Whats does this B cell depletion study mean?


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However, some subsets of pro-inflammatory B-cells were increased, indicating that some B-cells can “promptly arise” after Ocrevus treatment and that “anti-CD20 treatment does not reconstitute a fully healthy immune system or re-establish immune tolerance in all patients, supporting the need for retreatment,” the team wrote. An explanation?

The study showed what would be expected. You give ocrelizumab and that depletes naive and memory B cells and then you get a few immatutre/transitional B cells repopulating after depletion and these produce a cytokine called interleukin-ten. There was no major impact on T cell numbers but the of T cells remaining have a less activated signature, but hey disease is being controlled. You get fewer lesions (so you get less gadolinium) and as a consequence of that you get less nerve damage. However, there were also relative increases in GM-CSF- and
IL-6-producing B cells so let’s keep treating with ocrelizumab.

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine, so is it a good or a bad guy?It depends on what it is doing.

They say “no significant differences were observed in the total cell numbers (of T cells) but CD20T were reduced

Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS. José I. Fernández-Velasco, Jens Kuhle, Enric Monreal, Virginia Meca-Lallana, José Meca-Lallana, Guillermo Izquierdo, Francisco Gascón-Giménez, Susana Sainz de la Maza, Paulette E. Walo-Delgado, Aleksandra Maceski, Eulalia Rodríguez-Martín, Ernesto Roldán, Noelia Villarrubia, Albert Saiz, Yolanda Blanco, Pedro Sánchez, Ester Carreón-Guarnizo, Yolanda Aladro, Luis Brieva, Cristina Íñiguez, Inés González-Suárez, Luis A. Rodríguez de Antonio, Jaime Masjuan, Lucienne Costa-Frossard, Luisa M. Villar Neurology Neuroinflammation neuroimmunology 2021, DOI: https://doi.org/10.1212/NXI.0000000000000940

Objective To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS).

Methods In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months’ results. p Values were corrected using the Bonferroni test.

Results Ocrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd− patients with baseline sNfL >10 pg/mL.

Conclusions In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.

So further evidence that sNfL is a marker of neuroinflammatory activity

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  • MD, thanks for this post. I had seen the reference to pro inflammatory b cells and wondered whether this could have been an explanation as to why some patients worsen on ocrelizumab, so it was a question rather than a ‘demand’ which having looked again, it could have come across as. What a service though. Thank you 👍

    • I didnt see it as a demand. I have to read these papers… so why not do a blog post at the same time. This is how I tend to do posts and this is why you get so many B cell posts. However, I hope that educates you so that when we do work on B cells you can understand where we are coming from.

      As for the pro-inflammatory it all revolves aroung IL-6 and GM-CSF. However as I point out IL-6 can be pro or anti inflammatory it depends on how you look at the data. It seems that you cant report on anti CD20 without the inference that the effect is via the CD20 T cells. I suspect that this is a load of old cobblers but the T cell immunologists just can’t let go that every thing revolves around T cells. They make the view that anti-CD20 works directly via effects on T cells, I find this such a weak argument and it is even weaker when you have to explain how anti CD19 works also. The easier way to accomodate that view is that it is the B cells activating the T cells. That could explain anti CD19 and anti-CD20

      You could be right about why people worsen on anti CD20, I have not had time to sit down with the neuros to have a discussion about this. The only people who can address this are the neuros but the time slot for discussion of these things is taken up with dealing with our immediate work and teaching and covid related issues. If ProfG sees this maybe he can think about his experiences of disease break through on anti CD20, I have no idea how common this is. At the moment I am leaving ProfG alone so that he can concentrate on his recovery…and I can concentrate on the firefighting associated with the ProfGs accident and the COVID pandemic and our work

      • Thank you MD – very interesting post.

        I am interested to understand how neuros would determine whether a patient worsened on Ocrevus, i.e. new lesions on MRI OR worsening function (e.g. new balance issues despite no visible lesions) OR a blood test measuring a specific inflammatory marker?

        Once worsening is “determined” by a neuro, is the solution to press on until things stabilise OR would treatment normally be discontinued?

        Lastly, any worsening post Ocrevus – is it likely to improve significantly over time or this fixed in stone and the “new baseline”. My guess is depends person to person and age/other factors play part?

  • Thanks for the post. I see it is another B/T cell paper and I was thinking about this story of controversy a few days ago and few questions came to my mind.
    Why we need B cells to have relapses?
    Then if autoimmune T cells exist in MS, why they are not able alone to trigger relapses in B cells depleted patient? I mean, if some T cells are autoimmune they should be patrolling the body searching for their target so relapses should occur anyway… why the don’t?

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