A neuro-immune model of ME/CFS.

sIL-2R has now been rejected as a marker of autoimmunity. It is only a reflection of a chronically activated immune system.

 

Totally agree with Rich. To label it as an autoimmune condition doesn't make sense. Perhaps in a percentage of cases, but not overall.

 

It is the use of sIL-2R as a marker which I am rejecting. The model includes autoimmunity as a symptom which is not a condition and rather a consequence of the causal pathology.

 

I just realized that and will edit my earlier post.

 

I agree George -- very good to see that Gerwyn has broadened his acceptance of other possibilities besides just the retroviral model. He used to belittle anyone that dared question any aspect of that hypothesis.

Congrats to him and his coauthors for getting this paper written and published!

 

Feel free to send me the manuscript.

For starters, the abstract seems to indicate that what is called the initial infection is thought to have been cleared. I submit that it is not, and that if it were the mechanisms described in the model would collapse.

 

Hi Mula, a point I implied several times. It used to be considered an autoimmune marker due to its almost omnipresence in autoimmune disease, a point I have emphasized several times. Indeed, I have stated that the research has moved on from this. So this changes my argument not at all. Indeed I have already discussed it in the context of excessive T cell activation as one of the options. One of the other options that interests me is that sIL2r is only a surrogate marker for issues with tetrahydrobiopterin, though neopterin looks like a better marker. This ties right back into nitrosative and oxidative stress and I think methylation models. Bye, Alex

 

Hi Guido, there is ample evidence that the infections are not cleared, though clearly patients are not always viremic. In the case of Q fever for example, no detectable pathogen can be found - but they only look in the blood. In the case of herpes virus then clearance is not expected anyway. In the case of coxsackie virus the vast majority of patients have ample evidence of viral persistance in tissues, a finding that is also made with herpes family viruses. The issue seems to be that these pathogens are not in the blood. However, it is unclear if they are still capable of activity. In the case of herpes family viruses the latent viruses can still distort physiology. One thing Lerner has questioned is whether whole viruses are still present, or only persistent viral fragments. Even viral fragments could do damage as they would modify the immune response.

The classic model of autoimmunity has one or limited targets being substantively attacked - which means high antibody titres. In the case of CFS or ME it appears we have many targets with lower titres. Lower grade attacks on many targets will have more diffuse and more difficult to detect consequences, but there are still consequences.

The cause of the damage leading to autoantibodies being oxidative and nitrosative stress has reasonable evidence. This does not modify the issue with autoantibodies much. What it does tell us is that it is possible that ongoing oxidative and nitrosative stress are drivers of at least some symptoms, if not most - indeed I have elsewhere suggested that Rituximab and a protocol aimed at managing oxidative and nitrosative stress, plus treating inflammation, might be more effective and result in a higher cure rate. This might make Rituximab fully curative for responder patients.

What I have suggested in another thread is that there are two halves to the illness, and treating one without the other may only be minimally effective. One half is immune, the other is oxidative and nitrosative stress. I would be interested in seeing studies combining these two approaches, particularly using newer anti-B drugs - Rituximab is not the only one out there and very hard to find funding for.

With regard to the Morris&Maes paper, I am examing pieces of it one at a time in more depth. There are a number of interesting points worth more investigation.

Bye, Alex

 

Then why are many patients found to have no current infection? A model which does not map out a mechanistic explanation to explain this or the equally valid findings of various reactive viruses is not a model.

 

The percentage of patients with no tissue based infection is under 20% I think, and thats based on only one class of viruses, the coxsackie viruses. Fold in prevalence of all the others and it will probably push it to over 95%.Given the misdiagnosis rate, I think thats pretty good.

Active blood infections seem to be at a relatively low rate. I am not aware of anyone who has surveyed them all and reported the total prevalance rate for current infections, maybe the current Montoya Standford study will do that.

If you look at Herpes class viruses and discount children, the infection rate is probably clost to 100%. Everyone has them.

