Rituximab, the THRESHOLD theory

[Jenny]

Surely there would be no problem with copyright if the source was formally referenced, in the same way that a long quote from a publication should be referenced.

Jenny

 

[Andrew]

It depends on the copyright. For example, Hillary Johnson does not allow quotes without her permission, even if they are referenced.

 

[redo]

You're missing the whole point here. What I wrote was that the ME conference doesn't have the copyrights on it, since it's not their imagery (it's not "borrowed" from them, it from another source - and it's quite obvious if you take a close look at the image). The only people whom could claim copyright is Fluge/Mella, and I have strong reason to believe they wouldn't. I was asked by Snow Leopard of the source of it, but as I didn't want to reveal my contacts, I let it slip.

Not discussing the graph doesn't bother me. That's fine. No problem. What bothers me is the approach. The top down, "you're not worthy to even ask before moderating/notify after moderating" stuff. About discussing the theory in general (and that's a whole other issue), it might be that we shouldn't as it could easily slip into "this is what the authors have presented as fact" (and thereby moving it from theory into fact, obviously putting the authors in a awkward position). But again, that's another discussion.

 

[Levi]

Autoantibody "X"

Redo's intial thread premise:

Their theory is that when the Rituximab is given, it brings down the B-cells, but when that goes down, so does some other immune parameter of which they haven't identified yet. That doesn't mean that it isn't a known immune parameter, it means they don't know which it might be yet. That is displayed as "x" in the graph.

Autoantibody "X" = ACA's?
http://en.wikipedia.org/wiki/Cardiolipin
http://www.ncf-net.org/pdf/HokamaCardiolipinCFS2008.pdf
http://www.ncf-net.org/pdf/AnticardiolipinAntibodies.pdf
http://ajpcell.physiology.org/content/292/1/C33.full

Note that research indicates Rituximab therapy may be used to clear ACA's and allow successful pregnancy in women with APS/ACA's:
http://www.flimecfsforum.com/forum/index.php?f=35&t=511&p=846&rb_v=viewtopic#p846
Is there linkage from these various research angles?

Anyone got any guesses as to what it might be?

 

[ixchelkali]

I noticed in the video from Norway they mentioned that they believed the autoantibody target might be the sensory nerves. Do you recall if that was mentioned in the London presentation?

If there's an autoantibody, my guess for a target would be the hypothalamus. It controls, directly or indirectly, most of the functions that are disordered in ME/CFS, except for the immune system itself. And if you don't account for the immune dysfunction, you don't account for the persistant viral infections.

Maybe we should start a pool: is it autoimmune, and if so, what part of the immune system is involved and what cells are attacked?

 

[alex3619]

I am currently interested in the possibility that anticardiolipin antibodies are a red herring, or secondary. I suspect we get them for the same reason we get many of the cytokines - bacterial products in the blood. Bacteria make lots of cardiolipin, if LPS is getting into the blood then cardiolipin might be too, although I think bacteria deliberately shed LPS but cardiolipin would only be released from dying bacteria.

On the other hand if we develop antiobodies to bacterial cardiolipin, what impact will that have on us? It could well be damaging, but I am unsure. Are there cells in the body that have a lot of cardiolipin on the surface?

Bye
Alex

 

[richvank]

I am currently interested in the possibility that anticardiolipin antibodies are a red herring, or secondary. I suspect we get them for the same reason we get many of the cytokines - bacterial products in the blood. Bacteria make lots of cardiolipin, if LPS is getting into the blood then cardiolipin might be too, although I think bacteria deliberately shed LPS but cardiolipin would only be released from dying bacteria.

On the other hand if we develop antiobodies to bacterial cardiolipin, what impact will that have on us? It could well be damaging, but I am unsure. Are there cells in the body that have a lot of cardiolipin on the surface?

Bye
Alex

Hi, Alex.

In humans, cardiolipin is found in the inner mitochondrial membrane. The elevation of cardiolipin antibodies in ME/CFS may reflect mitochondrial dysfunction and early die-off of cells, with the immune system responding to the fragments. The antibody test developed by Dr. Hokama for ciguatoxin was found to cross-react with cardiolipin, and this may explain why he found a high rate of positives in PWMEs/PWCs.

Dr. Shoemaker reports that people with biotoxin illnesses also have elevated levels of anticardiolipin antibody.

Best regards,

Rich

 

[alex3619]

Hi, Alex.

