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Long-Lived Plasma Cells in Autoimmunity: Lessons from B-Cell Depleting Therapy

Jonathan Edwards

"Gibberish"
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5,256
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873528/

Maybe one of the reasons Rituximab doesn't work in all ME/CFS patients, not only do B cells remain in lymphoid organs after treatment but also B cell depletion promotes creation of much longer lived plasma cells pumping out autoantibodies.

The authors interpretation is a bit peculiar to my mind. Rituximab will not encourage creation of longer lived plasma cells since by killing memory B cells it cuts off new supply of plasma cells, at least autoimmune ones. Autoantibodies do not go up, but they may go down with variable speed. What does seem likely is that the plasma cells already in the spleen live longer - but this is not very surprising since there will be no competition from further new generation of plasma cells, which may be a major factor in spleinc plasma cells normally being short lived - i.e. unless they go off to bone marrow they get competed out within about three months. I entirely agree with the practical conclusion that targeting plasma cells on top of rituximab makes sense but I think we knew that right from 1998. The precise reasons why reamining plasma cells live a bit longer may not make a lot of difference!
 

leokitten

Senior Member
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1,542
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U.S.
Sorry @Jonathan Edwards my quick paraphrasing changed the meaning, should've been differentiation instead of creation:

"the B-cell depletion itself, by altering the splenic milieu, promoted the differentiation of short-lived auto-immune plasma cells into long-lived ones."
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Sorry @Jonathan Edwards my quick paraphrasing changed the meaning, should've been differentiation instead of creation:

"the B-cell depletion itself, by altering the splenic milieu, promoted the differentiation of short-lived auto-immune plasma cells into long-lived ones."

You did shift the meaning a bit, but the implication is sort of there in the paper - I think there is a slightly dubious use of counterfactuals in the argument - i.e. a slightly artificial conception of 'what would have been'. I amy be being unfair but I think they are trying to justify using some rather uninteresting data by using it to support a very good point that can bear repeating - so no harm done.
 
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53
Location
Oregon
I saw the word plasma cell and it immediately got my attention!

Plasma cells are notoriously difficult to target and treat, thus why treatments for multiple myeloma (plasma cell myeloma) are often times not successful. They are hardy little buggers, to put it bluntly. To toss in a little bit more confusion on the issue, the transition from mature B cell to plasma cell is not necessarily a discrete, quantum leap. There are numerous intermediaries along the way, some with more surface Fc receptors, less cytoplasmic Ig, and others more akin to mature plasma cells with few surface Fc and abundant Ig in cytoplasm. We see proof of this in the great diversity of mature B cell lymphoma subtypes. Sometimes, it can be very difficult to fit some of these cells into a definite diagnostic category. Also, some seemingly mature plasma cells show surface expression of CD20, so may in fact get targeted and depleted by Rituxan. One of the statements in the article I don't agree with is that splenic plasma cells lack CD138 expression. To my knowledge, that antigen is a defining feature of plasma cell differentiation. I have seen plenty of CD138 positive plasma cells in splenic tissue! Perhaps they are referring to splenic marginal zone, or post germinal center, B cells. Anyhow, interesting post!
 

Jonathan Edwards

"Gibberish"
Messages
5,256
I agree, after reading this paper and thinking the same thing about depleting plasma cells there are a number of anti CD319 mabs in research, e.g.:

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

Thanks for bringing this to my attention. I was not aware of CD319. Wikipedia is not much help because it just gives, under an entry for SLAMF7=CD319 that it is encoded by the SLAMF7 gene! I wonder if this is truly a plasma cell specific target? The problem with plasma cell targets like CD38 and CD138 has been that these targets are also present on cells you would not want to upset, like heart cells, for instance. There ought to be some plasma cell specific surface ligands but I had not found one until now.

The paper you quote reports a lot of completely irrelevant stuff about residual circulating plasmablasts, synovial fibroblasts and use of transgenic mice which we can do without completely (the synovial and circulatory environments are essentially unimportant here, what matters is bone marrow). All we need to know is whether or not this antibody targets something that kills non-malignant plasma cells without causing major problems through cross talk with other cells. I would like to know if, for instance, it produced hypogammaglobulinaemia in macaques (their surface markers tend to cross react pretty well) without killing them.

Interesting find. I will have to read up.
 

leokitten

Senior Member
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1,542
Location
U.S.
@Jonathan Edwards it looks like CD319 is a good, specific surface antigen for mature plasma cells.

