Science corner: Suppressor plasma cells or is it?


Today this is abit technical and it is abit of a lab lesson. Don’t read if you are not interested.

Why do I do these posts?

Well this is about learning and we can learn together. I am going to read these papers to understand them, so why not make a blog post at the same time. Some readers like the science. I know you come to get insight about MS but it is really ProfG and NDG who do the clinical stuff. I fill in the days when they are busy. I am going to read round them and look for related work to see how it fits.

I did some teaching today and we did a “reading of a paper” and the one message is that to understand a paper you have to read around the subject matter.

When I see these papers, I have to read and research them to see what it means about how B cells may be involved in MS. Last week we had a suggestion that immunoregulatory IgA control MS, following on from EAE experiments and on first glance that statement was supported by the paper below. So I thought I had better look.

Gaurav Kumar, Zahra Maria, Uday Kohli, Agnieshka Agasing, James L. Quinn, Rose M. Ko, Scott S. Zamvil, Robert C. Axtell. CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept Neurol Neuroimmunol Neuroinflamm May 2021, 8 (3) e973; DOI: 10.1212/NXI.0000000000000973

Objective B cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces (Some subsets of ) B cells, unexpectedly (appears to) exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE).

B cell maturation antigen. BCMA is a protein expressed by plasma cells (Antibody forming cells) in humans. It is also important in mice too. You can show this with TACI-Ig = atacicept or remove the protein by gene knockout and the mice lack plasma cells. In some trials in MS atacicept appearred to make MS worse. This blocks B celll growth factors BAFF and APRIL. If you do not make APRIL you can have defects in IgA accoridng to one study. If you block BAFF with an antibody it does not appear to make MS worse (Baker et al. 2020). What’s the difference?

O’Connor et al. J Exp Med. 2004;199:91 BM=bone marrow, LN lymph node, SP spleen

Methods EAE was induced in wild-type (BCMA+/+) and BCMA-deficient (BCMA−/−) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency.

Results First, we found that BCMA−/− mice had more severe EAE compared with BCMA+/+ mice (Are plasma cells immunosuppresive and the increased disease was associated with elevated anti-MOG B-cell responses. Regulatory plasma cells). Second, we found that anti-CD20 therapy attenuated EAE in BCMA−/− mice but not in BCMA+/+ mice. Now the killer experiment. Third, TACI-Fc attenuated EAE in BCMA+/+ mice but not in BCMA−/− mice. (There was no evidence that TACI-Fc which is essentially- TACI-Ig making disease worse) Mixed bone marrow chimeric (you get immune system with the gene knockout into the body of non knockout mouse). Cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages.

Conclusions BCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS

So they start of with rubbish EAE (black dots) and make it worse with a BCMA deficicency. We call this a gene knockout. It has no gene so it can’t make the protein,

They look and say there are more memory B cells, less regulatory cells etc.. They then do an experiement using EAE induced with myelin peptide, which is according to the author’s own past work is a B cell-independent model, and so should not work. They find no inhibition (left graph below) . But if you do this in BCMA deficient you see an inhibition. Not because of the drug but because the control group is nothing like the control group in the other experiments and here you have massive worsening you can see an inhibition (*Graph below on right black dots).

Now you do the same experiment again and give an atacicept like molecule/ There is no inhibition in the BCMA knockout mouse (right below) but you can now see the control group has got dramatically worse (graph on left below black dots = about 3. But above = about 1) and so you can now see the inhibition of the TACI-Ig.

So the conclusion is that TACI-Fc acts because of BCMA….However importantly you would say TACI_Fc inhibits EAE (above), this is 100% the opposite of what happens in humans where it is apparently augmenting a problem.

The suggestion is that BCMA acts as a brake for the transitional B cells, some people call these immature B cells and others call them regulatory B cells as the produce interleukin-10

Next up they show us the mechanism it works by affecting macrophages and so we look to see if this is true. Yep Tnfrs17 = BCMA (blue below) is found on macrophages in the mouse…..However slight problem


It is evident that BCMA is not expressed in human macrophages. This is confirmed www/ I stop researching this, bit as it is unlikely to be relevant to how acacicept was influencing MS

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  • Somne studies talk about regulatory roles of plasma cells

    PCs are not sensitive to anti-CD20, however blockade of the cytokines BAFF/APRIL with atacicept (TACI-Ig) results in a decrease in both B cells and PC. Unfortunately, atacicept treatment led to increased disease activity in MS patients, suggesting that PCs may be playing a regulatory role

    in the serum, anti-CD20 treatment elevated levels of BAFF and IgA, which inversely correlated with disease severity.!/9245/presentation/242

    Interferon-β treatment requires B cells for efficacy in neuro-autoimmunity.1

    Type I IFNs, which include IFN-β, elevate expression of B cell activation factor (BAFF), increase B cell activity and drive the production of autoantibody in systemic lupus erythematosus (SLE) and neuromyelitis optica (NMO), promoting inflammation(1–3). In one sense, these are “type 1 IFN diseases” where B cell autoantibody production is clearly
    pathogenic. In RRMS IFN-β also increases serum levels of BAFF and B cell activity(4, 5),
    yet in a seeming paradox IFN-β reduces inflammation and decreases relapses(6).


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