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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
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