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Implication of Epstein-Barr Virus Infection in Disease-Specific Autoreactive B Cell Activation

Discussion in 'Other Health News and Research' started by Ecoclimber, Sep 17, 2014.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Arthritis Rheumatol. 2014 Sep;66(9):2545-57. doi: 10.1002/art.38726.
    Implication of Epstein-Barr Virus Infection in Disease-Specific Autoreactive B Cell Activation in Ectopic Lymphoid Structures of Sjögren's Syndrome.
    Croia C1, Astorri E, Murray-Brown W, Willis A, Brokstad KA, Sutcliffe N, Piper K, Jonsson R, Tappuni AR, Pitzalis C, Bombardieri M.
    Author information

    Abstract

    Objective

    To examine whether the B cell tropic γ-herpesvirus Epstein-Barr virus (EBV) is aberrantly expressed in its latent and lytic forms within ectopic lymphoid structures (ELS) in the salivary glands of patients with Sjögren's syndrome (SS), and to investigate the relationship between EBV dysregulation, B cell activation, in situ differentiation of autoreactive plasma cells, disease-specific autoantibody production, and cytotoxicity.

    Sjögren's syndrome (SS) is characterized by lymphocytic infiltration of salivary and lacrimal glands leading to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes) ([1]). One of the hallmarks of SS is the formation of ectopic lymphoid structures (ELS) in the salivary glands. ELS are defined as B cell/T cell follicles with networks of stromal follicular dendritic cells (FDCs), supporting an ectopic germinal center (GC) reaction ([2-4]). ELS, which develop in ∼30–40% of patients with SS, represent functional niches whereby B cells undergo in situ activation and differentiation into autoreactive anti-Ro/La–producing plasma cells ([5]) and are strongly linked to the development of B cell lymphomas ([6, 7]).

    Although the pathogenesis of SS is still unclear, it has long been postulated that viruses, including Epstein-Barr virus (EBV), human T lymphotropic virus type I, and cocksackievirus ([8-10]), play an essential role in promoting the autoimmune dysregulation typical of the disease, possibly as a result of genetic susceptibility involving the type I interferon pathway ([11, 12]). EBV, a human DNA γ-herpesvirus that establishes an asymptomatic latent infection and can cause infectious mononucleosis ([13]), has long been postulated to promote autoimmunity in several chronic autoimmune diseases ([10, 14]), primarily due to its ability to infect B cells and alter their normal differentiation program, leading to the survival of autoreactive B cell clones ([15]).

    There is significant controversy concerning the question of whether EBV is implicated in the pathogenesis of SS, due to conflicting results regarding the expression of EBV proteins/nucleic acids in the salivary glands of patients with SS compared with patients with sicca or healthy control subjects. Some studies demonstrated increased EBV expression in patients with SS ([16-19]), and others failed to show differential expression between SS and control salivary glands, despite common evidence of the persistence of EBV in the salivary glands ([20-22]).

    Notably, none of the previous studies attempted to investigate EBV expression in the salivary glands of patients with SS in the context of ectopic GC-like structures. This is highly relevant not only because the “GC model” is widely used to explain how EBV gains access to the memory B cell compartment ([23, 24]), but also because ectopic B cell follicles in chronic autoimmune diseases represent preferential niches of EBV latency and reactivation ([25-27]). Furthermore, despite the strong evidence linking EBV and B cell autoimmunity, it remains unclear whether EBV triggers a breach of tolerance toward disease-specific antigens within ELS.

    The purpose of this study was to investigate whether the expression of latent and lytic EBV occurs preferentially in the salivary glands of patients with SS, in the context of GC-like structures and in situ differentiation of autoreactive plasma cells with specificity toward SS-associated autoantigens.

    METHODS:

    Latent and lytic EBV infection in the salivary glands of 28 patients with SS and 38 patients with nonspecific chronic sialadenitis (NSCS), characterized for the presence or absence of ELS, was investigated by reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemical/immunofluorescence staining.

