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

[Jonathan Edwards]

I don't know if the below are a dumb questions, but what the heck...

In autoimmunity, the immune system can start attacking cells of the body itself. Can the immune system also attack... the immune system?

Could this cause a perpetual war, with the body re-supplying both sides with new "soldiers"?

Or maybe there's only one side. Could defective immune cells actually be attacking other immune cells with the exact same defect?

Would any of this wind up looking like chronic immune activation?

I missed this question. I think the answer may be that autoimmunity is almost always a war within the immune system itself that spills over sometimes to other organs. Lupus would be the best example of the immune system fighting itself - with complement and anti-complement antibodies at centre stage. Or you could say rheumatoid was with anti-antibodies (rheumatoid factors) at centre stage.

 

[Bob]

From another thread...

I haven't read through all the recent comments so forgive me if this has been referred to already - that the paper on the initial B-cell study in the Invest in ME Research has now been published in hard copy. I mention it here as this work is being done in close collaboration with the Norwegian team and is adding value to the Phase III trials. Collaboration on the rituximab-related studies also includes researchers in Spain, Sweden and Germany. It will be, hopefully, be further facilitated by the European ME Research Group, formed in 2015 by the European ME Alliance, and as usual, by the Invest in ME Conference & Colloquium events, where the Norwegian rituximab research is presented and discussed. This UK research is being crowdfunded and a blog was posted by Let's Do It for ME today - http://ldifme.org/first-paper-published-from-iime-funded-research/

 

[Jo Best]

From another thread...

Thanks Bob. Apparently, it was published in an early view of the journal not hard copy yet.

 

[Gemini]

In autoimmunity, the immune system can start attacking cells of the body itself. Can the immune system also attack... the immune system?

Could this cause a perpetual war, with the body re-supplying both sides with new "soldiers"?

Example I'm most familiar with--in Selective IgA Deficiency, up to 40% of patients have IgG autoantibodies to IgA, i.e.,one compartment of the immune system, IgG, attacking another, IgA.

As a result many IgA deficient patients have no detectable levels of IgA.

 

[anciendaze]

Just a comment here. Immune systems are in a continual state of war not only with foreign pathogens, but also with their own cells that would cause autoimmune disease. Health is not so much a period of true peace as a kind of détente in which no faction risks going nuclear. There's a reason the thymus is close to the heart, since eliminating cytotoxic immune cells that would attack heart tissue is literally a matter of life and death. An enormous amount of selection takes place as immune cells mature. Both generating novel cell types as required and rigorous selection play major roles in normal immune function, but typically we don't become aware of this unless the situation is deemed pathological.

Now, on to the reason I came to this thread. I just noticed a new paper on the effects of Rituximab which seemed relevant to this discussion, though I have not finished reading. In the case of demyelinating diseases of the CNS it appears that, beyond depleting some classes of immune cells, Rituximab actually stimulates clonal expansion of other cells.

Rituximab induces clonal expansion of IgG memory B-cells in patients with inflammatory central nervous system demyelination

Added: after reading this paper, I found something suspected, that the repopulation by clonal expansion after treatment is largely a matter of chance. You might hope to deplete memory B-cells causing autoimmune disease, and have them replaced with naive B-cells, but it is entirely possible clonal expansion of surviving memory B-cells will return the patient to the status quo ante. B-cell depletion has other negative effects which present risks during the process. This is not a panacea.

We really need a better idea of which cells to target.

 

[Cheshire]

First Paper Published from IiME-funded Research at UCL - Layman's Summary

Recently the first paper was published from IiME-funded research which was initiated by IiME and supporters at University College London (UCL) [1].

We asked Dr Jo Cambridge and Fane Mensah from the UCL team to explain, in layman's terms, what the paper was describing.

This was their summary -

http://www.ukrituximabtrial.org/Rituximab news-Mar16 01.htm

 

[BurnA]

@Jonathan Edwards would you be able to compare this study with the recent NIH announced study in terms of level of detail or focus. This seems to be extremely focused, looking at particular molecules on b cells. It frightens me a bit , that such a study which appears to be extremely detailed could take such a length of time and not reveal anything conclusive.
Not that I expect every detailed study to reveal something conclusive but....
I find it easy to get excited about the NIH study due to its scale but would they be testing down to such a specific level of detail as this study does ? And if not is it less likely they would find anything ?


I hope I am expresssing myself clearly. I am beginning to see what you mean by Higgs Boson and not knowing what you are looking for. I get the impression there could be many studies of this type and scale and none would necessarily prove conclusive.

