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Extended B-cell phenotype in patients with ME/CFS: A cross-sectional study

deleder2k

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Summary
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous condition of unknown etiology characterized by multiple symptoms including fatigue, post-exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B-cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms. A possible but undefined role for B-cells has therefore been proposed. Studies of the relative percentages of B-cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B-cell subsets related to B-cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B-cells. The panel utilized IgD, CD27 and CD38 (classical B-cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control, and Fukuda ME/CFS criteria and 32 age/sex-matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (p<0.01) and expression (MFI; p=0.03) of CD24 on total B-cells, confined to IgD+subsets. Within memory subsets, a higher frequency of CD21+CD38- B-cells (>20%) was associated with the presence of ME/CFS (Odds ratio: 3.47 (1.15-10.46); p=0.03) compared with HC and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B-cell phenotype in patients with ME/CFS. These may reflect altered B-cell function and if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab-therapy
http://onlinelibrary.wiley.com/doi/10.1111/cei.12749/abstract

@Jonathan Edwards, what is your take on the paper? I know nothing about immunology, but I hope this is real research which can lead us somewhere. It looks like the opposite of immune babble to me ;).

Does this paper give us some insight why some patients respond to RTX, why some do not respond, and why we're seeing some respond to cyclophosphamide? Fluge has previously mentioned that they believe memory b-cells could be the reason why some do not have an response to anti CD20.
 

A.B.

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One thing not mentioned in the abstract (maybe because it's not as interesting?)

As shown in Figure 1, levels of total serum IgA and IgM were also not different from HC (Figure 1A & 1C), but IgG levels in ME/CFS patients were significantly raised when compared with HC ( p =0.02; Mann Whitney U test) and 7/35 had levels above the upper limit of normal range (Figure 1B).
In this study we did find that serum total IgG levels were elevated in some patients, as is often found associated with autoimmunity (53 55), but this has not been reported in other cohorts.
 
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Marky90

Science breeds knowledge, opinion breeds ignorance
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Would anybody be so kind and upload the paper? It`s not free, is it?

Edit: Sorted! :)
 
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http://onlinelibrary.wiley.com/doi/10.1111/cei.12749/abstract

@Jonathan Edwards, what is your take on the paper? I know nothing about immunology, but I hope this is real research which can lead us somewhere. It looks like the opposite of immune babble to me ;).

Does this paper give us some insight why some patients respond to RTX, why some do not respond, and why we're seeing some respond to cyclophosphamide? Fluge has previously mentioned that they believe memory b-cells could be the reason why some do not have an response to anti CD20.

http://www.ukrituximabtrial.org/Rituximab news-Aug14 02.htm
 
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http://onlinelibrary.wiley.com/doi/10.1111/cei.12749/abstract

@Jonathan Edwards, what is your take on the paper? I know nothing about immunology, but I hope this is real research which can lead us somewhere. It looks like the opposite of immune babble to me ;).

Does this paper give us some insight why some patients respond to RTX, why some do not respond, and why we're seeing some respond to cyclophosphamide? Fluge has previously mentioned that they believe memory b-cells could be the reason why some do not have an response to anti CD20.
As you can see from the author list, I was not personally involved in the execution of this project. However, it was set up at my recommendation. What I think is the most important message is that a well established B cell research group has become a new member of the ME research effort and that ME has a new young scientist, Fane Mensah, committed to the disease. The findings of the paper are modest, but interesting. The previous findings of Bradley and Bansal were not replicated but there is a suggestion that there may be a subtle shift in early B cell trafficking that may be hard to pin down consistently with traditional cell sorting techniques but may still prove consistent if techniques are refined. The high IgG is interesting and again raises the question as to whether there is B cell dysregulation in a proportion of ME cases that gets obscured because cohorts amy vary according to how they are collected. The team is careful to point out that this may be a chance finding.

Things move forward by small steps most of the time, until suddenly something falls into place. I think this study should be seen in the context of inter-group interaction. We now have the Fluge and Mella, Scheibenbogen, Blanco, Blomberg, Bansal and the UCL group all sitting down together at meetings discussing why they think they are or are not getting the same results and how to find ways to make findings reproducible. There continues to be a suggestion that B cells are not behaving normally in a subset of patients but it is not clear why. When the biobanks open for business in the near future I think we will be able to do a lot more cross-confirmation.
 

Sidereal

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I am unclear as to how patients were selected for this study. It says:

Patients diagnosed with ME/CFS fulfilling consensus criteria (Canadian, CDC and Fukuda) were selected for the study by Dr. Berkovitz (Royal London Hospital of Integrated Medicine) and Dr. Bansal (St. Helier Hospital NHS Trust).
In studies like this it matters if it's consecutive referrals or if the clinicians picked the patients based on some clinical impression e.g. perhaps fitting a more "autoimmune" profile in terms of having a positive family history. It does say that those with confirmed autoimmune disease were excluded.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
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Accepting family members as controls may not be ideal either. They might have similar tendencies without ever getting to a clinically significant stage.
This is true. I actually heard from my aunt that she experienced dizziness if she trained too hard, this was my first symptom..
 