    Glandular versus synovial production of anti-Ro 52, anti-citrullinated protein antibodies (ACPAs), and anti-EBV peptide antibodies was analyzed in situ or in vivo in human SS/SCID and human rheumatoid arthritis/SCID mouse chimeras.
    RESULTS:
    EBV dysregulation within inflammatory infiltrates was observed exclusively in ELS+ SS salivary gland tissue, as revealed by latent EBV infection and lytic EBV infection in B cells and plasma cells, respectively.

    Conversely, epithelial latent membrane protein 2A expression was observed in both patients with SS and patients with NSCS. Importantly, perifollicular plasma cells displaying Ro 52 immunoreactivity were frequently infected by EBV. Furthermore, ELS-containing SS salivary gland tissue that was transplanted into SCID mice supported the production of anti-Ro 52/anti-La 48 and anti-EBV antibodies but not ACPAs. Analysis of CD4+ and CD8+ T cell localization and granzyme B expression demonstrated that the persistence of EBV in ELS-containing SS salivary glands was associated with follicular exclusion of CD8+ T cells and impaired CD8-mediated cytotoxicity.

    DISCUSSION:
    Here, we report the novel finding that a dysregulated EBV infection, characterized by the expression of both the latent and lytic forms of EBV, is a specific feature of the salivary glands of patients with SS displaying ectopic B cell follicles organized as ELS.
    We show that LMP-2A, a protein expressed during EBV latency that mimics the B cell receptor signaling pathway ([36]), is selectively expressed by CD20+ B cells within B cell follicles, particularly in association with FDC networks.

    Furthermore, using both in situ hybridization and quantitative PCR, we show that the expression of EBERs, which are short nonpolyadenylated and nontranslated RNAs expressed during EBV latency ([13]), is strictly dependent on the formation of ELS in SS salivary glands but is virtually absent in ELS− SS or NSCS salivary glands.

    Specifically, EBERs closely correlated with CD19 mRNA, a cell marker expressed by B cells and plasma cells, and AID, the enzyme required for functional B cell activation leading to somatic hypermutation and class-switch recombination of the immunoglobulin genes ([37, 38]). Accordingly, in situ hybridization for EBER demonstrated colocalization of EBER with CD20+ B cells and perifollicular CD138+ plasma cells. Thus, it appears that latent EBV infection in SS salivary glands is associated exclusively with the presence of ELS with functional GC-like structures supporting in situ B cell activation and plasma cell differentiation.

    The close association of EBV with an ectopic GC response is extremely relevant, because EBV uses a GC-like growth program, which includes the expression of LMPs and EBERs, to transform latently infected B cells into proliferating blasts and convert these cells into long-lived memory B cells. Further signals, normally dependent on antigen stimulation and T cell help, favor plasma cell differentiation leading to viral reactivation ([13, 24, 39]).

    Accordingly, by investigating the expression of EBV proteins involved in lytic reactivation, such as BFRF1, we demonstrated that EBV reactivation is frequently observed in ELS+ but not ELS− SS or NSCS salivary glands, where BFRF1 expression is observed exclusively in CD138+ plasma cells surrounding FDC+ B cell follicles, suggesting local differentiation within the GC ([40]). Thus, salivary gland ELS, by providing B cell help in the context of an ectopic GC response characterized by the expression of strong B cell−activating signals, such as BAFF, represent protected niches for EBV latency and reactivation. Further supporting the importance of the SS salivary gland microenvironment for EBV reactivation is the observation that saliva from patients with SS directly reactivates EBV by inducing BZLF1, an early lytic-phase EBV protein ([41]).

    Overall, our work also reconciles conflicting data regarding the expression of EBV in the salivary glands of patients with SS compared with healthy individuals or patients with sicca, because previous studies failed to stratify SS salivary glands according to the presence of ectopic GC-like structures ([17-22]).

