Can the autoimmunity hypothesis explain the sporadic nature of ME symptoms?

[msf]

I have been thinking about this a lot recently, particularly when I notice my own symptoms waxing and waning. I guess the infective hypothesis would suggest that this is due (at least in part) to the dynamic interplay of infection and immune system - is there a similar or analogous autoimmune process that could explain why symptoms are better some days and worse other days?

I know that RA patients have flares but from a quick google there doesn't seem to an accepted explanation for what triggers them, apart from the usual suspects: infections and stress. What I would like to know is if there is some internal mechanism that could potentially explain flares. I have noticed that my ME flares do not seem to correspond to either infections (new ones that is) or stress, but rather to changes in my gut and diet. Are there any examples of autoimmunity being primarily gut-driven (I know this has been proposed for Reactive Arthritis) and if this was the case, would the autoimmune response to changes in the gut be expected to be a rapid one, and would this flare be expected to last for long after the gut returned to the prior state?

 

[A.B.]

@msf, do you find that several times a year there is a worsening of symptoms, lasting a few weeks to several months, with no apparent reason, and which coincidentally starts shortly after eating something, again with no apparent pattern in regards to the food?

 

[Bob]

I think a lot of ME patients have some sort of association between gut issues and their ME symptoms. I've come across a few hypothesis including: leaky gut; gut lining infection (enterovirus); gut flora dysbiosis; vagus nerve infection. And I might have forgotten some.

 

[msf]

A.B. I had longer flares last year, but these may have also have influenced by the weather. This year, after moving to a sunny country (Spain) and finding a diet that works for me (Fodmap) my flares only last for a few days. The rest of the time I only have the sleep disruption and the lactic acid feeling.

 

[msf]

Bob, I think Maes has already suggested a link between leaky gut and autoimmunity in ME, but what I find hard to get my head around is how this could cause flares, rather than an ongoing immune process - I guess another way to phrase my question would be, how responsive are autoimmune processes to outside stimuli?

 

[Bob]

@msf, interesting questions. I've wondered about the sudden nature of relapses as well, and how these might come about if autoimmunity is the cause of the illness. But gut symptoms could be caused by internal stimuli rather than external stimuli. Or, at least, there might be an external trigger but subsequent internal maintaining/perpetuating processes. If some cellular molecule is released as a result of an external stimuli, then that cellular molecule may trigger a chain reaction when it interacts with autoantigens. The chain reaction may take a long time to subside. But I'm coming from an academically uninformed place here, so this is guesswork.

 

[msf]

Me too. The Maes hypothesis would seem to be: increase in leaky gut=increase in bacterial translocation=increase in autoantibodies to the nitrosative and oxidative products of the interaction of the bacteria with the immune system. I hadn't considered the possibility that there might be antibodies already circulating, 'waiting,' if you like, for these products to be made. This model seems kind of back to front for me though, but then I know very little about the immune system.

 

[duncan]

Many compare ME to MS. We are all familiar with the MS lite nickname.

MS has RRMS: relapsing-remitting MS, where they speak of flare-ups or fluctuating neurological exacerbations.

Perhaps ME fits this model.

 

[msf]

It seems there is some argument about whether MS is a proper autoimmune disease though: .hindawi.com/journals/ad/2012/969657/

 

[Bob]

I hadn't considered the possibility that there might be antibodies already circulating, 'waiting,' if you like, for these products to be made. This model seems kind of back to front for me though, but then I know very little about the immune system.

To explain a sudden relapse, it seems to me that either the autoantibodies have to be 'waiting' for some metabolic molecule to be released for a chain reaction to start, or there is a sudden and devastating surge of auto-antibodies being produced as a result of a stimuli. I don't know enough about autoimmunity to know if either is a plausible hypothesis, or has been already been observed in auto-immune patients. I suppose it seems feasible for the immune system to release a sudden surge of auto-antibodies, because a sudden release of appropriate antibodies would be needed in response to an infection. I think I've read that there is a delay before appropriate antibodies are released in response to an infection, because the immune system takes a while to recognise the pathogen and to prime the immune cells. So perhaps that might explain the delayed response seen in PEM, if the autoimmune process is the same as the immune process, and responds to stimuli? But I'm getting precariously out of my depth here!

 

[msf]

I hadn't thought about the delayed-PEM angle. I'm really out of my depth too, but I'm hoping that by floundering around I will attract the attention of someone who knows about these things...

 

[Bob]

I hadn't thought about the delayed-PEM angle. I'm really out of my depth too, but I'm hoping that by floundering around I will attract the attention of someone who knows about these things...

Well, it's nice to flounder around, out of our depth, together! I hope we can find a life boat, with some flares and some provisions.

 

[MeSci]

I'm very interested in this thread but don't have time to read and think through it all yet. I think that it would benefit from input from @Jonathan Edwards, e.g. do the rituximab studies give us any clues?

 

[gregh286]

Me too. The Maes hypothesis would seem to be: increase in leaky gut=increase in bacterial translocation=increase in autoantibodies to the nitrosative and oxidative products of the interaction of the bacteria with the immune system. I hadn't considered the possibility that there might be antibodies already circulating, 'waiting,' if you like, for these products to be made. This model seems kind of back to front for me though, but then I know very little about the immune system.

