Long-lived plasma cell (LLPC) theory - Similarities between CFS and Lupus?

ryanc97 said:
For the studies, are there studies that showed difference in blood vs bone marrow NK cells? They have to measure both.
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For this one, frequency of total NK cells wasn't different between multiple myeloma responders and nonresponders in either bone marrow or blood.

What was different was higher proportion of CD16+ NK cells and lower TIM-3+ NK and HLA-DR+ NK cells in the bone marrow in responders. I'm not sure if they looked at the frequency of CD16+ NK cells specifically in the blood.

NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma, 2023
To this end, we compared BM [bone marrow] samples obtained from 21 responding patients (≥PR) with those from 30 nonresponding (primary refractory) patients by using flow cytometry (Figure 2A).
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The proportion of NK cells was similar between both the groups.
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Interestingly, nonresponding patients had higher proportions of HLA-DR+ (15.3 versus 9.3%, P = 0.043) and TIM-3+ NK cells (median 9.0 versus 5.6%; P = 0.005). In addition, nonresponders also had a lower proportion of CD16+ NK cells (73.3 versus 85.8%; P = 0.017).
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Similar to what we observed in the BM samples, the baseline frequency of NK cells in PB [peripheral blood] was comparable between responding and nonresponding patients.
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poetinsf said:
Such speculation is useless unless you can identify that subgroup somehow. Then you could run the trial again only on that subgroup to validate the theory. Otherwise, it's no different than saying that anything is possible. And that is how some people try to get away with failed trial.
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Isn’t the easier answer that if you argue that ritux worked for some, then you’re also arguing that saline worked for some because the groups were identical?
 
forestglip said:
I'm not sure if they looked at the frequency of CD16+ NK cells specifically in the blood.
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If I understood it correctly, this study looked at absolute count of CD16+CD56+ cells at baseline in the blood, like the ME/CFS study, and found no correlation with response to daratumumab:

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma, 2017
Total (CD16+CD56+) and activated (CD16+CD56dim, measured only in the SIRIUS study) NK cells were measured by real-time flow cytometry.
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logistic regression analyses confirmed the lack of a statistically significant relationship between ORR [overall response rate] and baseline NK-cell counts (P = .76)
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No significant differences in PFS [progression-free survival] were observed for baseline NK-cell counts [...] (P = .7 [...])
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forestglip said:
If I understood it correctly, this study looked at absolute count of CD16+CD56+ cells at baseline in the blood, like the ME/CFS study, and found no correlation with response to daratumumab:

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma, 2017
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That is interesting.

I wonder if the problem is with ORR, basically they did not regress the severity level in the patient alongside the NK cell baseline?

basically more severe MM patients might have had higher levels of NK and the effect cancelled out.
 
poetinsf said:
Such speculation is useless unless you can identify that subgroup somehow. Then you could run the trial again only on that subgroup to validate the theory. Otherwise, it's no different than saying that anything is possible. And that is how some people try to get away with failed trial.
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It is not clinically useless; there are many conditions where rituximab has not been proven as an effective treatment, and the subgroup for which it works is not identified, and they just give it to everyone because it still helps some %.... until they have better guns.
 
Pibee said:
It is not clinically useless; there are many conditions where rituximab has not been proven as an effective treatment, and the subgroup for which it works is not identified, and they just give it to everyone because it still helps some %.... until they have better guns.
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Do you have any examples?
 
Utsikt said:
Do you have any examples?
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There are plenty of conditions for which doctors give rituximab to everyone without knowing if it works. But of course that doesn't mean it helps some % in those conditions. Whether or not it is clinically useless there is unproven. The original suggestion was useless not because we don't know the subgroups in ME/CFS but because we can be fairly confident there aren't any and nobody is going to repeat the trial so we might as well keep our speculations free of suggestions it might work
 
Jonathan Edwards said:
The original suggestion was useless not because we don't know the subgroups in ME/CFS but because we can be fairly confident there aren't any and nobody is going to repeat the trial so we might as well keep our speculations free of suggestions it might work
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Is there a thread someplace where the argument/evidence against the existence of subgroups is laid out? I have not been able to find one and, given the popularity of the idea among so many ME/CFS clinicians/researchers/patients (and yes, I know that can be said of all kinds of wild notions and speculation), I would be curious.
 
DHagen said:
Is there a thread someplace where the argument/evidence against the existence of subgroups is laid out?
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The argument is simple common sense, which you can give statistical numbers to if you want.

The changes in scores seen after both rituximab and placebo were not trivial in a good number of cases. So we are not looking for a subgroup with a slight improvement. If a measly 10% of cases are responders then you would expect at least some difference between the two groups. There is a small chance it would not show up but the groups would need to be weighted quite a bit to give the completely null difference seen.

The other important argument is that any claim that there is a subgroup can only be based on some people getting quite a lot better. But people on placebo must have done to the same extent so the argument from cases is empty.

And I don't think you will find many clinicians or researchers who would be persuaded. There are always a few enthusiasts and unfortunately, in this age of social media, the enthusiasts dominate the narrative in the gossip space. Ask any intelligent clinician or researcher what they think from the results and they will say there was no evidence of a responder subgroup.
 
Jonathan Edwards said:
The changes in scores seen after both rituximab and placebo were not trivial in a good number of cases. So we are not looking for a subgroup with a slight improvement. If a measly 10% of cases are responders then you would expect at least some difference between the two groups. There is a small chance it would not show up but the groups would need to be weighted quite a bit to give the completely null difference seen.
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Thank you very much for the response and explanation - I believe I may have misunderstood the initial post, as I took it to indicate the absence of any ME/CFS subgroups overall, rather than with specific reference to the rituximab study. This is also useful information, however, at least for me - even if it may be merely common sense.
 
DHagen said:
Is there a thread someplace where the argument/evidence against the existence of subgroups is laid out? I have not been able to find one and, given the popularity of the idea among so many ME/CFS clinicians/researchers/patients (and yes, I know that can be said of all kinds of wild notions and speculation), I would be curious.
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I used to believe in subgroups but I believe now with the Dara trial there are no subgroups.
 

Autoantibody origins in lupus and in relapse post CAR-T therapy​


Abstract​

Anti-CD19 chimeric antigen receptor (CAR)-T therapy induces profound remissions in lupus by depleting B cells, challenging the longstanding view that treatment-resistant disease is sustained by long-lived plasma cells. Additionally, emerging relapses highlight the need to understand how pathogenic autoantibodies arise. Using molecular antibody tagging in mice with human monogenic lupus variants, we reveal that autoantibody-producing cell cohorts are long-lived but plasma cells are short-lived, requiring continuous replenishment from proliferating precursors. The spleen acts as a major plasma cell reservoir, with perivascular localization conserved in mice and lupus patients. Relapse after anti-CD19 CAR-T occurred through newly-generated B cells rather than treatment-resistant clones. Plasma cell depletion by anti-BCMA CAR-T failed to eliminate some precursors that become autoantibody-secreting. These findings demonstrate that continuous B cell-to-plasma cell differentiation, not intrinsic plasma cell longevity, sustains pathogenic antibody responses in lupus, supporting a potential benefit of adjunctive therapies after CAR-T, particularly in genetically predisposed patients.

Any potential relevance to ME/CFS @Jonathan Edwards ?
 
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