Discussion in 'General ME/CFS News' started by Sasha, Aug 31, 2014.
Yes, that would be more precise!
and this thread looks at what happens when microglia are overactive, and mentions gamma-interferon.
Thanks @MeSci for posting the thread. I'd missed it, don't know why would I .
After reading it I just realized that I'm currently taking 3 meds that might work on microglia activation with no abatement of my clear ongoing brain symptoms!!!
FYI the meds are VGC, LDN and PEA.
We'll keep on looking and trying ...
Yes. I talked to Hugh Perry at the CMRC and we were both interested in the idea of Fc receptors picking up low affinity antibody in the context of microglia. What I have not seen so far though is a focus on CD64/FcR1. It would seem to me to make sense because of the link to gamma interferon. I need to look more at the literature but it looks to me as if CD64 and gamma interferon may be used to set up a mutual positive feedback loop in early infection. Originally it was thought that just T cells made gamma interferon but there aren't many T cell sin brain so local gamma interferon ought to come from the microglia themselves.
Positive feedback loops in immune responses might sound illogical and dangerous - because they could lead to an explosive chain reaction. But there is no doubt B cells use such loops and so probably do phagocytes. It may be a good way of 'focusing' responses to injury - effectively one cell that finds some danger can say to others nearby 'hey wake up and come over here, there's something fishy going on'.
Another molecule that gets switched on by both CD64 binding and gamma interferon is TRIM21, which is part of the Ro complex that is the target in Sjögren's syndrome - which of course comes with severe fatigue. TRIM21 itself binds antibody and takes it into cells. Of course there are so many of these molecules and they do so many things that all this may be coincidence, but it might make some sense.
And of course positive feedback loops are just thing for making short term responses keep going if there is some shift in control thresholds.
Sjogren's does seem to have an interesting disease course and symptom list according to this review :
I'm dubious about 'viral onset' but this hypothesis caught my eye (bold added) :
PS - They discuss why they consider the mouse model valid. More detail than you may need :
Transcriptome Analysis of the Interferon-Signature Defining the Autoimmune Process of Sjögren’s Syndrome
Interesting, Marco. As you say there may be more on the model than we need. It is odd that the anti-Ro antibody response that is the hallmark of human primary SjS does not seem even to be mentioned. In part they are giving the usual two step genes-environment (i.e. virus) analysis that I think needs leaving behind us. But it is interesting that interferons do seem to figure so strongly. They even mention the TRIM proteins in passing as characteristic of the IFN signature.
What are VGC and PEA? (Can I just eat peas that are in very good condition? )
I think @Marco must have shares in the lab mouse industry...
I'm assuming that they are referring to non-retroviral RNA viruses that the wiki page states can be anything from influenza viruses to Ebola. I think we can safely rule out Ebola for now. If this interferon pathway is usually activated in response to a viral infection then it may lend some credence to 'viral onset', as previously discussed' - 'nudging' a pre-existing autoimmune process and 'unmasking' it.
One remaining concern I have is the Dubbo studies which if remember correctly had comparatively high rates (something like 10% reducing to 5% in time?) of 'CFS' following virus exposure which seem to me to be too high for a specific autoimmune mechanism?
Anyway It would be hypocritical of me to object when our three cats are systematically trashing the local rodent population on daily basis.
but are they doing it scientifically?
I don't know but they're bloody good at it!
So are mine. But I have noticed that, whilst from a combination of instinct and experience they have learned that chasing, catching, torturing, killing and eating mice is great fun, they don't generally try to extrapolate this to humans. If they try biting or clawing humans they soon learn that there are crucial differences between different species, so that they mustn't assume that what applies to one species is likely to apply to another.
In this they could perhaps be said to be more scientific than humans!
Yes I agree about the nudging. I don't want to give the impression that environmental triggers are not involved, particularly for ME. It is more that I think people miss the fact that the meat of the explanation lies in the unpredictably metastable nature of the regulatory mechanism that goes awry. I guess this is in a sense chaos theory and the existence of 'basins of attraction' away from the 'ground state' or whatever. Knowing how to beat the disease is likely to depend on understanding the metastability, not the viruses.
I guess the question is whether the post viral fatigue up to one year in Dubbo is even 'CFS' let alone ME or whether this is just how long it takes for a normal system to re-equilibrate if you kick it for six. I remember my six months post EBV fatigue as being unthreatening. For three months I was just glad to be able to walk about rather than lie in bed in a delirium, unable to even swallow my own saliva. And when I found at six months that I still could not go swimming or canoeing like the others, I just had a sense of frustration at how long it was taking to get well. Real ME seems to be slipping into a new attractor basin from which getting out is not just rolling back to the stable state.
And even if the distinction is blurred I am hesitant to lay down rules for autoimmunity prevalence. Anti-thyroid antibodies certainly occur in 10% of the population, even if most of them are healthy. I suspect autoimmune processes follow the rule that if they are moderately disabling the gene pool will tolerate the risk at a bit below 1%, like RA. If they are potentially fatal in young adults like lupus, they are only tolerated below 0.1%. Forms of ME might feed off antibodies that are in fact present in 25% of the population or even everybody, but as long as they do not push microglia into a new persistent attractor basin in more than 0.5% of people they are tolerated by the gene pool.
Could you clarify what you mean by tolerance by the gene pool? It sounds as though you are talking about evolution by natural selection, but modern humans have stopped evolving that way, haven't we? Are you referring to our past evolution?
There are a couple of studies where adolescents have been followed post infection (EBV or mono or are they the same thing?). I don't know if they are useful in understanding potential differences.
This one looks at cytokine levels over time and reports a gradual decrease in 'cfs'
The second one was lighter weight (I thing and only for 6 months):
Yes, evolution by natural selection. I don't think humans have stopped evolving. As far as I know Scandinavian blonde hair and fair skin is only 10,000 years old. And in terms of constant selection pressure against unfavourable gene forms that must still go on all the time. It may be evolution to stand still but it is still natural selection. I think we forget that this goes on all the time still. About 90% of native Caribbeans died out when smallpox was taken across the Atlantic. Amazon tribes are still being wiped out by visits from foreigners with 'flu' even today. Many women in south America with a European and a native American parent living at altitude have died in pregnancy because of a combination of genes suited to different environments.
I will stick to infection and I do not say it is a "classic" virus.
I think that natural selection is alive and well and that we can see it with ME. There are plenty of PWME here struck down before they had a chance to have kids.
I think that, barring a few exceptions such as those you cite, human evolution by natural selection has slowed greatly due to advances in medicine (e.g. keeping neonates alive who would previously have died), contraception, etc. Broadly speaking, if people live long enough to reproduce it doesn't matter in an evolutionary sense if they die at an age that we would now consider premature (e.g. 30 or 40), does it?
I suppose that there is still natural selection in utero and at the moment of, and stages leading to, conception though.
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