    In particular, previous work primarily focused on EBV infection of salivary gland epithelial cells, which is a physiologic site of EBV latency, as we also confirmed by demonstrating LMP-2A infection in ductal (mainly) and acinar epithelial cells of SS (ELS+ and ELS−) and NSCS salivary gland tissue. Nevertheless, it is conceivable that epithelial cell infection by EBV could directly contribute to the pathogenesis of SS in genetically susceptible individuals. In this regard, aberrant type I interferon responses due to insertion/deletion and single-nucleotide polymorphisms in related genes such as IRF5 and STAT4 ([11, 12]) might result in an aberrant immune response to EBV whereby persistent viral infection may culminate in the formation of ELS. Accordingly, we recently showed that ELS can be triggered by viral infection of the submandibular glands in a novel murine model of SS-like sialadenitis ([42]).

    A fundamental question regarding EBV reactivation within ELS is whether this process takes place in plasma cells bearing an autoreactive B cell receptor, thus linking EBV with the development of autoimmunity, a hypothesis that has long been formulated ([15]) but eluded formal demonstration even with sophisticated techniques ([43]).

    Here, by analyzing the immunoreactivity of lesional CD138+ cells toward Ro 52, a major SS autoantigen, we show that a significant proportion of perifollicular plasma cells lytically infected with EBV display an autoreactive phenotype. Strikingly, we also show that the autoreactive profile of EBV-infected plasma cells completely differs between ELS+ SS salivary glands and ELS+ RA synovium, whereby CD138+/BFRF1+ cells are specific for Ro 52 in SS and for citrullinated antigens in RA ([27]) but not vice versa. These observations, replicated in vivo by engrafting human ELS+ SS parotid gland tissue and RA synovial tissue into SCID mice, strongly reinforce the hypothesis that in situ autoimmunity in the context of EBV reactivation within ELS is driven by local antigenic stimuli that are disease specific. Additionally, the inability of ELS to prevent autoreactive B cells from entering GCs is likely to favor the differentiation of high-affinity autoreactive plasma cells from EBV-infected B cells ([44]), which are maintained within the salivary gland microenvironment by strong plasma cell survival factors ([45]).

    Another original observation in the SS/SCID mouse chimera model is that engrafted SS salivary glands with ELS sustained the production of human anti-EBV IgG antibodies, namely anti–EBNA-1 and anti-VCA, which closely associated with local anti-Ro/La production. This suggests that a humoral anti-EBV immune response takes place within ELS in the salivary glands of patients with SS and is closely linked with autoimmunity. This is particularly interesting not only because the anti-EBV antibody level is significantly increased in the serum of patients with SS ([46, 47]), but also because of molecular mimicry between SS autoantigens and EBV proteins. Interestingly, anti-Ro/La autoantibodies precipitate proteins that are complexed with EBERs ([48]), and EBNA-1 mimics Ro 52 ([49]). Moreover, cross-reactivity between α-fodrin, lipocardin, and EBV EA proteins was also described ([50]). Finally, EBV can induce the cleavage of α-fodrin, leading to induction of the antigenic 120-kd α-fodrin ([51]). Thus, our present data allow us to speculate that EBV may promote humoral autoimmunity within ELS not only by providing a survival/proliferative advantage to autoreactive B cells entering ectopic GC but also by promoting breach of self tolerance via molecular mimicry or posttranslational modification of SS-associated antigens.

    Investigation of the cytotoxic immune response in SS salivary glands suggested that the dysregulated EBV infection observed in patients with ELS+ salivary glands may be favored by the follicular exclusion of cytotoxic CD4+/granzyme B–positive T cells, which accounted for only a minority of granzyme B–positive cells within B cell follicles (but represented >80% of cytotoxic cells in ELS− SS and NSCS salivary glands). In ELS+/EBV+ samples, an unusual population of CD4+/granzyme B–positive cells seemed to substitute for cytotoxic CD8+ T cells; this observation is very interesting, because circulating cytotoxic CD4+ T cells have been described in chronic viral infections, including EBV ([52]).

