As nobody really knows what causes autoimmunity, I cannot expect a surefire medicine. I would go for anything that has a chance and has low side effects. Do you know any good thread or any link on valtrex side effects? Experiences by eople who took it long term?

@Lolinda The same as for a whole range of things, foods, drugs, supplements - really intense abdominal pain

I get pulsations that do not let me sleep. But I tolerate a small dosis. When I am badly deficient, I tolerate also hgher doses for a day or two. Currently, I experiment with transdermal vit D. I tried today and yesterday the 25x rdv dose on skin. So far no prblems at all!! Will see in some weeks how it resorbs (elevated vit D levels in a blood). I red research that it resorbs.
Additionally, I liked this idea to increase resorption:
https://raypeatforum.com/community/threads/transdermal-topicals-best-practices.8833/
"Penetration-rate can be enhanced up to 100X simply by disturbing the outermost layer of skin with a brush. Search pubmed for the study. They used a rotating brush..and from memory, I think they found the asymptote at around 60 seconds."

 

[Hip]

Do you know any good thread or any link on valtrex side effects? Experiences by eople who took it long term?

No, unfortunately not. But generally, if there are side effects from Valtrex, people may switch to Famvir, which is better tolerated, and has similar antiviral efficacy.

 

[taniaaust1]

I just came across some research from this year which I thought was interesting due to a new cell type has been found which is kills viral infected B cells (wow a lot of researchers worked on this study)
http://www.nature.com/ni/journal/v17/n10/full/ni.3543.html

CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles

• Yew Ann Leong,
• Yaping Chen,
• Hong Sheng Ong,
• Di Wu,
• Kevin Man,
• Claire Deleage,
• Martina Minnich,
• Benjamin J Meckiff,
• Yunbo Wei,
• Zhaohua Hou,
• Dimitra Zotos,
• Kevin A Fenix,
• Anurag Atnerkar,
• Simon Preston,
• Jeffrey G Chipman,
• Greg J Beilman,
• Cody C Allison,
• Lei Sun,
• Peng Wang,
• Jiawei Xu,
• Jesse G Toe,
• Hao K Lu,
• Yong Tao,
• Umaimainthan Palendira,
• Alexander L Dent

Nature Immunology 17, 1187–1196 (2016) doi:10.1038/ni.3543
Received 19 July 2016
Accepted 29 July 2016
Published online 03 August 2016

Abstract

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells'
............................................

This new research leaves me to wonder IF we do have infected B cells, maybe the fault isnt in the B cell but could this mean we have issues with our "follicular cytotoxic T cells?

I had severe EBV mono when I was a teen for 10 weeks, my body didnt fight it off well so I also had extreme symptoms with it too. Ive always believe I have something wrong or different with my immune system due to that. I wish I could get my folliular cytotoxic T cells tested.

maybe I should put this study in the other research area as it could have implications for us in some way.

 

[taniaaust1]

I started a thread for that new research in the research area of the forums.

Im wondering if lyme disease affects B cells?

 

[Hip]

I posted the following elsewhere, but it may be worth posting in this thread too:


Very interesting point made at timecode 45:50 in this talk by Dr Fluge, when a member of the audience asks Dr Fluge if it is possible to rule out the theory that ME/CFS may be driven by an intracellular infection of B-cells, such as an infection with Epstein-Barr virus.

Since rituximab kills the B-cells, this drug would also wipe out any intracellular infection in these cells, and thus in theory, this could explain how, if the B-cell infection were causing ME/CFS, rituximab can cure ME/CFS.

Dr Fluge replies by staying that he cannot entirely rule out such a possibility, but points out that rituximab kills the B-cells within days, so he says that if ME/CFS were directly caused by a B-cell infection, it would be difficult to explain why it takes 7 or 8 months before ME/CFS patients treated with rituximab improve. If ME/CFS were directly caused by a B-cell infection, you would expect the improvements to appear as soon as the B-cells were killed, days after rituximab is given.

Dr Fluge then mentions the case of a patient who was very sick, suffering for years with chronic Epstein-Barr virus infection, including infection of the B-cells (verified by B-cell biopsy). She had very high levels of EBV in her blood, and antivirals made no difference.

This chronic Epstein-Barr patient was referred to Dr Fluge: she was give rituximab, and sweated profusely for two days, but by the third day felt completely healthy.

So it is clear that when a patient's symptoms are due to chronic Epstein-Barr virus infection of the B-cells, rituximab cures their symptoms in a matter of days.

But with ME/CFS patients, it takes 7 to 8 months before the cure or improvements manifest.


So Dr Fluge says in his view, B-cell infection is not directly causing the symptoms of ME/CFS, but says he thinks viral infection does have something to do with ME/CFS, though he thinks it is the immune response after infection that is the driving factor, probably targeting and causing a dysfunction in the energy metabolism.

 

[junkcrap50]

About 15 years after the beginning (2004) did the tests to see if I had autoimmunity
but they were all negative, then as regards my case ME is not multifactorial autoimmune it .....

From what I've learned, the standard autoimmunity blood tests are not nearly sensitive enough and only pick up autoimmunity when you've already reached a stage of organ failure or full disease state. But autoimmunity likely begins much earlier when you either don't have any symptoms or are beginning to and not enough autoantibodies to test positive on typical tests.

I had an autoimmunity test, along with others, done by Cyrex labs, who claims to have extremely sensitive autoantibody tests. I tested positive for most all of the autoimmune antibodies. I then had typical antibody tests done by Quest for the same antibodies or same autoimmune conditions, and I tested negative for all of them.

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I would go for anything that has a chance and has low side effects. Do you know any good thread or any link on valtrex side effects? Experiences by eople who took it long term?

I know of people's experiences of taking valtrex long term. Dr. Martin Lerner has published papers on CFS (including 1 double blind trial) treating patients with long term valtrex. Avg. treatment length = 2.5 years. Some studies patients were on anti-virals for 3+. And some patients needed longer treatment and were on valtrex for 6 years. You can find his papers and more info on his website: www.treatmentcenterforcfs.com or if you google "Dr. Martin Lerner CFS" you'll find healthrising and phoenix rising articles discussing his research.

 

[eljefe19]

I am considering a Rituximab/rifampin/valcyte/Oxymatrine stack to address the immune dysfunction comprehensively. Will be seen at OMI next week.

Also targeting mTorC1, Ceramides, and PDH based on the latest Fluge and Mella paper. DCA/Leucine+glutamine/high dose niacinamide/PA/pantothenic acid high dose/creatine/pantethine

 

[Gingergrrl]

Dr Fluge then mentions the case of a patient who was very sick, suffering for years with chronic Epstein-Barr virus infection, including infection of the B-cells (verified by B-cell biopsy).

@Hip I bolded the last part of your sentence re: B-cell biopsy b/c I had not heard of that before! How do they biopsy the B-cells? Do you know what the procedure is?

So it is clear that when a patient's symptoms are due to chronic Epstein-Barr virus infection of the B-cells, rituximab cures their symptoms in a matter of days.

What if someone started with chronic EBV infection of the B-cells but then in later years, the infection turned autoimmune? Could the RTX still cure their symptoms in a matter of days? Or would this only apply to someone in the active viral stage (prior to it turning autoimmune)? I hope this question makes sense. It does in my head .