1. Patients launch a $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
New Exercise Study Brings Both Illumination and Questions
Simon McGrath looks at new objective evidence of abnormal response to exercise in ME/CFS patients, and the questions that researchers are still trying to answer ...
Discuss the article on the Forums.

Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. natasa778

    natasa778 Senior Member

    Messages:
    1,358
    Likes:
    1,108
    London UK
    Ditto, what a great thread! I am coming to this late and still going backwards on posts, but in case it hasn't been brought up I was wondering if there is any data on HERV-K and RT activity in RA patients relative to rituximab responses?
    (in the absence of data any speculative thoughts would be much appreciated :) ). This question in the light of findings such as this one in RA http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883104/ , and increased HERV activity found in ME.

    Also, before we say 'only a consequence', here an interesting suggestion from the paper linked above
    EBV and its (potential) involvement in B cell dysfunction has been brought up here already ... but shouldn't the potential for 'collaboration' between HERVs and EBV, and other herpesviruses, in B cell dysfunction also be considered? (discussed briefly, with further links, in this paper, see chapter Herpesvirus—ERV Interaction: Does EBV Use a HERV for Stimulation of B Cell Growth?)


    Edited to add:
    I have just come across this paper 'Autoimmune disease: A role for new anti-viral therapies?'
    that discusses some of the points raised above
    garcia and ukxmrv like this.
  2. Dolphin

    Dolphin Senior Member

    Messages:
    6,519
    Likes:
    4,901
    There's a copy of this somewhere on YouTube which has English subtitles (one might have to press "cc" or something underneath to get the subtitles on the screen).
  3. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
    Coeliac disease is peculiar in that it is the only 'autoimmune' disorder in which we know what the T cell response is to. As you say it is gliadin, which is not a self protein, but a food element. It is unclear why a T cell response to food should be harmful unless the antigen is being presented in an unusual way. The autoimmune aspect of the disease is the B cell response - which is to the self protein tissue transglutaminase. To make sense if this it seems likely that B cells recognising transglutaminase pick up this attached to gliadin and present gliadin to T cells. If so the mistake that causes coeliac disease may not be having T cells that recognise gliadin but having B cells that recognise transglutaminase that can present the gliadin. Transglutaminase will be present all the time. The question would be whether you have to have gliadin around to trip the anti-transglutaminase response, or boost it. You need the gliadin to cause the gut damage but it is not clear you need it to make the antibodies. So there may not be quite a parallel here.

    I think your basic line of thinking is right though. One other point I would make is that effects of antibodies do not have to involve inflammation. In RA they do but in myasthenia or immune thrombocytopenia they do not. Effects on nervous system need not involve inflammation. The antibody might just block a receptor - as it does in myasthenia. I am sceptical that most people with ME actually have inflammation of the nervous system (i.e. encephalitis). I think that part of the name is unfortunate. It seems much more likely that in most cases there is neurological malfunction but not via inflammation. In a few rare cases there may be true encephalitis but this may turn out to be a subset with a different sort of mechanism.
    Sam Carter, Legendrew and Firestormm like this.
  4. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
    Rituximab is a protein, so it will not be metabolised by liver enzymes in the way that small drug molecules tend to be. I am not quite sure which cells would be most likely to metabolise it but my guess is that it would be scavenged by cells like macrophages when it has become damaged by oxidation or whatever. These cells would then digest the protein to amino acids with internal proteases. There are lots of macrophages in spleen and liver sinusoids but they are in almost all other tissues too.
    MeSci likes this.
  5. lansbergen

    lansbergen Senior Member

    Messages:
    993
    Likes:
    454
    These patients need help most urgent.

    In my opion it fluctuates and when I started taking levamisole the brain was the first place to improve.
    garcia likes this.
  6. user9876

    user9876 Senior Member

    Messages:
    684
    Likes:
    1,549
    Jonathan Edwards

    Sometime back in this thread I think you made a comment about imflamitary arthritis being different in children. Do you think this will be the case with ME? I've seen it said that children are more likely to recover but on this forum there seem to be quite a number of people who have been ill since their teenage years. Having a teenage daugter with ME i'm hoping that Rituximab will eventually offer a viable treatment for her. Since you were asking about thyroid problems I thought I would also say we have a family history of thyroid problems.
    Firestormm likes this.
  7. Firestormm

    Firestormm Senior Member

    Messages:
    5,819
    Likes:
    5,941
    Cornwall England


    Click the 'captions' button (bottom right after hitting play) for subtitles.