    In summary, the current study demonstrates that in salivary gland ELS, intimate EBV–immune cell interactions take place, with profound repercussions on the aberrant B cell activation and local autoimmunity typically observed in patients with SS. Of critical relevance, it also demonstrates that this process is disease specific, indicating that following breach of tolerance for specific putative autoantigens, EBV infection contributes to the survival and perpetuation of autoreactive B cells.
     
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  2. A.B.

    A.B. Senior Member

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    Very interesting. With
    do they mean that depending on what happens, different autoimmune diseases can result?
     
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  3. Jonathan Edwards

    Jonathan Edwards Senior Member

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    What I think they think they mean is that the interactions between EBV and autoreactive B cell proliferation in germinal centres in salivary glands is specific to Sjögren's syndrome. What they do not seem to have thought through is that this has to be true because Sjögren's syndrome is the only situation where you get B cells in salivary glands. Effectively they are saying that Sjögren's syndrome is specific to Sjögren's syndrome. I am afraid a lot of this sort of thing goes on in immunology.

    The real problem with the study is that there are no relevant controls to show that EBV has any causal role. The only meaningful experiment would be to take a few thousand people who have never had EBV and let them live and breed on an island for a generation or two and see if they got less Sjögren's syndrome (with no EBV).

    We know that the EBV does not cause the salivary glands to be colonised by lymphocytes because in most cases the affected glands are almost entirely colonised by T cells. B cells only come in and make germinal centres in really gross cases. The story in the paper seems to have the cart before the horse.

    As it is we know that we all have EBV passed on from one B cell to another throughout our lives and when B cells proliferate EBV tends to spill around. It also normally spills around in saliva, which is why mono is called the kissing disease. I cannot find anything in this study which is over and above what we would assume to occur based on what we know of the way EBV lives. And I cannot see any link between the EBV and the autoimmune response. We have the same old presumption that infection triggers autoimmunity but no explanation as to why one should think it does!
     
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  4. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Sjogrens could possibly respond to treating ebv with antivirals or as done in ms research where t cells are treated with ebv vaccines and reintroduced into the patient. There has been good responses treating ebv directly in MS.
     
  5. Jonathan Edwards

    Jonathan Edwards Senior Member

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    But, Heapsreal, people with heart attacks, people with acne, people with kidney stones, even people with grey hair and with toothache have EBV in their germinal centre B cells. Would you treat them with anti-virals? We need a little logic to the science. The pity is that this does not feature much in the way people write papers these days.
     
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  6. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I think they need to develop proper testing to find out if ebv is active or not, this would help, as currently testing for these herpes viruses is very inaccurate.

    But the proof in the pudding is the research going on in MS where they are actively treating ebv and getting good improvement, surely this shows its an issue. Its also commonly known that immune suppressed people can have different herpes viruses reactivate and cause problems. I would call someone with cfs who testing shows low nk function and cd8 t cell function to be immune suppressed, as these immune cells are well know to control and fight viruses, with these systems down it makes sense to most that these viruses could then become an issue.

    I agree with you that most people have ebv but those with a dysfunctional immune system, these viruses can be prone to reactivate throughout the body. Its not blinded placebo work but surely the research done by immunologist Dr Lerner as well as Dr Peterson and many other doctors who have had success treating sub groups with these viruses means something.

    I think its very naive to think they are benign in everyone.

    I dont think antivirals is for everyone, but if it wasnt for antivirals, i wouldnt be working and functioning at a much higher level then i once was. It was not a coincidence as over the years i have stopped and started treatment and seen a return in cfs symptoms and testing has shown my total lymphocyte and subsets all increase as well as ESR when i went off this treatment and then an improvement in these results when treatment was resumed. Am i recovered no, but im worker 30 plus hours a week and currently able to exercise again, much higher than i once was.