Sounds plausible....i suffer myself from angioedema and over last 20 years try to narrow it to a trigger without success. This is typical of idiopathic recurrent angio/urticaria.
I HAVE however seen occurrences escalate post alcohol..with low correlation and impossible to replicate..which lead me to believe the gut has been made "more porous" post consumption.

I had leaky gut test done and in range but "high" end of leakiness.
its possible we have more sensitive auto antibodies.

 

[alex3619]

We focus on the autoimmune angle, or the damage via other mechanisms, but we forget the body tries to repair itself or compensate by alternative mechanisms. Its like a war, in which one side gets a victory, then is forced back. As the battle lines move, analogously our symptoms shift. So many models fit with fluctuating symptoms.

Let me be clear about the notion of bacterial translocation though ... there is no such thing according to evidence and thoery. What has been identified is translocation of bacterial products, including toxins such as LPS which can exert major shifts in immune response.

 

[msf]

Do you mean there is no such thing in ME?

http://www.ncbi.nlm.nih.gov/pubmed/10659341

This is what happens in disseminated Yersinia Enterocolitica infection: the bacteria moves from the gut lumen to the mesenteric lymph nodes, spleen, liver, etc.

 

[MeSci]

I have been thinking about this a lot recently, particularly when I notice my own symptoms waxing and waning. I guess the infective hypothesis would suggest that this is due (at least in part) to the dynamic interplay of infection and immune system - is there a similar or analogous autoimmune process that could explain why symptoms are better some days and worse other days?

I know that RA patients have flares but from a quick google there doesn't seem to an accepted explanation for what triggers them, apart from the usual suspects: infections and stress. What I would like to know is if there is some internal mechanism that could potentially explain flares. I have noticed that my ME flares do not seem to correspond to either infections (new ones that is) or stress, but rather to changes in my gut and diet. Are there any examples of autoimmunity being primarily gut-driven (I know this has been proposed for Reactive Arthritis) and if this was the case, would the autoimmune response to changes in the gut be expected to be a rapid one, and would this flare be expected to last for long after the gut returned to the prior state?

I think we will need some info on the rate of turnover, lifespan, etc., of the various cell types involved in (auto)-immunity. I am fairly sure that @Jonathan Edwards has posted this info somewhere, and he has explained the complex processes involved in the immune system and aspects of autoimmunity.

I looked at connections between autoimmunity and leaky gut in my blogpost here. See the section headed 'Connections between leaky gut and autoimmunity'.

I have had some rethinks about this, along with reading Prof Edwards's info in PR, and accept that molecular mimicry is probably not involved during production of autoantibodies or the cells producing them (I forget the details thanks to my ME brain!), but rather during the weeding out of inappropriate antibodies/antibody-producing cells - if it occurs at all. An analogy might be when you are weeding your garden and a particular weed looks very similar to one of the things that you planted, so you don't pull it up.

I think there have been some excellent PR articles on how autoimmunity may develop and will have a look for them when I have time.

My instinct is that autoimmunity is an underlying condition in ME but not directly involved in the flares/PEM, but could easily be wrong about that. I think that it creates the conditions that make us vulnerable to getting PEM, but other triggers are the direct causes.

 

[MeSci]

Here are some threads which may aid this discussion.

http://forums.phoenixrising.me/index.php?threads/in-brief-autoimmunity-and-me.25704/

http://forums.phoenixrising.me/inde...erence-2014-part-1-autoimmunity-and-me.30812/

http://forums.phoenixrising.me/inde...glia-connection-in-me-cfs-fibromyalgia.30605/

http://forums.phoenixrising.me/inde...up-microglia-could-be-driving-symptoms.30645/

 

[msf]

Hmm, looking at that microglia thread reminded me that the best explanation for the gut-related symptoms is increased production of cytokines, particularly leptin. I guess an increase in autoimmunity would take longer to have an effect. I am really curious to see what effect if any, Ritux will have on gut symptoms (I understand this is part of the Phase 3 trial). I hope they note whether it has an effect on the lactic acidosis too.

 

[MeSci]

I hadn't thought about the delayed-PEM angle. I'm really out of my depth too, but I'm hoping that by floundering around I will attract the attention of someone who knows about these things...

My current view about the delay in PEM, at least in my case, is that PEM is largely due to mineral/electrolyte depletion and possibly dehydration. My reasoning is that overexertion appears to be a cause of my polyuria (excessive urination). Having found that I am prone to salt deficiency - which seems to be common in ME - and having an extremely-high urine sodium level in 2010, whilst blood sodium was low, I presume that this polyuria is the cause of mineral deficiency. The fact that others here gain great relief from IV saline also supports this theory.

My PEM bears an uncanny resemblance to a hangover. These too are largely due to electrolyte depletion and dehydration.

What I haven't yet figured out is why we get electrolyte depletion after exertion, but I think I am fumbling my way towards it. We seem to get an increase in blood acidity (a fall in pH) as a result of exertion. It looks as though this can promote electrolyte loss in urine, but I have already forgotten how! I had been thinking that it must be lactic acid/lactate that was involved, but now wonder whether other sources of acidity could do the same.