 

[Jonathan Edwards]

The NIH study sounds big and that is good. But attention to detail also matters. There is probably never much point in asking these questions even of one's own work as long as one is doing one's best to get an answer. Nobody knows how the answers are going to turn up.

 

[Sasha]

I don't know if people have noticed the layman's summary that Jo Cambridge and Fane Mensah produced for IiMe:

http://www.ukrituximabtrial.org/Rituximab news-Mar16 01.htm

We would like to thank all the patients - and their friends and families - for participating in the UCL B Cell Phenotype study.

As a result of their generous donations of time and blood, we are delighted that our B cell Research Programme (funded by IiME) has been compiled and accepted for publication in a peer reviewed journal, Clinical and Experimental Immunology.

This is the official Journal of the British Society of Immunology.

The initial aim of our studies was to investigate whether there was any difference between surface markers expressed on B cells from patients with ME/CFS and those from age and sex matched healthy controls.

We looked at the % cells positive and also the number of markers per B cell, of 18 different markers expressed on B cells.

As you are aware, promising results have been reported from Norway in 2 earlier B cell depletion (Rituximab) trials and we are investigating many aspects of B cell function which may indicate, firstly, why Rituximab seems to work and to also identify patients most likely to benefit from this or related therapies.

In our study we have found no significant differences between the 10 traditional B cell subsets of ME/CFS patients compared to those from controls.

We then added in additional markers in order to further extend this characterization.

Here we did find an increase in a molecule expressed on ‘new’ B cells, that is the ones most recently exiting the bone marrow.

This is a differentiation marker called CD24.

CD24 polymorphisms (genetic changes) have also been described in different autoimmune diseases.

CD24 is a cell ‘adhesion’ molecule which is involved in the way B cells interact with other cells and with their surroundings.

This marker is important in the early stages of B cell maturation, where it is also at its highest expression and it is where we have found the differences.

We have also found another B cell phenotype which may be related in a negative way with disease duration.

We hope to extend these studies to other ME/CFS cohorts in other centers.

We will now continue to investigate the functional consequences of these changes in CD24 expression to get a better picture of what these findings may mean in relation to ME/CFS symptoms and in relation to what is found following Rituximab therapy.

Are you able to give us any kind up update on the programme overall, @Jonathan Edwards?

 

[BurnA]

I don't know if people have noticed the layman's summary that Jo Cambridge and Fane Mensah produced for IiMe:

http://www.ukrituximabtrial.org/Rituximab news-Mar16 01.htm



Are you able to give us any kind up update on the programme overall, @Jonathan Edwards?

Thanks Sasha. Yes this summary is what prompted my question above. This study sounds so detailed, my opininion is that if there is going to be a breakthrough in the next 3 or so years it will come from UCL or a similar type research facility doing highly specific work.
I think the NIH and OMF studies are great and badly needed but my laymans guess is it will take 2-3 years for them to get to the level of detail required to make a significant breakthrough.

Of course their initial studies may lead them in a different direction altogether than current work, so the wait could very well be worth it.

In the meantime If the current ongoing research is looking in the right places it might be just a question of time before they find something. The more studies like this that I see the more I realise how difficult it must be for researchers.

I am kind of fascinated that the UCL group who already knew so much about b cells, could be involved for about 2 years trying to figure out the rituximab response and still find nothing conclusive. In my naivety when I first read about this study I thought they would have it cracked by now!
It is difficult for me to fathom the magnitude of the task.

 

[BurnA]

I don't know if people have noticed the layman's summary that Jo Cambridge and Fane Mensah produced for IiMe:

http://www.ukrituximabtrial.org/Rituximab news-Mar16 01.htm



Are you able to give us any kind up update on the programme overall, @Jonathan Edwards?

Thanks Sasha. Yes this summary is what prompted my question above. This study sounds so detailed, my opininion is that if there is going to be a breakthrough in the next 3 or so years it will come from UCL or a similar type research facility doing highly specific work.
I think the NIH and OMF studies are great and badly needed but my laymans guess is it will take 2-3 years for them to get to the level of detail required to make a significant breakthrough.

Of course their initial studies may lead them in a different direction altogether than current work, so the wait could very well be worth it.

In the meantime If the current ongoing research is looking in the right places it might be just a question of time before they find something. The more studies like this that I see the more I realise how difficult it must be for researchers.

I am kind of fascinated that the UCL group who already knew so much about b cells, could be involved for about 2 years trying to figure out the rituximab response and still find nothing conclusive. In my naivety when I first read about this study I thought they would have it cracked by now!
It is difficult for me to fathom the magnitude of the task.