    I just wish you wouldnt turn your back on the idea of herpes viruses being implicated, but have it sit in the back of your mind when undertaking research and have it as a possible subset. I believe the autoimmune theory of cfs/me will also be a subset and wont be for everyone.

    Also because its not covered extensively in medical journals doesnt mean it doesnt exist. I believe that due to the lack of research dollars in cfs/me is the reason why it isnt more commonly posted in research journals, just like many other things in cfs/me. Just take the time to read Dr Martin Lerners work and keep an open mind. Herpes sub group is a group that can be treated, i think its worth seeing if there is a relationship with those that respond to rituximab, if not, then we now have 2 sub groups of cfs/me patients that have treatment that can improve their quality of life.

    cheers!!!
     
    Last edited: Sep 18, 2014
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  7. Jonathan Edwards

    Jonathan Edwards Senior Member

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    Maybe I shouldn't interfere. But quite a lot of people on PR seem to be keen to try to find a good footing for understanding the biological basis of MEs and that needs clear thinking. And my other excuse is that by discussing these things on PR, and trying to argue a case for careful thinking, I find my own thoughts are getting clearer all the time - and that will feed directly into setting up research.

    I said 'good footing' rather than 'scientific' because I am not wanting to imply we need some narrow 'scientific method'. We need common sense. And in ordinary life, as much as science or for Hercule Poirot in an Agatha Christie murder story, we prove things not by 'loads of evidence', but by checking that everything fits. This paper is not even about ME. Nor is MS about ME.

    Some years ago I found water on the windowsill in our sitting room bay window. There was water dripping from the downstairs level bay roof. Loads of evidence for a leaky roof it seemed. But I went upstairs and found a damp patch there too. It turned out the water was getting in through the attic window frame and tracking under the rendering. Loads of evidence can be wrong.

    I have looked through Dr Lerner's papers and also the extended summary put out by his clinic. There is a lot of evidence there but the more I go into it the less it all fits together. Dr Lerner himself does not believe in reactivation of the sort we see in profoundly immunodeficient individuals, but rather a sort of partial activation in which only viral components are produced rathe than whole virus. I am unclear what that would lead to. And we know that even in normal people EBV virus replication does occur, since there is passage to new B cells and secretion in saliva. It does not seem to add up.

    Another point that may be worth making is that I very much doubt that low lymphocyte counts or low NK function assays tell us anything much about immunodeficiency. In a trial of the anti-CD52 Campath 1 antibody in RA it was found that patients, who sadly got no better, had virtually no circulating T cells for periods of years after the treatment. But there was little or no evidence that this led to any problems with immunodeficiency. As I understand it the immunodeficiency of AIDS is not so much due to low CD4 counts as to the way the virus interferes with the function of the cells that remain.

    I am not turning my back on any ideas here. I am turning the ideas over in my mind. It may be true that ME patients have different antibody profiles to EBV (although it is not clear to me that this has been found to be consistent across research groups). That might mean the virus is in a different state of replication, but it might mean that in ME there is some shift in antibody regulation that happens to show this way for EBV antibodies but might equally show up if one looked at antibodies to other viruses.

    What I would like to be sure is that nobody thinks that this particular paper is telling us anything about the ability of EBV to cause either Sjögren's syndrome or ME. The findings are what we would expect from what we know about EBV already, I think. Old stories remain popular. People were trying to pin Sjögren's on EBV back in 1982 when my mother was involved in the research, but it has never fitted together to my mind.
     
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  8. daisybell

    daisybell Senior Member

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    Apologies if I'm not being very bright here, but I just wanted to ensure that I am thinking straight!

    If antibody regulation was impaired, that would account for the improvement seen with anti-virals...? Would this be for that sub-set of ME folk only? Does that seem to account for that type of ME fully, or is it just part of the problem?
     