In humans, cardiolipin is found in the inner mitochondrial membrane. The elevation of cardiolipin antibodies in ME/CFS may reflect mitochondrial dysfunction and early die-off of cells, with the immune system responding to the fragments. The antibody test developed by Dr. Hokama for ciguatoxin was found to cross-react with cardiolipin, and this may explain why he found a high rate of positives in PWMEs/PWCs.

Dr. Shoemaker reports that people with biotoxin illnesses also have elevated levels of anticardiolipin antibody.

Best regards,

Rich

Hi Rich, I am aware of mitochondrial cardiolipin, but how do antibodies cross both the cell membrane and mitochondrial membrane? It doesn't make sense to me. What might make sense is dying mitochondria might release cardiolipin to the cell membrane, and its the membrane that is attacked. Which is why I asked about cells that might contain a lot of cardiolipin - if any is displayed, the antibody does not have to cross multiple barriers.

However, something occurred to me as I was writing this. A high rate of cell loss in CFS and ME might release lots of cardiolipin, which might lead to cross reactivity if the fragments contain othe molecules. I also wonder how much cardiolipin is in macrophage membranes if they have absorbed dying cells.

Bye, Alex

 

[dsdmom]

Hi, Alex.

In humans, cardiolipin is found in the inner mitochondrial membrane. The elevation of cardiolipin antibodies in ME/CFS may reflect mitochondrial dysfunction and early die-off of cells, with the immune system responding to the fragments. The antibody test developed by Dr. Hokama for ciguatoxin was found to cross-react with cardiolipin, and this may explain why he found a high rate of positives in PWMEs/PWCs.

Dr. Shoemaker reports that people with biotoxin illnesses also have elevated levels of anticardiolipin antibody.

Best regards,

Rich

Rich,
Could you clarify something for me? Does your above post mean that you believe the paper from 2009 is incorrect? That's how I am reading your post and I'm just not sure if that is indeed what you mean.

Thanks!

 

[Levi]

Neoplastic disease Process?

For those needing to review the history of this ancient hypothesis look here:
http://www.ncf-net.org/forum/summer-vol13-1.htm

I find it interesting that the lastest and greatest research in ME/CFS is basically revisiting dated theories that have long ago been discarded by many. Is the concept that ME/CFS is related to a neoplastic disease process in any way supported by successful treatment with an anti-cancer drug? Just wondering.

Rich,
Could you clarify something for me? Does your above post mean that you believe the paper from 2009 is incorrect? That's how I am reading your post and I'm just not sure if that is indeed what you mean.

Thanks!

 

[Vitalic]

For those needing to review the history of this ancient hypothesis look here:
http://www.ncf-net.org/forum/summer-vol13-1.htm

I find it interesting that the lastest and greatest research in ME/CFS is basically revisiting dated theories that have long ago been discarded by many. Is the concept that ME/CFS is related to a neoplastic disease process in any way supported by successful treatment with an anti-cancer drug? Just wondering.

Is the fact it's an ancient hypothesis necessarily a negative feature? The idea of evolving species had been around long before Darwin developed his theory, sometimes it takes a new discovery or a new way of thinking applied to an old idea to make everything fit together. The concept of autoimmune involvement sounds very logical to me, I can't believe there are still people hanging onto the idea that there is one specific pathogen or group of pathogens causing this illness, XMRV should have been the last nail in the coffin for that line of enquiry.

 

[richvank]

Hi, Alex and dsdmom.

Alex: Yes, that's what I meant. The cell dies and comes apart, releasing its fragments to the blood plasma, and the immune cells have access to the fragments, including the cardiolipin, and raise antibodies to it. The antibodies don't have to cross membranes.

dsdmom: I'm not sure which paper from 2009 you are referring to. Do you mean one of Dr. Hokama's papers? He is the one who discovered the cross reactivity that I mentioned. His test was an antibody test, and apparently part of the ciguatoxin molecule looks like part of the cardiolipin molecule, so the the antibody test responds to both.

Best regards,

Rich

 

[Levi]

I don't recall saying that it WAS a negative feature. To the contrary, my guess is that the mystery of CFS has probably already been unraveled, and the answer to a biological cause is already well explained in some small initial study, periodical editorial, or even an internet thread somewhere. If there is a negative feature, it is that the abundance of these small starts, theories, and postulations are not followed up, never adequately funded or translated into a well powered strongly evidence based and scientifically rigorous work.

Perhaps if there were a small tax, say $1 per theory, that must be paid in order to chime in from the peanut gallery and discuss the cause of ME or CFS it might be better. Then, we would have a huge source of income for funding the dearly needed research that will be needed to actually get clarity for the biological causation of the illness.

