• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Interesting study of mono/glandular fever that could be relevant to ME

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Re Dubbo


I agree that is a strong reason to say the Dubbo conclusion is not enough. We keep looking for evidence for immune changes in ME and it is still unclear that we have anything reliably reproducible, so I feel one cannot discount a sensitisation 'loop' within the brain as being all there is remaining long term in some people. And people with bipolar disorder presumably have brain loops and they have relapses and remissions. But ME does seem to need other factors in explanation - as you say for the pattern of crashes and some of the specific symptomatology. An ongoing fluctuating immunological drive of the sort we see in autoimmunity would fit very nicely. I guess I am just an ultra-sceptic even about the ideas I am keen on.

Interesting that you mention bipolar as an analogy. I actually don't recognise a relapsing/remitting nature. Yes I have crashes in response to overexertion but every day is pretty much the same but with a number of step changes in additional symptoms/loss of function over the decades. Relapsing/remitting to me suggests something along the lines of MS where phases span weeks or months which easily fits an autoimmune model.

I'm a bit rusty on the details but I seem to recall that bipolar disorder can vary temporally. Some have alternating manic/depressed phases over weeks while some 'fast cyclers' can flip from one phase to another in a matter of minutes.

Until recent years, two or three times a year I would have strange periods lasting from a few hours to half a day where I would suddenly feel pretty much 100% well which of course was recipe for doing normal things and crashing again back to the usual steady state.

A brain loop could easily accommodate that sort of rapid cycling but could a direct autoimmune process?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
What do you think of the gastrointestinal symptoms that are common in ME/CFS? Do you agree that the gut is a good place to look for interesting abnormalities?

I have been thinking that monitoring of GI function, such as motility for instance, might be a useful way of showing alteration in autonomic function that was not confounded by 'de-conditioning' or under 'voluntary' influence. Gut used to be a bit difficult to study, being hidden away, but there are now all sorts of methods for looking at it.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
A brain loop could easily accommodate that sort of rapid cycling but could a direct autoimmune process?

No. I think that is also a key argument. But if the autoimmune aspect was feeding in to brainstem mechanisms the way a norovirus response can you can get flipping from fever to nausea to gut pain to back to fever and so on with transitions in the space of minutes. When the brainstem feels it is time to make a point it can turn the world upside down very fast even if the stimulus remains pretty constant. What I cannot quite get my head around is how you work out how to tie all the bits of mechanism together to explain crash timescale.
 

lansbergen

Senior Member
Messages
2,512
I have been thinking that monitoring of GI function, such as motility for instance,

During flares there is constipation but I am not convinced it is low motility. I think it is related to dry mucosa. At the end of flare liquid production increases and when the bout of diraree occurs flare is over. Before the diaree the stomach fills so fast it causes projectile vomiting
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
So, this is the right question, because I did not get what I said quite right. The random events are unlikely to change much. What seems more plausible is that a cytokine bath will overcome some threshold that is just about keeping the veto to anti-self in place. Allow a bit more leeway and the random event catches a loop.

This is actually what I was suggesting in my previous post. When I was taking about less specific risk factors, I was referring to more than just the antibody feedback loop itself, it is the also the veto events which can be altered by environmental or genetic factors. EBV has been speculated as a virus that can interfere with those veto events.

I'm trying to think of it from a signaling point of view, eg a signal with a carrier frequency and harmonic, along with other biological events that will add other components to that signal until it overcomes a threshold and shifts into an altered state of regulation (eg a positive feedback loop). This is also why measuring a single blood test number can be misleading - the important part is the regulation over time.

I also find it interesting to consider is the kinetics of the shift of antibody affinity as mature B-cells are released from the germinal centre over time and the role this plays in relapse-remitting conditions.
 

Jon_Tradicionali

Alone & Wandering
Messages
291
Location
Zogor-Ndreaj, Shkodër, Albania
I became ill between ages 4-6 with a flu like virus and never recovered. Therefore, I'm very sceptical of it being EBV. BUT, it is VERY LIKELY that any virus, regardless of it being EBV, HSV or even Influenza A can provoke a chronic response. As another user said above me, a virus/bacteria super infection is a likely scenario. Also, superinfections equals decreased antibodies to the virus and and decreased detection of the virus in superinfected cells (possibly explains why viruses in PWCFS are detected inconsistently).

