anne_likes_red
Senior Member
- Messages
- 1,103
The talk is here now:
Agreed with the above comments - this was really interesting.
Agreed with the above comments - this was really interesting.
Webinar with Dr. Alan Light on Novel Gene Variants in ME/CFS and Fibromyalgia
- Thread starter RL_sparky
- Start date
A.B.
Senior Member
- Messages
- 3,780
Would this result in children born to mothers (but not fathers) with ME/CFS having a very noticably increased chance of having ME/CFS themselves later in life?
Seems to be true in my family at least.
Seems to be true in my family at least.
It might come down to how the testing is being done, and where the sample is coming from in the body. The concept is called heteroplasmy, which means that different cells in the body can end up with different mitochondrial mutations.
Mitochondrial DNA is not inherited in the same manner as chromosomal DNA. You don't get one copy which pretty accurately replicates itself and ends up everywhere throughout the body. Instead, approximately 200,000 maternal mitochondria are in an egg cell, and bits end up in various cells of the embryo.
If the maternal mitochondria feature some mutations, different embryonic cells can end up with a different prevalence of that mutation, and often none of it at all. Mutations can largely get filtered out at the embryonic stage, as cells with too much of a mutation load die off, and the healthier cells flourish and replicate their non-mutated mitochondrial DNA.
The term for this process is the mitochondrial bottleneck. The result is that destructive mutations get largely filtered out with each new generation. This is why some mitochondrial mutations may be relatively common (usually still under 1% prevalence rate in the general population) while leaving most carriers unaffected, or with a mild case of one or two symptoms.
But the cells with the mutated mitochondrial DNA can also replicate. Then when there's enough of the mutant version in a particular type of cells, symptoms develop. Depending on how well the mutation was filtered out by the mitochondrial bottleneck, it might just be one part of the body affected: the eyes, hearing, the brain, the heart, the muscles, etc. Or a combination of systems, or pretty much everything. This is also how mitochondrial diseases often do not clearly manifest until adulthood, as it might take time for a mutation to take over part of the body.
On a more personal note, I have a pathogenic mutation on MT-ND1, one of the mitochondrial genes mentioned in the slides. It's a gene which has been identified as causing various mitochondrial disorders, including MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes). Maybe I have other mutations too - 23andMe doesn't test for some of the most common pathogenic ones.
I developed diabetes recently, which is somewhat common in mitochondrial diseases, and the usual drug for it caused me the listed (but very rare) side-effects associated with lactic acidosis. Those symptoms were indistinguishable from the muscle pain, muscle weakness, headache, and muscle burn I get from ME, aside from the onset not being triggered by activity, and the scary-fast fashion in which those symptoms intensified.
Accordingly, I would not be the least bit surprised if genetic mitochondrial disease (primarily MELAS) forms at least one large subset of the patients diagnosed with ME, especially the ones who have had stroke-like episodes. And I would be very surprised if the metabolic mechanism behind other cases of ME is much different.
voner
Senior Member
- Messages
- 592
@Jonathan Edwards, you have any comments?
BurnA
Senior Member
- Messages
- 2,087
I can imagine what he thinks about the molecular mimicry bit.
- Messages
- 12
- Location
- BC
How does this tie into these two recent gene studies?
Dr. D. Patrick RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease. Clin Infect Dis 2017 ciw767. doi: 10.1093/cid/ciw767
Australia. Kinase gene discoveries - The paper by Chack, Staines, Johnston and Marshall-Gradisnik, Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients, was published in Gene Regulation and Systems Biology, July 2016. (The authors refer to CFS/ME in the paper but the criteria they use, ICC, “recommends that only the name ‘myalgic encephalomyelitis’ be used to identify patients meeting the ICC because a distinctive disease entity should have one name. Those who fulfill the criteria have ME; those who do not would remain in the more encompassing CFS classification.”)
Dr. D. Patrick RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease. Clin Infect Dis 2017 ciw767. doi: 10.1093/cid/ciw767
Australia. Kinase gene discoveries - The paper by Chack, Staines, Johnston and Marshall-Gradisnik, Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients, was published in Gene Regulation and Systems Biology, July 2016. (The authors refer to CFS/ME in the paper but the criteria they use, ICC, “recommends that only the name ‘myalgic encephalomyelitis’ be used to identify patients meeting the ICC because a distinctive disease entity should have one name. Those who fulfill the criteria have ME; those who do not would remain in the more encompassing CFS classification.”)
