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.
Click to expand...

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).
Click to expand...
The proportion of NK cells was similar between both the groups.
Click to expand...
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).
Click to expand...
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.
Click to expand...
 
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.
Click to expand...
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.
Click to expand...

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.
Click to expand...
logistic regression analyses confirmed the lack of a statistically significant relationship between ORR [overall response rate] and baseline NK-cell counts (P = .76)
Click to expand...
No significant differences in PFS [progression-free survival] were observed for baseline NK-cell counts [...] (P = .7 [...])
Click to expand...
 
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
Click to expand...
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.
Click to expand...

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.
Click to expand...
Do you have any examples?
 
Utsikt said:
Do you have any examples?
Click to expand...

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
Click to expand...
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?
Click to expand...

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.
Click to expand...
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.
Click to expand...
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 ?
 
ryanc97 said:
Hi everyone,

So as you know I am a big fan of Fluge and Mella and the Daratumumab/Cyclophosphamide hype train. Why is because to me it looks like the remissions induced by Dara indicate that LLPC dysfunction is the cause.

My working theory is that post infection, you have this vulnerable window where any exertion triggers a faulty evolution of a batch of B cells into faulty LLPCs that produce harmful AABs for the rest of your life giving you CFS.

But then, if LLPCs are the culprit, does this not bear similarity to Lupus, which is an auto-antibody driven disease. And Daratumumab and Teclistamab have been trialed to some success in Lupus patients.

So to me, if LLPC theory is true, then it would seem Lupus and CFS are the same kind of disease, but of course, CFS QoL is much worse than Lupus QoL, so the AABs produced are probably more damaging.

An example is that you can go to the Lupus reddit and search the term 'exercise' and you get results suggesting Lupus patients can exercise no problem.

> Two other immunologic markers were recognized in the 1950s as being associated with lupus: the biologic false-positive test for syphilis and the immunofluorescent test for antinuclear antibodies. Moore, working in Baltimore, demonstrated that systemic lupus developed in 7 percent of 148 individuals with chronic false-positive tests for syphilis and that a further 30 percent had symptoms consistent with collagen disease.

I would like to ask @Jonathan Edwards on the history of Lupus, from my understanding, some scientists in the 1950s discovered that majority of Lupus patients had this ANA antibody? How does this compare to the current state of researchers in CFS looking at autoantibodies? Like Scheibenbogen?

And how does this reconcile with LLPCs or at least one of Plasmablast/SLPC/LLPC being the problem?

TLDR - Daratumumab and Teclistamab, two treatments looked at by Fluge/Mella and Habets (ok I know he is not a proper researcher) have been used in studies to treat serious Lupus patients with success.

I also find the difference in papers administering MABs to Lupus patients quite interesting. The researchers focus on the biomarker, ANA, and do not focus on the patient response, like SF36, step count etc. They use Scores on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K, a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity).

So since the treatment (targeting lymphocytes) is the same, perhaps they are similar and we can learn something about CFS by looking at the history of Lupus, it's discovery, and it's current treatments? Are they part of the same picture or related?

When someone comes in to say no AABs have been detected in CFS, is it possible the technology just isn't there to detect the AABs produced by CFS? I know we've all heard about B2ADR AABs, GPCR AABs, is there maybe hidden ones that the current tests just dont screen for?
Click to expand...
Linking ME/CFS to long-lived plasma cell dysfunction offers a logical explanation for its chronic and relapsing nature. When these faulty plasma cells continue producing autoantibodies, the immune system stays in a constant state of activation. Treatments such as Daratumumab that target plasma cells could clarify whether the mechanism overlaps with Lupus, where similar immune pathways cause sustained inflammation and tissue damage.
 
robby66 said:
Linking ME/CFS to long-lived plasma cell dysfunction offers a logical explanation for its chronic and relapsing nature. When these faulty plasma cells continue producing autoantibodies, the immune system stays in a constant state of activation. Treatments such as Daratumumab that target plasma cells could clarify whether the mechanism overlaps with Lupus, where similar immune pathways cause sustained inflammation and tissue damage.
Click to expand...
Did you use ChatGPT to write this
 
You must log in or register to reply here.
Back
Top Bottom