A quick PubMed search will give you plenty to wrap your mind around.

Oropharyngeal group A streptococcal colonization disrupts latent EBV infection

http://www.ncbi.nlm.nih.gov/m/pubmed/23935199/?i=36&from=strep co infection

Epigenetic dysregulation of EBV latency and development of autoimmune disease

(Last paragraph is of special mention as it details how molecular mimicry triggers a pathogenic process)

http://www.ncbi.nlm.nih.gov/m/pubmed/21627044/?i=2&from=/18432410/related

Immunopathogenesis of chronic inflammatory diseases of the pharynx].

"It was shown that the efficacy of the effector protective factors of the immune system was insufficient to suppress the persistent EBV infection combined with staphylococcal or streptococcal infections."


http://www.ncbi.nlm.nih.gov/m/pubmed/23268242/?i=4&from=strep herpes
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Which aspect(s) of the timescale are the issue?

The total pattern of response over many hours followed by persistence of effect for much longer periods. It is not so much that I cannot think of explanations as that I cannot work out how you would argue the case for one rather than another with so many variables to play with.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
Until recent years, two or three times a year I would have strange periods lasting from a few hours to half a day where I would suddenly feel pretty much 100% well which of course was recipe for doing normal things and crashing again back to the usual steady state.

This is interesting, as I don't think I'd ever have described feeling 100% well and that includes the periods of 'remission' during the first 2 or so years when my condition was frequently relapse/remitting. During remissions, I'd say maybe 85%, but I still didn't have quite the same amount of energy when cycling etc.

These days I'm always in pain, it is just a matter of severity. I've had a constant headache for almost 14 years now.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
The total pattern of response over many hours followed by persistence of effect for much longer periods. It is not so much that I cannot think of explanations as that I cannot work out how you would argue the case for one rather than another with so many variables to play with.

Too many possibilities is the problem generally and its a pity it wasn't possible to start eliminating various possibilities as less likely. Or to propose a mechanism, test it to destruction and start again. Unfortunately as you say there are probably too many variables and not enough data to have a meaningful stab at it using either approach.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
This is interesting, as I don't think I'd ever have described feeling 100% well and that includes the periods of 'remission' during the first 2 or so years when my condition was frequently relapse/remitting. During remissions, I'd say maybe 85%, but I still didn't have quite the same amount of energy when cycling etc.

I'm probably speaking relatively as I'm pretty sure cycling would have been out of the question. Yet subjectively that's how it felt. Every day I feel 'unwell' 100% of the time. During these short periods of 'remission' the unwell feeling was gone.
 

lansbergen

Senior Member
Messages
2,512
In the early years just out of the blue I could feel very well for a short time. At those occasions there was an inner drive to overdo. I tried to do all the overdue chores at once.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
That might seem strange until you realise that a random internal event followed by a perpetuating process is entirely reasonable as a basis for immune diseases. It is of course the main mechanism in cancer - a random mutation leads to a failure of control of cell growth. The immune response is interesting in that it is the one system in the body that uses a random internal mutation followed by a change in regulatory signals to do its daily work. All antibodies are initially generated at random and are produced in significant amounts if they engage a new positive feedback loop.

I should know this, as I studied it, but it was a while ago and I am getting a lot of brain fog at the moment.

But what kind of mutations are we talking about here? Are they changes in the sequences of base pairs or the epigenetic type (esp. methylation) which govern expression?

My fog is such that I'm not even sure I got the question right!
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
During flares there is constipation but I am not convinced it is low motility. I think it is related to dry mucosa. At the end of flare liquid production increases and when the bout of diraree occurs flare is over. Before the diaree the stomach fills so fast it causes projectile vomiting

I don't get that at all. I have looser bowels and greater frequency when I am more ill, often with nausea as well. Constipation sometimes occurs when I am feeling better and can be corrected by eating more fruit.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I should know this, as I studied it, but it was a while ago and I am getting a lot of brain fog at the moment.