    Thanks to Sammy1 who first posted the video on the forum I believe :)
  8. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
    I think it is important not to get muddled about viruses in these diseases. And I am not accusing PR posters of being muddled, just the people writing papers. In order not to be too rude I will try and generalise. Papers that look at viruses in patients with autoimmunity nearly always give the impression that the virus is somehow explaining some part of the causation - often a 'trigger'. But when we look at the results it does not look as if they would explain anything to do with disease causation.

    In the Magnusson paper all that is found is that RA patients with more EBV in bone marrow respond to a treatment better (we do not know if it is just this treatment or any treatment). We already know that more or less everyone has EBV in their B cells at a certain stage of maturation. So what the EBV findings here seem to be telling us is that patients who respond to a treatment better have more B cells at a particular stage of maturation in their bone marrow. That might tie in with Dr Bansal's work on B cell populations but it does not imply that EBV is causing anything. It might be true that people who respond better handle EBV differently but it is a big jump to saying that this helps cause the disease. On the contrary, it might be that if these people respond better to treatment they have milder disease.

    The presence of EBV may facilitate the development of various autoimmune diseases but these bone marrow data would not seem to tell us anything about that. To my mind a lot of immunologists are still hidebound by the idea that autoimmunity arises from an interaction between genetic and environmental factors, with the environmental factor often thought of in terms of an infective 'trigger'. EBV infection occurs in infancy and in late teens and in neither group is there any suggestion of increased incidence of RA. In setting up a theoretical model for a disease one has to find one that predicts the right statistics for the epidemiology. The epidemiology of RA shows a genetic bias but is otherwise as far as we can see random. (Except that smoking increases risk.) People feel they need another factor to explain who gets RA and when, but they do not seem to realise that it will have to be a random factor. In general viruses are either everywhere or pass from person to person in epidemics. Nobody has ever caught RA.

    An extension of this gene/environmental trigger idea is almost universally believed in by immunologists but belongs to the stone age of the 1960s to my mind - something called molecular mimicry. The idea is that if you come across a foreign antigen that looks very like a self antigen you may get 'cross reactivity'. This idea was proposed for rheumatic fever and became accepted by everyone, despite there being no evidence. When rheumatic fever was cured by penicillin all the infectious disease physicians became 'immunologists' and brought their ideas with them. But it makes no sense. If a foreign protein is like a self protein you are less likely to respond to it. If cross reactivity was easy we would all have all sorts of autoimmune diseases. With the probably exception of post-infective polyneuropathy there is really zero evidence that it happens. What we do know happens is that a foreign protein can get involved in an autoimmune reaction to a quite unrelated molecule that it can bind to - like the coeliac case Andrew raised. But in most cases both the foreign and the self molecule are around all the time. The autoimmune reaction comes at random out of the blue. The point of the vicious cycle model based on random immunoglobulin mutation is that it makes sense of this. The random nature of the immune response is normally completely invisible, because of clonal selection in response to presence of antigen but for antigens that are always available, like self ones, the sudden random appearance of a response does make sense.

    I think viruses may well be more relevant to ME because ME is more likely to be quite a mix of different diseases and in some cases unusual ways of handling viruses might be very important. However, I do not think attempts to chase virus causes of RA are of much interest here. Even in ME I would personally want much firmer evidence for viral involvement before using anti-viral agents. There is a significant possibility that the 'trigger' illness that some people have, is not a trigger at all. If a form of immune dysregulation is set up that disturbs the control of messenger molecules involved in responses to viruses then the first sign of that may well be a disturbed, or amplified and prolonged, response to a virus - any old virus. We know from RA that autoimmune processes may set up years before they actually show themselves in terms of symptoms. An anamnestic boost to an autoimmune response from a non-specific infection is quite feasible as a reason for first symptoms, but the immune response itself would already have been there.

