Immune complex meditated pathology in ME/CFS - low grade complement activation symptoms

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Dear all

I would like to share some thoughts of mine and get your opinion.

In my five year personal research I have come to suspect that myself and probably a subset of ME/CFS patients can trace their symptoms to constant low grade complement activation induced by immune complex creation. This is what is called Hypersensitivity Type 3 and is very well explained in this video:

The reason why this pathology in ME/CFS does not turn into rheumatoid arthritis, Lupus or other known auto immune diseases is that the immune complexes in our case do not deposit in any membrane/wall/synovial fluid so there is no tissue damage - just symptoms of sickness that do not go away. They are also not of classical inflamation with ESR and C reactive protein in blood but of a constant low grade one.

I theorize that the immune complex creation comes from a special type of uncontrolled IgG/IgA rheumatoid factor (autoantibody to antibody) creation in disrupted plasma B-cells. This is similar as to rheumatoid arthritis but without the IgM rheumatoid factor and also of different affinity. The viral onset in ME/CFS explain the intial creation of rheumatoid factor to clear infection but in this case the orginal antigen is long gone.

Since rheumatoid factor is a antibody against an antibody this leads to constant 24/7 creation of very small IgG to IgG immune complexes that are soluble and circulate the bloodstream making it a systematic disease. With the creation of immune complexes the complement system gets activated and signals to neutrophils the site for phagocytosis. It is my believe that this signaling and phagocytosis process creates the sickness symptoms in a subset of ME/CFS patients.

As a possible biomarkers to identify this pathology would be raised IgG/IgA (not IgM) rheumatoid factor binding to human antigen (not rabit antigen), lowered C3/C4 complement proteins and low neutrophil count. The lowered C3/C4 and neutrophils does not necessarily need to be under cut-off since the immune complexes are very small (much smaller than in RA and Lupus) but they are in higher quantity and are more systematic.

The reason this has not been fully identified before is because this is probably only a subset of ME/CFS patients so a pattern has been hard to identify in such a diverse group. Rheumatoid Factor is usually not tested unless their is a suspicion of RA and even then most clinical assays would not pick up the special affinity IgG/IgA part so that would go unnoticed. ME/CFS patients are then not checked for C3/C4 complement since the complement system has not been associated with the disease and doctors have very limited understanding of this complex process. And finally most doctors do not put full clinical weight into low neutrophils unless it is serious neutrophenia.

What strengthens this theory of mine is that complement activation is increased after physical exercise which directly correlates to PEM symptoms. This would also explain why we have unrefreshing sleep since this immune complex clearance is most active when there is no other disruption same as when RA patients wake up with swollen joints.

Am I on the right path here?
What are your thoughts?
Does anyone think they have a similar pathology?
Anyone with similar test results?

Questions and comments are highly appreciated.

Best regards,
Sveinn Benediktsson
 

ellie84

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I did blood tests for autoimmune diseases. Everything was in range, except C3 complement, which was slightly depleted. Then I repeated them after a while and C3 complement was in range again. Neutrophils in range. I haven't been assessed for CFS yet, but I'm pretty sure they would diagnose me with it.
 
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Thanks for the input ellie84. I actually think that with this illness lowered values but in range is enough to cause symptoms. Antibody to antibody immune complexes are probably the smallest particles that can circulate your bloodstream but they still need to be cleared out and when that happens the chemokines/cytocines singaling causes various systematic symptoms appear.
 
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  • Am I on the right path here?
    • I think so - I've mentioned this before in other threads - but I also think that ME/CFS is largely antibody-driven. Like you mentioned above - a really nasty virus or bacteria leads the body to create a bad antibody, which causes systemic downstream problems. ME/CFS shares a lot of symptoms in common with the autoimmune disease Primary Biliary Cholangitis - which is caused by an antibody specific to mitochondria. I'm also surprised to learn that we are continuing to discover new antibodies - I figured this would be a "solved" problem - but is actually a lot harder than it sounds.
    • Also on this point - antibody production is driven largely by Plasma B-Cells - which have lifespans of months to decades depending on the type of B-Cell. Drugs like Rituximab haven't worked since they cannot target long lived Plasma B-Cells which live in bone marrow - however the success stories may be from early ME/CFS patients who have immature B-cells producing these antibodies.
  • Anyone with similar test results?
    • My IgA, IgM, IgG, and WBC panels always come back completely healthy and in-range.
    • I don't think there is a feedback loop that would cause the unchecked creation of antibodies. I do think that the devil is in the details though - sure the total count of antibodies looks healthy, but what is the composition of those antibodies from a function perspective?
 

pattismith

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I agree with that the auto-immune hypothesis still looks a possible option in a subgroup, but then we should expect some succeed with corticoid therapy, shouldn't we?
 