Forbin
Senior Member
- Messages
- 966
I may have this wrong, but...
Fluge and Mella have hypothesized that there is some as yet unknown factor in the blood (possibly an antibody) that drives ME. Dr. Davis also mentioned at the Florida conference that he also thinks "it's in the blood." Whatever this is, my impression is that they think it is affecting the mitochondria.
I suppose it is possible that there is also something different about the mitochondria in ME patients that makes them susceptible to whatever it is that's in the blood. In other words, your mitochondria might have to be genetically susceptible and you'd have to have some other process creating this unknown factor in the blood. Just my guess, at the moment.
Last edited:
Kati
Patient in training
- Messages
- 5,497
Hi @Sharon Van Isle one thing I notice from Dr Patrick's study is he sequenced RNA from whole blood, and Dr Light looked specifically into white cells (immune cells)- so for that reason, the results might have been different. I would like to hear from researchers whether it makes a difference or not.
The results from Dr Patrick's team are disconcerting and concerning as this is the second negative paper in a row.
Last edited:
Though I do not have the scientific knowledge to comment authoritatively here (wish I had!), I imagine these different areas of research could end up helping to fill various gaps in the same puzzle. They are all working tirelessly to find the answers, and when they get there it may well be a composite of their respective efforts. Especially as ME/CFS likely is more than just a single underlying condition.
nandixon
Senior Member
- Messages
- 1,092
Last edited:
Jonathan Edwards
"Gibberish"
- Messages
- 5,256
I am afraid it does not make a lot of sense in terms of immunology as I understand it. There seems to be a lot of speculation based on tenuously linked ideas and not a lot of data. I do not see how a problem with mitochondria gives you autoimmunity. My understanding is that autoimmunity occurs at random and certainly an autoantibody could lead to mitochondrial dysfunction (i.e. the other way around).
People seem to be reporting research in very confusing ways - so that patients get confused between genetics and gene expression etc. RNA in blood is pretty much the same as RNA in white cells, since only the white cells in blood make RNA. Immune cells in blood tend not to be doing much so I don't think RNA in blood would tell you anything about autoimmunity.
M Paine
Senior Member
- Messages
- 341
- Location
- Auckland, New Zealand
@Jonathan Edwards, is it your view that persistent or prolonged activation of the innate immune system via mitochondrial pathways would not increase the likelihood of randomly acquired auto-immunity?
Jonathan Edwards
"Gibberish"
- Messages
- 5,256
I think so. Autoimmunity involves a failure in a specific feedback signal loop for a single antigen. There is no evidence for innate system activation making that more likely to happen and there is no reason why it should. The errors that allow loops to develop are, as far as I can see, random immunoglobulin gene mutations and the frequency of these is not changed by any stimulus - mutation occurs on a regular daily basis whether or not there is any challenge from a microbe or a stress in the innate system.
In popular immunological mythology triggers are almost always invoked but this seems to be simply because people do not understand the sort of dynamics described by chaos theory. The people who do have an interest in this in ME/CFS are Broderick and Craddock, with their systems modelling.
Sing
Senior Member
- Messages
- 1,784
- Location
- New England
To clarify my understanding, is your meaning that Broderick and Craddock do understand the sort of dynamics described by chaos theory? What have they found so far?
M Paine
Senior Member
- Messages
- 341
- Location
- Auckland, New Zealand
Would it not be true that if a person was undergoing prolonged innate immune activation, that could lead to them producing more new antibodies? The chance of creating new auto-immune antibodies would increase purely because they are creating more new antibodies?
Jonathan Edwards
"Gibberish"
- Messages
- 5,256
Yes, they understand. I am not sure they have 'found' anything so far but they are taking a sophisticated approach to problems.
Jonathan Edwards
"Gibberish"
- Messages
- 5,256
No, the number of antibody species you produce is as far as I know constant. Your bone marrow produces about a billion new B cells a day and each has a different antibody. There is no need for the rate of production of different antibodies to change when you meet an infection or stimulus to the innate system. This is the central point about B cell diversity working by selection, not instruction. Unfortunately, 90% of immunologists do not understand the mathematical basis for this so we get these theories about 'triggers' for autoimmunity.
M Paine
Senior Member
- Messages
- 341
- Location
- Auckland, New Zealand
@Jonathan Edwards Even thought the amount of recombination, and proliferating naive B-cells may be constant, that's aside the point. The question is, if more B-cells are activated, does not then the random occurrence of auto-immunity become increased purely by nature of immunology's dirty little secret working it's magic?