 

[green_monster]

A paper has just been published in 'Immunity' by a different team at UCL.

A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus

It concerns Lupus / B cells contributing to SLE / response to Rituximab possibly determined by genes

Full paper here
http://www.sciencedirect.com/science/article/pii/S1074761316300504

Both the ME paper and this Lupus paper mention the maturation of B cells and both mention CD24.

Have the findings from these two papers got anything in common? Can this Lupus research shed any light on B cells and Rituximab in ME? I'm really curious. Are you able to make any comment on this, @Jonathan Edwards?

 

[Jonathan Edwards]

A paper has just been published in 'Immunity' by a different team at UCL.

A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus

It concerns Lupus / B cells contributing to SLE / response to Rituximab possibly determined by genes

Full paper here
http://www.sciencedirect.com/science/article/pii/S1074761316300504

Both the ME paper and this Lupus paper mention the maturation of B cells and both mention CD24.

Have the findings from these two papers got anything in common? Can this Lupus research shed any light on B cells and Rituximab in ME? I'm really curious. Are you able to make any comment on this, @Jonathan Edwards?

Lots of people at UCL picked up on our rituximab work and have set up their own projects. To be honest I am doubtful that regulatory B cells are a real phenomenon. I have never been able to make much of the idea. I doubt this is of any relevance to ME.

 

[BurnA]

For Twitter fans...Fane has started #tweeBing

https://twitter.com/i/web/status/717761633490173952

 

[Jo Best]

For Twitter fans...Fane has started #tweeBing

Just a reminder of links to Invest in ME news about Fane in 2015 -

July: Fane wins UCL IIT early career researcher poster competition of all microbiology projects at UCL on his project "Extended B-cell phenotype in Myalgic encephalomyelitis/Chronic Fatigue Syndrome: a cross sectional study",
speaks at young scientist meeting at GlaxoSmithKline, Royal Free and UCL postgraduate day,
and the European Congress of Immunology in Vienna.
"Fane’s enthusiasm is creating enormous awareness of ME in the academic research community."
"Fane's commitment and dedication to this research and the cause is admirable."
http://www.ukrituximabtrial.org/Rituximab news-Jul15 01.htm (inc. other news about students).

May: Dr. Jo Cambridge and Fane Mensah Speak at IIMEC10 conference (available on DVD) -
http://www.investinme.eu/IIMEC10.shtml#agenda

January: ME/CFS – Through The Eyes of a Young Researcher -
http://www.ukrituximabtrial.org/Rituximab news-Jan15 01.htm

 

[Marky90]

He seems utterly devoted to solving the mystery. Fantastic!

 

[Jo Best]

It's 10 years this month that Invest in ME set up as a charity, and especially as it's ME Awareness Month, a timely note of my appreciation of Invest in ME for engaging the keen interest of @Jonathan Edwards in the field of ME/CFS research and huge thanks to him for staying the course and making an invaluable contribution.

Extracts from Jonathan Edwards statement following the 2013 Invest in ME Conference:
http://www.ukrituximabtrial.org/Rituximab news-July13 01.htm

"My interest in ME/CFS was sparked when I was invited, unexpectedly, by IiME to the IiMEC8 Conference in May.

"The meeting was impressive: not just professional science, but at a high level. I was particularly impressed that negative findings were given adequate weight.

"It became clear to me that there was a community committed to identifying and encouraging the very best research in a difficult and neglected field.

"After the IiME Conference I began thinking about my personal experience of patients and friends with ME/CFS. I was sent a copy of ‘Lost Voices ‘ by IiME, which made me think more. It struck me that, whether or not results are positive, further trials of rituximab for ME/CFS should be encouraged not only because impact on life for those affected can be so severe but also because further trials could give clues to disease mechanism. I am retired and would not be personally involved but have suggested to IiME that I would be happy to advise and to encourage others to set up a trial." From - http://www.ukrituximabtrial.org/Rituximab news-July13 01.htm

A Let's Do It for ME blog published today -
http://ldifme.org/2016/05/05/lets-celebrate-10-years-of-invest-in-me/

includes an online group card to be delivered 31st May, which well-wishers are welcome to sign -
http://www.groupcard.com/c/yfljtH8RVOR/

and a donation link with more info on the charity and their projects -
https://secure.thebiggive.org.uk/charity/view/6239

Jo Cambridge will be presenting at London IIMEC11 3rd June -
http://www.investinme.eu/IIMEC11.shtml#agenda