On Wikipedia:
"Another important surface antigen is CD319 (SLAMF7). This antigen is expressed at high levels on normal human plasma cells. It is also expressed on malignant plasma cells in multiple myeloma. Compared with CD138, which disappears rapidly ex vivo, the expression of CD319 is considerably more stable.[10]"

Differential expression of SLAMS and other modulatory molecules by human plasma cells during normal maturation

Also found another anti CD319 mab that's in clinical trials, Elotuzumab, for mutiple myeloma. http://en.m.wikipedia.org/wiki/Elotuzumab

Would be exciting to see what anti CD20 + anti CD319 would do for autoimmune diseases and ME/CFS.
 
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leokitten

Senior Member
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1,542
Location
U.S.
Also found that B cell maturation antigen (BCMA), also called CD269, is showing to be a useful target for plasma cells and there are anti-BCMA antibodies being developed, again for multiple myeloma. BCMA also seems to be essential for plasma cell survival.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
Elotuzimab looks intriguing! Could a positive phase 3-trial warrant a study with it on ME-patients?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Elotuzimab looks intriguing! Could a positive phase 3-trial warrant a study with it on ME-patients?

I think the problem with using a plasma cell removing drug at this point is that it would produce a major hole in the person's immunity which might not be easy to patch up with re-vaccination. This might be justifiable in myeloma and it might be justifiable in ME with an autoimmune basis but it would be hard to justify in cases of ME that turned out not to be autoimmune. I think plasma cell targeting will need to be explored in other autoimmune diseases before it is fair to try it in ME even if the phase 3 rituximab trial is positive.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
What about plasmapheresis together with anti CD20 to relieve a person of ME symptoms?

Plasmapheresis has the advantage of producing a rapid benefit but it is very expensive and at least in the past with quite serious side effects at times. The benefit will only be temporary - maybe 3-6 weeks. If short lived plasma cells are still around there would be a relapse before they finally die off (assuming autoimmunity). I think if the B cell approach proves to work it may be more sensible to wait for the rituximab to do its job, but there are neuroimmunologists who like plasmapheresis for other conditions.
 

deleder2k

Senior Member
Messages
1,129
If the benefit is temporary, say 3-6 weeks - then one could argue that 2 rounds were enough before one would see benefit with RTX.

I didn't know that it could lead to serious side effects. F&M have also been suggesting MTX. Could a combination of Anti CD20 and MTX be beneficial produce a more rapid benefit than RTX alone? Does MTX "attack" plasma cell and stop cells from dividing?
It seems that patients repond from 6 weeks to 104 weeks with Rituximab. We need something that eases symptoms quickly.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
If the benefit is temporary, say 3-6 weeks - then one could argue that 2 rounds were enough before one would see benefit with RTX.

I didn't know that it could lead to serious side effects. F&M have also been suggesting MTX. Could a combination of Anti CD20 and MTX be beneficial produce a more rapid benefit than RTX alone? Does MTX "attack" plasma cell and stop cells from dividing?
It seems that patients repond from 6 weeks to 104 weeks with Rituximab. We need something that eases symptoms quickly.

I understand the desire for a rapid response but I think the logistics of testing plasmapheresis properly may be more complex than the likely benefit justifies. There are too many unknowns I think, although I may be wrong.

Methotrexate might help early on but patients with RA do not like it much and it has too broad an action for it to provide us with explanatory information. Again I lack enthusiasm for that avenue, but only in the sense that I think it would be better to focus resources elsewhere.
 

deleder2k

Senior Member
Messages
1,129
Thank you for your answer, professor.

I know that Haukeland has experimented with the use of plasmapheresis. To my knowledge they have decided not to pursue it further.

I have been talking to a few individuals included in the latest study - and they have all responded favourably. Lets hope that cyclophosphamide does the job.
 

Sasha

Fine, thank you
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17,863
Location
UK
https://www.facebook.com/permalink.php?story_fbid=909625032428489&id=171411469583186

MEA said:
WE'RE ALMOST READY WITH ANOTHER ANNOUNCEMENT ABOUT MITOCHONDRIAL RESEARCH FUNDING

Dr Charles Shepherd writes:

The MEA Ramsay Research Fund will shortly be making an important announcement about further funding for mitochondrial research in ME/CFS.

We have recently funded a study that was carried out by Professor Julia Newton et al in Newcastle. We are currently co-funding (with the MRC) a study at the University of Newcastle costing £30,000 and we have donated £5000 to assist Dr Joanna Elson in Newcastle with her work on mitochondrial DNA.

The MEA RRF regards mitochondrial research as a high priority research item.

http://www.bbc.co.uk/news/health-33509823

How apropos!
 
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2,087
I have been talking to a few individuals included in the latest study - and they have all responded favourably. Lets hope that cyclophosphamide does the job.

Is this the cyclophosphamide trial and if so can you elaborate ? I've read the side effects of cyclo can be bad, is that why the trial doesnt include mild ME patients ?