    Also, a number of immunologists seem to think there is some mystery about the response to rituximab. People often say there is no correlation between level of B cell depletion and benefit. I have no idea who invented that idea - there is a very clear correlation. For some reason people want to find another explanation but since we predicted what would happen with rituximab in advance (and published it in Brit J. Rheumatology) I cannot quite see the need!
    aimossy, Battery Muncher, Bob and 4 others like this.
  9. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
    With inflammatory arthritis the childhood forms are quite distinct - at least now we can see that after the painstaking work of people like Barabra Ansell. Some have chronic eye disease, some have rash, of sorts that never occur in RA. So we can tell that a 12 year old has 'real RA' or an unrelated childhood illness. I strongly suspect there will be different mechanisms for some young people with ME but I am not getting the feeling that there will be the same black and white distinction. On the other hand that may just be because by definition we are dealing with illnesses with no obvious tissue structural changes visible and my personal experience of ME cases is very small.

    I have to say that links to thyroid disease do tend to ring autoimmune bells in my head and that may be encouraging. There will be some people who have both problems by chance though, I guess. The problem is that like Agatha Christie, diseases leave bogus clues around the place as to who dunnit.
  10. Helen

    Helen Senior Member

    Messages:
    442
    Likes:
    380
    Sweden

    Thank you for this information. As ME-patients have been shown to have more genedefects in the livers phase 1 and 2 detoxification I was a bit worried that this could be a problem for some people.
  11. user9876

    user9876 Senior Member

    Messages:
    684
    Likes:
    1,549
    Does this mean that the genetic bias comes in the form of differences in the stochastic process for generating antibodies.
  12. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,040
    Likes:
    3,393
    Cornwall, UK
    I had brain fog yesterday and still haven't been able to organise my thoughts on receptors, but looked at a few documents and will just throw out a few brainstorming thoughts that may be relevant and connected:

    In some illnesses, perhaps including ME, there is, or is sometimes, preceding chronic stress (e.g. in childhood) that causes chronic hypercortisolaemia. Cortisol damps down the immune system, thus could allow opportunist infections to have more effect than usual and maybe get to places they can't usually, due to stress-induced hyperpermeable barriers, esp. BBB or gut mucosa.

    Then the hypercortisolaemia is replaced by hypocortisolaemia, or at least an abnormal pattern of cortisol secretion. This would allow the immune system to become overactive. Perhaps it could permit the (ongoing?) production of a wide range of antibodies.

    There seem to be mixed findings re what has caused the drop/abnormality in cortisol production - less CRH or ACTH? Could this be due to autoantibodies against one or both of these? Some seem to think so. In this case, it could provide a vicious-cycle-type positive feedback loop.

    Another possibly-analogous phenomenon is Type 2 diabetes, which initially involves hyperglycaemia and hyperinsulaemia, then hypoinsulinaemia.

    Still in a bit of fog so apologies if this is incoherent. Just wanted to put it out there before my brain mislaid it completely!
  13. Firestormm

    Firestormm Senior Member

    Messages:
    5,819
    Likes:
    5,941
    Cornwall England
    Intriguing.

    Fascinating.

    Could the immune dysregulation be an inherited factor? And might it relate to a parent who has an autoimmune disease - for example - Rheumatoid Arthritis? I know we are kicking around ideas but Mum has RA and you know her symptoms and level of disability while not wholly similar to my own - certainly are in some ways.

    I don't believe you have spoken about genetic-susceptibility on this thread - although you did provide some interesting thoughts about pregnancy a while back; and I was just wondering where you think this dysregulation might stem from if not from what is considered by us to have been a 'trigger' (in my case viral) event? Thanks :)
    Legendrew likes this.
  14. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
    I think Firestormm is asking much the same thing. And the answer seems to be yes. The genetic factors for RA (different in some cases for other autoimmune diseases) are having two X chromosomes, having the DR4 tissue type and having a variant of the PTPN22 gene. Two X chromosomes makes you female and all we can say is that there are quite a lot of differences in regulation of immune responses between male and female, any of which might be relevant, but females have to make antibodies for babies as well as themselves so that might be a clue. Most autoimmune disease are 3 times commoner in women. Lupus is 9 times commoner which ought to be telling us something (Three squared??) Ups and downs in hormones, as MeSci suggests, might be relevant here since female hormones go up and down and lupus mostly occurs during childbearing years.