  9. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I wasn't actually suggesting that an antibody dysregulation showing itself as high EBV titres would explain anything in itself. Just that there are other possible explanations for such high titres (in the few that have them).

    But although antibody dysregulation would not obviously tie in to improvement with anti-virals, looking at Dr Montoya's 2013 J Med Virol paper, I don't think there is any inconsistency. He gives as his first suggestion for the mode of action of valganciclovir 'immunomodulation' rather than an effect on virus (which he places second). Valcyte is, I understand it, a DNA replication poison, which commonly has a major effect on human blood cells as well as virus replication. So it is likely to have an effect on dividing B cells and short term antibody production.

    The study must also cast doubt on whether improvements on valcyte are more than a placebo effect. If, as the study indicates, there is no major difference in response from placebo then we have to accept that people improving on valcyte may be improving for reasons other than the drug itself. This is the standard reality of studying drug treatments. We are in the same situation with rituximab and, for that matter with CBT and GET. As far as I can see we do not yet have the sort of hard evidence for treatment effects we need to start relying on.

    I also understand that even in patients that improved after valcyte antibody titres did not change. If the antibody titres were evidence of replicating virus and the drug removed replicating virus this is potentially a problem for the theory that the drug is working by removing virus. Which may be why Dr Montoya went for the other explanation first? (But it would not seem to fit with valcyte correcting a B cell dysrgulation as a cause for the high titres either.)
     
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  10. daisybell

    daisybell Senior Member

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    Thank you!
     
  11. A.B.

    A.B. Senior Member

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    @Jonathan Edwards: ME/CFS research urgently needs some form of reliable, objective test. Repeat CPET might be a candidate, but there is concern about its negative effects on the more severely ill patients. Do you have ideas what could be done?
     
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  12. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I guess his results of treating cfs/me with ebv only with valtrex is what adds up. He also has other research involving different viral subsets and bacterial subsets he has treated with improvement in many patients. Hardly just a story. These types of results deserve further research, again getting these research dollars is the issue.

    Again you seem to have a bias towards thinking natural killer cells are unimportant. It doesnt take much to find research on natural killer cell defiency syndromes which isnt a far stretch to include low nk function. Its common to find recurrent herpes virus infections where antiviral prophylaxis treatment is a standard practice. http://www.uptodate.com/contents/nk-cell-deficiency-syndromes-treatment
    I can only guess that many years ago when you were at university that the knowledge of nk cells was in its very infancy.

    Maybe you should read your little story on the water leaking on the windowsill. Its quite possible that T cells have alot more importance in other illness outside of RA. Again just like i have mentioned before of the findings in MS where improving T cell function to ebv, thats right those unimportant T cells and people with MS improved. I guess this is an example of T cells playing an important part in another condition outside of RA.

    Another interesting opinion, even though aids survival rates correlates to cd4 t cell numbers. I wonder how hiv/aids patients would go without those unimportant T cells?

    I dont think thats what was meant, but rather to show that EBV may be imlicated in other autoimmune diseases. It may be worth looking into ebv and sjogrens syndrome again, as the year 1982 you stated was when they were trying to pin ebv to this disease. Im sure technology has improved greatly since then as well as the knowledge of EBV as it would have only been discovered a mere 15yrs or so prior.

    Interesting that u mention this paper isnt about ME or MS but you continue to refer most things back to RA throughout your post on phoenix rising. Maybe this is something you should recall when u say nk cells and t cells arent important, this may be so in RA but theres no evidence to say they arent important in ME ;)
     
    Last edited: Sep 20, 2014
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  13. Jonathan Edwards

    Jonathan Edwards Senior Member

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    The 2 day CPET is interesting but as you say it seems troublesome as a measure, particularly if one wanted to use it repeatedly in a longitudinal study. I think it is also lacking in explanatory value. By that I mean that it is a bit like measuring joint swelling arthritis. It might be 'objective' if you are lucky but it says nothing about an mechanism. In contrast a CRP level tells you that there is some cytokine activation so it is much more powerful as a measure. I think some physiological measure that is a bit upstream is what is really needed, but so far I cannot see what it is likely to be.
     