NO model currently available explains the persistence of viral fragments and unproliferating viruses such as coxsackie, though its possible that these viruses have a natural latent form. Herpes family viruses certainly do. There is some speculation about this but it is not sufficiently detailed to be called a model.

Bye, Alex

 

I found this paper that talks about the relationship between autoimmune disease and viruses where they suggest that Herpes viruses which are latent in the body may become active in the area affected by the auto immune disease (due to the attraction of large numbers of B cells to the area). They suggest that this might lead to a relapse - hence the value of treating autoimmune diseases with anti-virals. They refer to mouse experiments to support there hypothesis. I wondered if this would help in trying to understand possible autoimmune and localised viral activity?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065340/

I did post this in a separate thead:
http://forums.phoenixrising.me/index.php?threads/autoimmunity-anti-virals-and-herpes-viruses.18532/

 

Hi user9876, a feedback loop between viral infection and autoimmune disease as the link you posted suggests could be very interesting. I am currently reading the full paper:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065340/pdf/ar1691.pdf

I will write some more when I have finished.

Bye, Alex

This is a simplification, but here goes:

The paper refers to pathogens with a specific life cycle. They infect mucosa (eg mouth lining), further infect blood cells where they are dormant, and then finally infect mucosa again which makes the mucosa infective.

The dormant pathogens can replicate if they reach suitable tissues. Immunocompromised areas of the body, such as from an autoimmune attack are suitable sites for replication. When replicating they destroy more cells and release more cell components as targets which amplify the autoimmune response.

Effectively they have been able to show, in a limited sense, that an autoimmune disease causes increased virus replication. Details are lacking, this is primarily from empirical evidence, including mouse models.

What is interesting is the dormancy criteria. Dormancy is a normal part of the life cycle of these pathogens, and the pathogen list is very familiar to anyone with CFS or ME, including EBV and Coxsackie viruses. What that implies is there are cellular conditions in which the virus becomes latent naturally - something which we already know, but this paper shows that inflammatory reactions can induce virus replication. Again this is already known, but they showed that sites of autoimmune attack have a higher viral load.

The key implication for me is this: pathogen replication may be restricted to tissues with a high inflammatory response. An implication might be that we can use tissue virus load to imply inflammation, or inflammation might imply viral load in ME. This is a testable idea. Based on what we know of coxsackie virus, the implication is that gut mucosa might be a major site of inflammation in ME and CFS - which is not a surprise.

A further implication is this: the pathogen travels inside blood cells. It does not require high viral titres in the blood. It only releases the pathogen at specific locations.

Since such inflammation increases an autoimmune response, I wonder if this could amplify an autoimmune attack on the gut, causing increased LPS translocation, creating more inflammation, and hence more virus replication. So the cycle continues.

They are looking at combining immune modulation drugs (typically suppression) with antiviral and antimicrobial agents. To that I would probably add antiinflammatory agents.

Bye, Alex

 

Thanks Alex I think you have got more out of the paper than me. I don't have a biological background so I find myself guessing details. There seems to have been a lot of talk of viruses and autoimmune disease as competing theories so I've been trying to read around a bit. I've also been reading papers around Rituximab with various auto immune diseases since this seems to fit in somewhere.

 

Hi use9876, the cool thing about the paper is it covers both bacteria and viruses. What they have in common is their lifecycle. This could be an answer to a big question - why so many pathogens seem to be able to cause ME or CFS. Bye, Alex

 

Alex, this is a really interesting argument on dormancy and recurrence in particular tissues leading on to more infection. (I think that's what you're saying.) On the behavioural side, my husband and I have been trying very hard to control our activity levels so as to do as much as we can but not enough to bring on a setback. Perhaps your explanation is looking under the surface to show what may be happening when a setback occurs—which demonstrates how important it is to avoid setbacks whenever possible!
Cheers, Lynne