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ME/CFS B-Cell Study/Rituximab Implications

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15,786
However, treatment with anti-B-cell therapy using Rituximab has recently shown benefit to CFS patients. We therefore postulated that patients with CFS had a subtle humoral immune dysfunction, and performed extended B-cell immunophenotyping. We undertook a detailed characterisation of the proportions of the different B-cell subsets in 33 patients with CFS fulfilling the Canadian and Fukada criteria for CFS and compared these with 24 age and gender matched healthy controls (HC).

So they're using a real ME definition - great to see that happening in the UK! Also nice to see the Rituximab research sparking interest from immunology researchers who weren't previously active in the ME arena.

CFS patients had greater numbers of naïve B-cells as a % lymphocytes - 6.3 % versus 3.9 % in HC (P=0.034), greater numbers of naïve B-cells as a % of B-cells - 65 % versus 47 % in controls (P=0.003), greater numbers of transitional B-cells - 1.8 % versus 0.8 % in controls (P=0.025) and reduced numbers of plasmablasts - 0.5 % versus 0.9 % in controls (P=0.013). While the cause of these changes is unclear, we speculate whether they may suggest a subtle tendency to autoimmunity.

Also very interesting stuff. I think they're basically saying that we have a normal amount of B cells, just too many naive (unexposed to antigen) and transitional B cells (exposed to an antigen but not released from lymph nodes?), which would seem to imply that we have a low amount of circulating mature B cells. I think :p

It looks like the plasmablasts are created from (mature?) B cells, so those might be low as a result of insufficient numbers of mature B cells.

I'm a little confused by their conclusion regarding "a subtle tendency to autoimmunity", since they also state:
Patients with CFS do no have hypogammaglobulinaemia, predisposition to recurrent bacterial infections or symptoms of autoimmunity.
(Their typo, not mine. For a change.)

Should be interesting to read the entire thing, if someone has access.
 

snowathlete

Senior Member
Messages
5,374
Location
UK
That typo could be 'not' but it could be something else. It seems an odd statement to me if it is 'not' because arguably we do have symptoms of autoimmunity, and as already pointed out, this seems to conflict with their subsequent statement.

Anyway would these higher types of b cells mean that we had lower than normal levels of antibody producing B cells? But I'd have though Rituximab makes that situation worse, at least at first. As there seems to be a delay after Rituximab before patients improve, perhaps that corrects the levels meaning we get more antibodies but is be surprised if it was that simple and direct.

So much we don't know.
 

snowathlete

Senior Member
Messages
5,374
Location
UK
Does anyone know how these results compare to known autoimmune diseases?

The statement, "a subtle tendency to autoimmunity", might suggest that they have seen the same sort of B cell type proportions elsewhere.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
Patients with CFS do no have hypogammaglobulinaemia, predisposition to recurrent bacterial infections or symptoms of autoimmunity.

Ive had symptoms of autoimmunity.. my frozen shoulder when I was in my 30s, specialist said it must of been caused by that due to the age when my issue happened and hence why I had an abnormal state of healing happen. Ive heard of many of us having some kind of issues. (he put it down to my insulin issue as he couldnt think of anything else but surely I wouldnt be getting diabetes complications before Im even a diabetic with only a prediabetes state).

Maybe the ones who wrote that didnt know that many of us do at times get signs of autoimmunity.
...............

This new study is exciting and Im so happy they used the Canadian definition as well so we all at least know it was a good patient group which was used. (I hope they get a lot of thank yous from the ME/CFS community esp since we have such a reputation of knocking studies thou of cause they are usually poorly done ones who get our knocking).

Wondering if Dr Wessely or one of his boys will be involved now in doing a study on this same thing with his CFS criteria. He wont be happy about this study. (maybe he's got a new psych study ready for others to publish for him if this new study starts looking like it may make too much news). Study like this is damaging on his views.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
http://onlinelibrary.wiley.com/doi/10.1111/cei.12043/abstract

This was posted on another site.

Small B-cell study reports B-cell abnormalities in ME/CFS patients vs healthy controls.

Study of B-cell number and function should be a priority to understand Rituximab treatment.

This study should be used to push Advocacy efforts into more government funding as we need to get these studies done (using the same canadian criteria). It should be a priority.

We should make sure our societies are pushing for more funding and using this study as an example of one of the areas of study need.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
'Patients with CFS do no(t) have .......symptoms of autoimmunity'

I'd like to see the full paper to read this in context but this strikes me as a strange conclusion.

I would have thought that the symptoms would reflect the organ affected in single organ disorders or; if systemic, there would be a wide range of symptoms that would largely overlap with ME/CFS symptomology.

Are there symptoms that are common in autoimmune diseases but not in other types of disease?

I can't find a reliable source of 'common autoimmune symptoms'.

This summary is the best I can find at the moment :

http://www.allergy.org.au/patients/autoimmunity/autoimmune-diseases
 
Messages
16
the neuroinflammation up my spine and into my head, the lesions on my brain -- those are very clearly signs of autoimmunity, the way my body is always wired and i don't get colds, and when i finally do get colds i actually sleep -- all very much signs of autoimmunity. i'm happy about this paper but we all know that where we are in the me research right now is way ahead of where these scientists are: namely, we all know here already that there are definitely subsets of patients. some might be totally in the autoimmune camp (I know I'm one) and others may not, and the people studied for this probably are not. And that's fine. But it's very dangerous for us to have researchers like these saying what ME definitely is or isn't when a) they're not right, not across the board and b) ME 100 percent isn't one thing. And if the public believes it is, then every time some new paper saying this is exactly what ME is comes out, we're going to be at the mercy of the public's reaction to that one paper. that's why the XMRV fiasco was both so compelling and then so very defeating. we can't repeat that. the public needs to understand the multifariousness of this disease so that we're not doomed to repeat their sudden interest and then disinterest, so that people stop speaking for us who don't have the authority to...