  14. A.B.

    A.B. Senior Member

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    Does a test really have to say something about the mechanism? If so, we might have to wait for a long time, if the technology to measure the relevant parameters even exists yet.

    Edit: just to make sure we're on the same page. I'm interested not in a diagnostic test, but merely some test that can tell us whether a person has had an overall improvement in health.

    What about actimeters to measure the amount of activity over several weeks (or even months if tolerated)? While one could say that activity levels are entirely under control of the patient and therefore subject to the placebo effect, as far as I know, placebo effects fade over time. If we track activity levels for long enough, could we distinguish between intervention and placebo effects?
     
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  15. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I guess that actimeters provide some sort of standardisation but they may not actually measure whether or not someone is well. The true 'placebo' effect, as for painkiller studies, lasts a short time but all sorts of factors may produce effects that look like 'placebo' indefinitely. A lot of what appears as a placebo effect in trials hs to do with patients trying to fulfil therapists expectations for reasons relating to interpersonal interaction. And even for an actimeter this could be a problem. For instance, a week before an assessment visit a person may start doing more exercise because they are thinking about the assessment and reporting how they are doing. A person might also do more at a stage when they were feeling they needed to get better and once they got better they might say - why bother, I'm well now, I don't really need to do that much this week. For the person who is seriously incapacitated where the actimeter is measuring the difference between being in bed all day and getting to walk around the garden it may give a useful indication of ability to exercise but I suspect that at slightly higher levels of activity it may be influenced by all sorts of irrelevances. It is often a mistake to think that something that gives you a number is more use than how someone says they feel if what you really want to know is how they feel. Most people trying to design ME trials seem to think actimeters could be useful but they also introduce complications to the analysis which may make the project unwieldy.
     
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  16. Daffodil

    Daffodil Senior Member

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    hi heap. I have never heard of MS patients being treated with antivirals and doing better. if you have a link to this, would love to read about it.
    xoxo
     
  17. deleder2k

    deleder2k Senior Member

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    At Haukeland, Fluge and Mella are doing a sub study on Flow-mediated dilatation, to see whether the severity of ME correlate with the decrease in FMD. Very interesting!
     
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  18. NK17

    NK17 Senior Member

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    I agree that CPET doesn't tell us much about the pathophysiology of ME and it's also potentially dangerous for a large part of PWME by triggering severe relapses, but it's a start.
    Maybe what we really need is cytokines testing pre and post CPET.
    I took the CPET almost 2 months ago causing a major flare up of "viral" symptoms.
    I'm not fond of being sick as a dog with awful aches and pains, respiratory and GI tract issues, but at this point into the disease I needed some objective measure of my inability to sustain normal everyday activity and consequently proving that I'm disabled.
    I'd love to have my CRP and ESR to come back elevated and that is why I summoned and scraped the bottom of my energy barrel resources to be taken to my new PCP. She ran a few tests which will probably come back normal.
    I know that Fluge and Mella have been monitoring their ME patients with CPET pre and post rituximab intervention, it's an ongoing thing and I think that it's very important.
    Ideally we would all be assessed through CPET at specialized ME clinics, what Dr. Montoya's calls CoE Centers of Excellence.
     
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  19. NK17

    NK17 Senior Member

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    You can look up Dr. Michael Pender from Queensland and his work on MS.
    Prof. Gavin Giovannoni's is another clinician/researcher in the MS field that I would suggest you follow and read about.
    But @heapsreal might come to the rescue with other sources and info.
     
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  20. NK17

    NK17 Senior Member

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    Very very interesting indeed @deleder2k!
    Do we have any more details about this ramification of the amazing detective work that Fluge and Mella are doing?
     

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