    The other two are a bit clearer. DR4 is a variant of the Class II MHC molecule DR that is the 'handle' that B cells use to present antigen fragment peptides to T cells. A lot of people are thinking that DR4 increases risk for RA because of the way it binds peptides that carry citrulline. So it would alter the threshold for getting into an anti-citrulline loop. The threshold effect may be wider than this though. This mechanism would not alter the way antibodies are randomly generated, but it could alter the likelihood of a bad antibody getting caught up in a loop. People have looked at the genes that are involved in the diversity of antibody species themselves (e.g. heavy cahin or Vh genes) and not found much.

    PTPN22 does various things for lymphocytes but one thing looks relevant. It is involved in what is called receptor editing. When a new B cell is born it makes an antibody species at random. If this antibody species does not fold up properly or is 'substandard' in other ways the B cell may be given another chance to make a different antibody species. (A bit like a second service in tennis.) This is called receptor editing. It is pretty easy to see that a change in the 'fussiness' of antibody quality control and receptor editing could affect the likelihood of generating bad antibodies that looped. This fits in very much with ideas from people like Bansal and Samuels who have suggested that B cells are coming out of bone marrow not properly 'policed' for potential autoreactivity.

    So, yes, the genetic factors look as if they may be setting the system up for a crash based on random generation of antibodies that in another person would be policed out.
    aimossy, Valentijn, MeSci and 3 others like this.
  15. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
    Something I forgot to add to the last post is that one sort of genetic difference that might allow certain types of B cell error to occur would be a difference in NK cell, or more generally cytotoxic cell, function. I was interested to see the paper:
    Mol Med Rep. 2011 May-Jun;4(3):535-40. doi: 10.3892/mmr.2011.447. Epub 2011 Mar 4.
    Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome.

    Pasi A, Bozzini S, Carlo-Stella N, Martinetti M, Bombardieri S, De Silvestri A, Salvaneschi L, Cuccia M.
    NK receptors are strange. I am not convinced that poor killing of K562 target cells as reported in ME should be considered a 'defect' but it may indicate a difference. The above authors think in terms of clearing cells infected with pathogens but killer cells are involved in getting rid of unwanted B cells with no pathogen involved. I would be very interested to know if anyone else had found something similar to the above.
    Legendrew likes this.
  16. lansbergen

    lansbergen Senior Member

    Messages:
    993
    Likes:
    454
  17. Marco

    Marco Old blackguard

    Messages:
    1,175
    Likes:
    817
    Near Cognac, France
    Not quite the same but it may be relevant? This is from something I've been working on taking a similar 'first principles' approach (to add to the 95% of chaff!) :

    I was also intrigued by your comments on encephalomyelitis and the suggestion that inflammation is unlikely to play a part in most cases of ME. Is it possible to make a distinction between inflammation that results in gross tissue pathology in diseases such as RA or coeliac disease (or in edema in meningitis) and the type of neuroinflammation (involving raised pro-inflammatory cytokines, extracellular glutamate, oxidative stress and mitochondrial dysfunction) proposed as underlying conditions such as major depressive disorder and dementia that don't (as far as I'm aware) involve gross tissue damage?

    As above I would tend to suggest that any autoimmune involvement in ME would be more akin to the various types of autoimmune encephalitis (or stiff person syndrome) that affect neurotransmitters than RA, coeliac etc. Do you you happen to know if these autoimmune encephelatides (?) cause gross tissue damage?
    rosie26 and MeSci like this.
  18. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    385
    Likes:
    2,121
  19. lansbergen

    lansbergen Senior Member

    Messages:
    993
    Likes:
    454
    The opposite in autisme with the other arm ( HLA-C2 ligand )

    http://www.sciencedirect.com/science/article/pii/S0889159112001973
  20. Helen

    Helen Senior Member

    Messages:
    442
    Likes:
    380
    Sweden
    Jonathan Edwards . It would be very interesting if you would take your time to comment on Rich Van Konynenburgs hypothesis about Rituximab. I have followed his research for three years and so far I haven´t found anything that doesn´t fit in to his hypothesis about glutathione depletion due to one or more genetic defects in the methylation cycle ( primarily MTHFR and/or MTRR/MTR) as a necessary (but not sufficient) factor for ME. At least after that Rich made us aware of that when the methylation capacity is decreased, it is better to take mecobalamin than hydroxycobalamin (that doesn´t need to be methylated ). But I am not at all an expert in infections or immunology...

    Best regards


See more popular forum discussions.

Share This Page