But what kind of mutations are we talking about here? Are they changes in the sequences of base pairs or the epigenetic type (esp. methylation) which govern expression?

My fog is such that I'm not even sure I got the question right!

The first sort of mutation is a translocation of various genes that encode parts of the antibody molecule. Each pro-B cell starts with a large set of alternative genes for the heavy chains of IgM, IgG, IgA etc and two alternatives for the light chain called kappa and lambda. When the B cell starts to mature it translocates these genes - i.e. shuffles them around in the chromosome by cutting bits out and pasting them somewhere else until it has a randomly selected single set of heavy and light chain genes stitched together in such a way that the cell can only make anantibody with those randomly chosen alternatives. The mechanism is even more complex because the heavy chain is built up from V, D and J gene segments if I remember rightly. Some segments have up to 50 alternatives to choose from.

At this stage there are no swaps in individual base pairs in the expressed sequences but bits are chopped out. Although this translocation mechanism is entirely normal and physiological for Ig genes it is uncannily similar to what happens in a number of cancers and we now know it is performed using an enzyme called AID that is probably also responsible for the translocations that cause lymphomas. The common principle for both normal Ig translocation and cancer is that pieces of transcribed sequence are moved into relation with a promoter sequence that gives the command to produce protein. In some cancers it looks as if a promoter that is permanently 'on' gets stitched on to a growth factor receptor gene so the cell is programmed to keep growing.

The second random step for B cells is when they undergo affinity maturation in germinal centres. At this point individual bases are swapped for new ones so that a new amino acid is encoded, or extra copies of base triplets are inserted adding more amino acids. So all these mechanisms are at nucleotide base level, not methylation. The detailed mechanism was worked out by Michael Neuberger. The AID enzyme is used to 'shoot a hole' in the DNA with instructions to repair 'however you like'. This produces an almost completely random change.

The usual assumption os that in a germinal centre Ig gene mutations simply randomly compete for 'higher affinity' for a given antigen. However, it is of course possible for a single base pair change to create an antibody with a completely new binding capacity to an unrelated antigen. There must be 'border check points' to ensure every time a B cell goes in or out of a germinal centre the anti-self veto is re-imposed. But just as in computer malware there will always be a small possibility of producing an antibody that can cheat the check point. That is how I think autoimmunity occurs - but exactly when in the above story it occurs is hard to say.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Could that be the magnesium? I do not take that

I don't take a lot of magnesium, only as part of a multi-mineral supplement. I have had the diarrhoeal type of IBS on and off for decades - long before taking supplements or getting ME.
 

msf

Senior Member
Messages
3,650
Prof. Edwards, I just read about a theory of Crohn's Disease in which the 'net pro-inflammatory cytokine status' leads to a propensity to develop the disease...could a similar mechanism be at work in ME, and could such a mechanism involve positive feedback?
 
Messages
3,263
This is a very good point which I had forgotten about. It would be very easy to diagnose a 'mono' illness as EBV infection on the basis of IgG antibody or a wishful thinking +ve Monospot. I guess nobody looks for virus itself as a routine.
There was at least one study of MS that used a military sample (of hundreds) and was able to link the onset of IM to a change from EBV seronegativity to seropositivitiy. I know its not ME, but it is relevant to the argument in general. I'll try to dig it out.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Prof. Edwards, I just read about a theory of Crohn's Disease in which the 'net pro-inflammatory cytokine status' leads to a propensity to develop the disease...could a similar mechanism be at work in ME, and could such a mechanism involve positive feedback?

I am not sure what a net pro-inflammatory cytokine status would be as a propensity. A net cytokine status sounds like the result of some propensity, rather than a propensity. This does not sound like a scientific concept. If I remember rightly part of the propensity to Crohn's is a gene variant involved in certain innate immune response mechanisms. That might lead to increased levels of certain cytokines. But I am unclear what 'net' is supposed to mean. It sounds like the old idea of 'cytokine balance' which I have never thought very meaningful.