Gijs

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Unfortunately no game changer yet (?). @ professor Edwards: can we say that there is some B cel dysfunction in ME-patiënts? Or what does it mean in terms of disease, can you say with these findings that there is something medically wrong with these patiënts?
 

Marco

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Although they present (in the abtract at least) only group comparisons, presumably the individual data might indicate whether or not we are dealing with a possible autoimmune sub-set?

Within memory subsets, a higher frequency of CD21+CD38- B-cells (>20%) was associated with the presence of ME/CFS (Odds ratio: 3.47 (1.15-10.46); p=0.03) compared with HC and there was a negative correlation with disease duration.
The negative correlation with disease duration looks counterintuitive assuming the findings have any relevance to the diesease process. On the other hand if we assume that only a proportion of ME/CFS cases involve autoimmunity and that this proportion is reasonably consistent across cohorts then perhaps this particular cohort is not particularly 'well mixed' with fewer autoimmune cases in the longer duration patients?
 

Scarecrow

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The negative correlation with disease duration looks counterintuitive assuming the findings have any relevance to the diesease process. On the other hand if we assume that only a proportion of ME/CFS cases involve autoimmunity and that this proportion is reasonably consistent across cohorts then perhaps this particular cohort is not particularly 'well mixed' with fewer autoimmune cases in the longer duration patients?
Do you remember the comment made by @Jonathan Edwards several months ago - and I forget the exact phrase - by it was in relation to B cells appearing to be the opposite of autoimmune?
 

snowathlete

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Good to see research like this, it's what we need. There are some very good names involved now and I'm delighted to hear they are all talking. The question I have is what can we do to help them get funding for more studies? It should be easy but it's not because of the nonsense of UK funding into ME/CFS.
 

mango

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No, the suggestion was that there was something odd going on. I'll see what I can find later.
perhaps this?

Which might raise the strange idea that ME is a problem with B cells that are the opposite of autoimmune. That might not seem to make any sense but without saying anything too much there is just a whiff of a suggestion in the lab that ME B cells might be strange in the opposite way to the autoimmune situation.
http://forums.phoenixrising.me/index.php?threads/me-cfs-and-tregs-confused.36116/#post-570509
 

Jo Best

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Good to see research like this, it's what we need. There are some very good names involved now and I'm delighted to hear they are all talking. The question I have is what can we do to help them get funding for more studies? It should be easy but it's not because of the nonsense of UK funding into ME/CFS.
The research is currently being crowdfunded by Invest in ME Research to enable it to proceed without doubt or delay over grant applications. Two opportunities to help this weekend are:

1. anyone willing and able can have their donation of £5 or more matched by the Big Give Christmas Challenge Project for two more 4th year medical students to be directly involved in the Invest in ME Research Projects. The donation link is here - https://secure.thebiggive.org.uk/donation/to/6239/24084 & info here - https://secure.thebiggive.org.uk/projects/view/24084

2. and / or vote for the charity to win £300 in this week's People's Choice Award in the Galaxy Hot Chocolate Fund - an email address is required and you're sent an email to confirm your vote - https://www.galaxyhotchocolate.com/fund/profiles/invest-in-me

This paper is the initial study in the B-cell research prerequisite to a UK trial of rituximab, and meanwhile adding value to the Phase III Norwegian trial. Ways to donate to this research are listed here - http://www.ukrituximabtrial.org/IIMEUKRT Donate.htm

Crowfunding for the Invest in ME Research Strategy was started by people with severe ME (in 2011 for foundation study on leaky gut) launching the Let's Do It for ME campaign. We have also lobbied for more public-funded biomedical research, but got on with raising the funds ourselves for specific research, as the need is urgent and given that careful science takes long enough as it is. Various ways to join in are at http://ldifme.org/
 

Gemini

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One thing not mentioned in the abstract (maybe because it's not as interesting?)
@A.B. thanks for posting this interesting quote from the paper:

"In this study we did find that serum total IgG levels were elevated in some patients, as is often associated with autoimmunity (53,55) but this has not been reported in other cohorts."

Dr. Lipkin remarked a while ago the one consistent finding in his ME/CFS studies was polyclonal hypergammaglobulemia which involves elevated IgG levels. I don't have access to this paper, is it referring to the same thing do you know by any chance?

Polyclonal hypergammaglobulemia has been associated with infectious disease and known to resolve after successful antiviral treatment for example in HIV/AIDS.