I really hope people on here feel the way I do about this...i'm so tired of every one jumping on one thing, like this is gonna be the thing. i mean, i know for me, i'm looking toward the autoimmunity stuff, toward b cells, toward rituximab, yes. but i know my reality, while very complicated, is just my reality. and while others may share it, they may only share parts but not the entire whole and that still others may be very different...
 
Messages
15,786
Over the last decade we have observed an elevated prevalence of persistent fatigue in our patients with primary antibody deficiency and speculated on subtle B cell dysfunction in CFS.

So it looks like they got interested in a similar way that the Rituximab researchers did.

Importantly, Rituximab does not simply deplete CD20+ cells (B-cells) but has many mechanisms, including down regulating CD40L and CD80 on B-cells, decreasing CD4 effector cells, reducing NK cell numbers and activation, inducing macrophage maturation and reducing TNFa secretion and increasing the suppressive function of T regulatory cells [11]. However, the onset of B-cell depletion did correlate with reduction in symptoms, and with the expected appropriate lag phase.
So it might be more involved than simply depleting B-cells, though that seems to be an important aspect.


Defective antibody class switching and antibody production would result in recurrent infection, as seen in primary immunodeficiency states; however, a milder defect may lead to inappropriate immune response and possibly autoimmunity.

I think they're suggesting that autoimmunity may be a milder result on a spectrum that also includes immune deficiency.

Thus CFS patients may have some unusual, unrecognised autoimmune disease, or it is possible that CFS patients are unable to control lymphotropic viral infections due to some defect of B-cell memory or T-cell dysfunction.
I think this is what they're trying to figure out in this study, or at least getting a better idea about.

They also talk about auto-reactive B-cells usually getting destroyed when they're made, and speculate that we might have a problem with that destructive process.

Importantly, increased numbers of transitional B-cells have been reported in several patient groups with defective humoral immunity, including patients with SLE [27] [28], X-linked Lymphoproliferative disease, CVID, patients recovering from haemopoietic transplantation and neonates [29].

ZOMG, we're being compared to people wot have real diseases! :cool:

At some point, B cells can become either follicular B-cells or marginal zone B-cells. Follicular B-cells might become plasmablasts or memory B-cells, but the marginal zone B-cells always become plasmablasts.

One explanation for reduced plasmablasts in the CFS cohort is that increased numbers of transitional B-cells and naïve B-cells may overwhelm the B-cell maturation process, which may consequently become suboptimal. Alternatively T-cell help provided by cytokines may not support naïve B-cells to develop into plasmablasts.

They also seem very interested in eventually studying the B-cells before and after Rituximab use, to see how that alters B-cell populations. They're also interested in whether severe patients have more extreme results, since they were just studying moderate cases where some immune symptoms were only intermittent.


In conclusion we have observed patients with moderate CFS to have increased proportions of transitional and naïve B-cells and reduced plasmablasts. The precise basis for these findings is unclear and our work does not allow clarification of whether these changes are the cause of the CFS symptoms or the result of patient inactivity, sleep disturbance or raised stress. The therapeutic response to Rituximab suggests that B-cells are some how involved in the pathogenesis or perpetuation of CFS symptoms.

I don't much like the statement of possibility that B cells are the result, not the cause (which could imply our B-cells are messed up as a result of a theoretical false illness belief causing inactivity). But I think it's a good thing that they're admitting the issue isn't settled, instead of taking a political stance. Much more respectable than the conclusions psychological researchers to draw out of thin air anyhow :p
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
The Hospital Anxiety Depression scale (HADS) and clinical history were used to determine the presence of significant depression and anxiety. Clinically depressed patients (HADS depression >7) and those with significant anxiety (HADS anxiety >7) were excluded as both are known to affect the immune system. While low mood may be evident in those with CFS owing to the chronic nature of the symptoms, it is distinct from major depression as CFS patients do not generally exhibit the classic symptoms of depression: guilt, anhedonia and low motivation [13-15].

I'm beginning to think its a pity they were excluded.

If included and analysed separately we might have learned something. They may have had the same profile as controls; the same as the rest of the 'CFS' cohort; an altered profile in the opposite direction or perhaps even a more extreme profile than the rest of the cohort.
 

Enid

Senior Member
Messages
3,309
Location
UK
Thanks Gemini for posting - very interesting findings - as they say all grist to the mill (of understanding ME). Another move forward.
 

Gemini

Senior Member
Messages
1,176
Location
East Coast USA
This study should be used to push Advocacy efforts into more government funding as we need to get these studies done (using the same canadian criteria). It should be a priority.

We should make sure our societies are pushing for more funding and using this study as an example of one of the areas of study need.

I agree completely.

Advocates should make the FDA aware of this study's conclusion that "The therapeutic response to Rituximab suggests B-cells are somehow involved in the pathogenesis or perpetuation of CFS symptoms."

janet.woodcock@fda.hhs.gov Dir. Center of Drug Evaluation & Research
sandra.kweder@fda.hhs.gov Deputy Dir. of the Office of New Drugs

Researchers planning ME/CFS Rituximab trials should consider Dr. Bansal's interest "to monitor B-cell subsets of CFS patients before and after Rituximab treatment and monitor repopulation of the different B-cell subsets with the return of symptoms."