Is the fact it's an ancient hypothesis necessarily a negative feature? The idea of evolving species had been around long before Darwin developed his theory, sometimes it takes a new discovery or a new way of thinking applied to an old idea to make everything fit together. The concept of autoimmune involvement sounds very logical to me, I can't believe there are still people hanging onto the idea that there is one specific pathogen or group of pathogens causing this illness, XMRV should have been the last nail in the coffin for that line of enquiry.

 

[Vitalic]

I don't recall saying that it WAS a negative feature. To the contrary, my guess is that the mystery of CFS has probably already been unraveled, and the answer to a biological cause is already well explained in some small initial study, periodical editorial, or even an internet thread somewhere. If there is a negative feature, it is that the abundance of these small starts, theories, and postulations are not followed up, never adequately funded or translated into a well powered strongly evidence based and scientifically rigorous work.

Perhaps if there were a small tax, say $1 per theory, that must be paid in order to chime in from the peanut gallery and discuss the cause of ME or CFS it might be better. Then, we would have a huge source of income for funding the dearly needed research that will be needed to actually get clarity for the biological causation of the illness.

Yes quite, I didn't mean to suggest that is what you implied, it was more of a reflection on some views that I read elsewhere (particularly Deckoff-Jones' blog). There is definitely a sense that some crucial work is being undervalued or missed amidst the profusion of different theories, hypotheses and speculations. That is why the Norwegian study is possibly the first thing I've felt positive about since I've been following the literature, because it has the capability to narrow down the scope of enquiry, even if it turns out that the drug itself is not a viable intervention at the very least it may help uncover the mechanisms involved.

 

[alex3619]

Hi, Alex and dsdmom.

Alex: Yes, that's what I meant. The cell dies and comes apart, releasing its fragments to the blood plasma, and the immune cells have access to the fragments, including the cardiolipin, and raise antibodies to it. The antibodies don't have to cross membranes.

dsdmom: I'm not sure which paper from 2009 you are referring to. Do you mean one of Dr. Hokama's papers? He is the one who discovered the cross reactivity that I mentioned. His test was an antibody test, and apparently part of the ciguatoxin molecule looks like part of the cardiolipin molecule, so the the antibody test responds to both.

Best regards,

Rich

Hi Rich, at face value your explanation would then mean that anticardiolipin antibodies wont cause damage - which was my point. They would then be a marker but not pathological. If you take into account that some cells might absorb the cardiolipin, and so it might be present in the cell membrane, then you have a basis for anticardiolipin antibody damage - in any and every cell type that can do this. I still do not see how ACAs can cross two membranes to attack mitochondria and then damage mitochondria. It can only cause cell death. This does not mean they can't cause mitochondrial damage, only that it is an hypothesis and not demonstrated at this point. It is far more likely to my current understanding that mitochondrial damage is caused by other factors, including cytokines and oxidative stress. These other processes may well be mediated by CD20 cells, which is why Rituximab appears to work. However, we are probably talking about a range of cytokines and regulatory molecules, I don't think its going to be simple. Also, this does not rule out that the antibody problem causing CFS and ME symptoms that has been hypothesized might be to some other target - I am only discussing anticardiolipin antibodies.

Bye
Alex

PS If their are dying mitochondria then cardiolipin may be absorbed by the cell making it a target for immune distruction. It occurs to me that if too many cells are being targeted, the body might well take measures to switch off NK cell function - or face imminent death.

 

[Levi]

Hi Alex,

Funny, I did not take that message away from Richvank's posts at all. Perhaps he will clarify. There is damage, and there is mitochondrial damage. They are not interchangable terms. If the immune system sees released cardiolipins in the bloodstream due to the damaged cell fragments Rich is speaking of, then it may mount an immune reaction that produces cytokines and chemokines. Which in turn can cause illness. And like you say it is probably not simply explained.

Hi Rich, at face value your explanation would then mean that anticardiolipin antibodies wont cause damage - which was my point.

Since elevated ACAs are found in other autoimmune diseases like Lupus (SLE), it is quite simple to establish that they cause damage, and this has been well-researched. an obvious target for ACA's is the human heart valve:

CONCLUSION:
The incidence of echocardiographic abnormalities is high in SLE patients, most often in valves and pericardium. The aCL is probably related to valvular damage in SLE patients.

http://www.ncbi.nlm.nih.gov/pubmed/17062932?dopt=Abstract
It is worthy of note that cardiac valve damage in ME/CFS has been well documented by a number of clinicians over the years. Again, a possible linkage that has not been adequately researched. I find it sad that research into the biological causation is so fragmented and incoherent.