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  • I think so - I've mentioned this before in other threads - but I also think that ME/CFS is largely antibody-driven. Like you mentioned above - a really nasty virus or bacteria leads the body to create a bad antibody, which causes systemic downstream problems. ME/CFS shares a lot of symptoms in common with the autoimmune disease Primary Biliary Cholangitis - which is caused by an antibody specific to mitochondria. I'm also surprised to learn that we are continuing to discover new antibodies - I figured this would be a "solved" problem - but is actually a lot harder than it sounds.
Thanks for pointing me to Primary Biliary Cholangitis. I agree there are definite similarities. The thing with traditional antibodies is that they will in almost all cases cause tissue injury and that is how they initially get detected. Majority of ME/CFS do not have any confirmed tissue injury so if this is to be an autoimmune disease the process has to be in blood or other bodily fluid like spinal fluid and be cleared there before it hits tissue.

It does not surprise me that we are still finding auto-antibodies. The possibilities are almost endless and unless we know were to look we will never find the right one. Tissue injury usually give the scientists the first hint just like when they first found spinal/brain in MS patients. Then they could make a biopsy and find the auto-antibody from there.


  • Also on this point - antibody production is driven largely by Plasma B-Cells - which have lifespans of months to decades depending on the type of B-Cell. Drugs like Rituximab haven't worked since they cannot target long lived Plasma B-Cells which live in bone marrow - however the success stories may be from early ME/CFS patients who have immature B-cells producing these antibodies.
This is also a very interesting point you mention here. Remember that in the Fluge/Mella Phase I/II studies the response rate was 6-9 months instead of the traditional 4-6 weeks as in RA. I suspect that is because the auto-antibodies in ME/CFS are of IgG type coming from B plasma cells in bone marrow and their lifespan is 9 months. Rituximab only depleted the peripheral B cells eventually stopping new auto-antibody creating B cells to mature and enter the bone marrow. This would at least explain the delayed response.

  • My IgA, IgM, IgG, and WBC panels always come back completely healthy and in-range.
  • I don't think there is a feedback loop that would cause the unchecked creation of antibodies. I do think that the devil is in the details though - sure the total count of antibodies looks healthy, but what is the composition of those antibodies from a function perspective?
My IgM/IgG/IgA levels have always been in range. Also my IgG subgroups. My WBC is completely normal including a full Cluster of Differentiation analysis (CD3,4,8, 16,19,56, etc) expect for low or lowered neutrophils. In my opinion low neurophils is always suspicious because they are doing the housework. The IgG/IgA that was abnormal was the special auto-antibody rheumatoid factor (RF) which is auto-anitbody towards your own antibodes. That relates to my explanation above that the whole auto-immune process in ME/CFS never leaves the fluid. That is also why it is so systematic. This is actually the feedback loop that is suspected in RA an explained by Jonathan Edwards as self perpetuation of autoreactive B cells:

self perpetuation.png
 
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I agree with that the auto-immune hypothesis still looks a possible option in a subgroup, but then we should expect some succeed with corticoid therapy, shouldn't we?
Well here is the big caveat since we are not taking about traditional inflamation of swelling, redness and tissue damage. That kind of inflamation would increase the numbers of neutrophils not decrease them. Cortisteriod therapy works wonders on that. This is more on a chemokine/cytokine signaling level that create the ME/CFS symptoms and steroids to have some but limited impact.

The former one comes in flares as actue state but the latter on is more constant and chronic. I believe that traditional inflamation is followed by an massive increase in IgM antibodies but the low grade one Im refering to is with IgG antibodies, something that the body is constantly doing and usually does not cause any issues.

I hope this explains my thought but I lack the detailed understanding and biology here but I would be great if anyone could explain the difference further.
 
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Well here is the big caveat since we are not taking about traditional inflamation of swelling, redness and tissue damage. That kind of inflamation would increase the numbers of neutrophils not decrease them. Cortisteriod therapy works wonders on that. This is more on a chemokine/cytokine signaling level that create the ME/CFS symptoms and steroids to have some but limited impact.

The former one comes in flares as actue state but the latter on is more constant and chronic. I believe that traditional inflamation is followed by an massive increase in IgM antibodies but the low grade one Im refering to is with IgG antibodies, something that the body is constantly doing and usually does not cause any issues.

I hope this explains my thought but I lack the detailed understanding and biology here but I would be great if anyone could explain the difference further.
Would IVIG help?
 

sometexan84

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You're sort of on the right path. It's autoimmune. But RF and others will still show up negative for many (like me).

It's definitely not as specific as what you're saying. We all have different conditions in this forum.

Test for a bunch of auto-antibodies that correspond w/ autoimmune conditions sharing your symptoms. You'll stumble on something.

What sucks is, like @ShepherdK said, they are actually still discovering new auto-antibodies.

Another thing to do is look for auto-antibodies tied to infections you have or have had.