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Plasma cells as an innovative target in autoimmune disease with renal manifestations

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
This seems like an intriguing article,
Does anyone have access, so to give their verdict?
I gather it`s relevant for us that treatments like rtx may not in a subset be effective against long lived plasma cells indirectly, and this has been discussed here before.

"Autoantibodies are secreted by plasma cells and have an essential role in driving the renal manifestations of autoimmune diseases such as systemic lupus erythematosus and antineutrophil cytoplasmic autoantibody-associated vasculitis. Effective depletion of autoreactive plasma cells might be the key to curative treatment of these diseases. Two major plasma-cell compartments exist: short-lived plasmablasts or plasma cells, which result from differentiation of activated B cells, and long-lived plasma cells, which result from secondary immune responses. Long-lived plasma cells reside in survival niches in bone marrow and inflamed tissue and provide the basis of humoral memory and refractory autoimmune disease activity. Unlike short-lived plasmablasts, long-lived plasma cells do not respond to conventional immunosuppression or to therapies that target B cells. Existing therapies that target long-lived plasma cells, such as proteasome inhibitors and antithymocyte globulin, as well as promising approaches that target survival factors, cell homing or surface molecules, deplete the whole memory plasma cell pool, including cells that secrete protective antibodies. By contrast, we have developed a novel strategy that uses an affinity matrix to deplete pathogenic long-lived plasma cells in an autoantigen-specific manner without removing protective plasma cells. Targeting B-cell precursors to prevent replenishment of autoreactive long-lived plasma cells should also be considered."

@Jonathan Edwards? :)

http://www.nature.com/nrneph/journal/vaop/ncurrent/full/nrneph.2016.20.html
 

msf

Senior Member
Messages
3,650
Dunno if it´s included in the above group, but there is a trial of Rituximab in IgA Nephropathy going on at the moment.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
After reading the article I think we might be looking at something very essential for ME/CFS. Long lived plasma cells were not known of before 1997, and cyclo and rtx are ineffective in removing them!
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
Just read this on wiki.. "Differentiation of mature B cells into plasma cells is dependent upon the transcription factors Blimp-1/PRDM1 and IRF4."

Is it possible to target these transcription factors @Jonathan Edwards? Or will it cause too big of a hole in a persons immunity, as I seem to recall you have suggested before, when it comes to plasma cells.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Just read this on wiki.. "Differentiation of mature B cells into plasma cells is dependent upon the transcription factors Blimp-1/PRDM1 and IRF4."

Is it possible to target these transcription factors @Jonathan Edwards? Or will it cause too big of a hole in a persons immunity, as I seem to recall you have suggested before, when it comes to plasma cells.

I am not sure there is much point in targeting the switching signals (transcription factors). Once the cells are plasma cells they are invisible to such targeting. If you remove b cells with rituximab there are no B cells to be switched. The problem is the mature plasma cells hiding away for years in bone marrow. There probably are ways to deplete them but at the moment there is very little political will in the science community to explore this - except perhaps from Andreas Radbruch's group. Still, it is useful to know all the pathways and it is just conceivable that blocking the plasma cell generation step would be a more easily reversible way to block continued plasma cell presence than continued rituximab usage.
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
I am not sure there is much point in targeting the switching signals (transcription factors). Once the cells are plasma cells they are invisible to such targeting. If you remove b cells with rituximab there are no B cells to be switched. The problem is the mature plasma cells hiding away for years in bone marrow. There probably are ways to deplete them but at the moment there is very little political will in the science community to explore this - except perhaps from Andreas Radbruch's group. Still, it is useful to know all the pathways and it is just conceivable that blocking the plasma cell generation step would be a more easily reversible way to block continued plasma cell presence than continued rituximab usage.

Cool, gotccha!

Is that group conducting any research now?

And do you think it`s possible that some mechanism independent of B-cells, may keep those presumed dysfunctional long lived plasma cells (or maybe short lived as well), alive for longer than "usual"? (as far as i understand, there`s very little research on their longevity)

I`m actually having another bone marrow biopsy in three months, when I have been approx 4 months on rituximab. I`ll ask them to have a look out for plasma cells and b-cells, to compare my biopsies. Could be interesting!
 
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Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
As a side note,

I`m perplexed as to why there`s a lack of political will to look into this. I mean, surely long lived plasma cell removal will be the holy grail for many known autoimmune diseases (such as Lupus), but probably also for some undiscovered ones. Of course the LPP`s when pathological, are part of a larger immune dysregulation, but they still must be dealt with somehow.

There seems to be two approaches drug companies take before conducting research

Either,

1. Money on the table beforehand from the governement or others

or

2. Going all out on the basis of a reasonably well founded hypophesis

I miss a scientific culture where the latter is the rule rather than the exception.
 

wastwater

Senior Member
Messages
1,271
Location
uk
Hi there I'll try
I have a rare genetic disorder riegers syndrome and someone else who has it managed to get a whole genome scan,
and only faults came back on chromosome 6,
IRF4 was one gene that was mentioned Along with CCR6
AS I think riegers syndrome,for some,maybe 20 percent,seems to come with an immune problem very much like ME/cfs with fibromyalgia being the most common diagnosis
This is what raised my interest
For completeness the other genes were HUS1B FOXQ1/F2 and C1 plus GMDS that has something to do with NADP+
 
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wastwater

Senior Member
Messages
1,271
Location
uk
IRF4 is also called MUM1
An article mentioning MUM1 and CFS which maybe of interest
EBV-driven B cell lymphoproliferative disorders:from biology, classification and differential diagnosis to clinical management
At www.nature.com
Side note :CCR6 was an error
 
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wastwater

Senior Member
Messages
1,271
Location
uk
IRF4 is interferon regulatory factor 4 (T helper cells th2 th17 th9 )
GMDS is GDP-manose 4,6-dehydratase ,I think this can be involved in congenital disorders of glycosylation,im not sure what glycosylation is but have seen it mentioned on PR
might be involved in glucose and carbohydrate use
 
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wastwater

Senior Member
Messages
1,271
Location
uk
Professor ulf Klein, B cell disorders and amazingly two locations for riegers syndrome
Study's non Hodgkins lymphoma
Probably a B cell disorder for me then,wonder if rituximab would work
Research axenfeld Rieger syndrome for autism and ME
FOXC1 for IRF4 at 6p25 and FOXO1A for 13q14
Don’t know if ulf is even aware there Axenfeld Rieger Syndrome genetic locations,that’s a good thing as it’s not the important bit the B cell dysfunction is
 
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