Not so much of a cure then? Anti-CD20s fall short of the finish line.


Drum roll please!….

It was only a matter of time before someone designed this experiment. Albeit, it’s in an animal model, but the content is still by far the juiciest I’ve seen in MS research this year.

The major finding of this work is that depleting B cells alone using anti-CD20s doesn’t get rid of all inflammation in the neuronal tissue.

The authors of this work demonstrate that despite getting rid of virtually every B cell from the meninges (the lining of the brain and spinal cord) using an anti-CD20, a collection of immune cells called ectopic lymphoid follicles still managed to form in the neuronal tissues. It’s not that the anti-CD20 had no impact because B cells were depleted to some extent in these follicles. These collections of immune cells called ectopic lymphoid follicles have been found in the brains of individuals with progressive disease versus relapsing disease.

The authors also found that B-cell depletion didn’t alter the disease course in their chronic EAE model (i.e. it didn’t work so well as a treatment). Mice are not men, and 65 million years of evolution might lead to certain differences between the two. B cells and plasma cells in mice do differ.

So what does this mean? It means that B cells are not essential to the formation of ectopic lymphoid follicles (see figure below (F) that shows the correlation between disease severity and size of the ectopic lymphoid follicles). Anyone with an immunology background could have told you this, but it’s amazing how research can become siloed overtime.

From a clinical point of view, this clearly has implications for progressive MS. Ocrelizumab (anti-CD20) is licensed for primary progressive MS, and rituximab is used world-wide off label for evolving/transitioning MS.
Figure: ɑCD20 mAb Applied After EAE Onset Does Not Change the Clinical Course of Spontaneous EAE or the Size of mELT(A) Experimental setup. As soon as 2D2xTh mice developed a score of ≥3, they received a weekly dose of 100 µg of ɑCD20 (n = 11) or isotype control mAb (n = 14) over a period of 28 days. Another 5 mice were euthanized and dissected directly after developing a clinical score of ≥3, without receiving treatment. They served as histologic reference at disease onset for the remainder of the mice for which treatment commenced at that stage. (B) Clinical course of EAE during application of ɑCD20 or isotype mAb. (C) Representative HE (upper left panel) and B220 (lower left panel) staining of the spinal cord mELT of mice at EAE onset and respective quantification in all mice (right panels). (D) Representative HE-stained cross-sections of the thoracolumbar part of the spinal cord of ɑCD20 mAb-treated and isotype-treated mice (left) and representation of the distribution of mELT along the spine with 14–16 sections analyzed per animal (right). (E) Quantification of the mean area of mELT per section. (F) Correlation of the mean area of mELT per section with the mean EAE score over the observation period. ɑCD20 mAb = anti-CD20 monoclonal antibody; EAE = experimental autoimmune encephalomyelitis; HE = hematoxylin & eosin; i.p. = intraperitoneally; mELT = meningeal ectopic lymphoid tissue; n/N = mice showing mELT/total number of mice analyzed; ns = not significant.


Neurol Neuroimmunol Neuroinflamm. 2021 May 21;8(4):e1012. doi: 10.1212/NXI.0000000000001012. Print 2021 Jul 2.

Anti-CD20 Depletes Meningeal B Cells but Does Not Halt the Formation of Meningeal Ectopic Lymphoid Tissue

Rosa Margareta Brand Verena Friedrich Jolien Diddens Monika Pfaller Francesca Romana de FranchisHelena Radbruch Bernhard Hemmer Katja Steiger Klaus Lehmann-Horn 

Objective: To investigate whether anti-CD20 B-cell-depleting monoclonal antibodies (ɑCD20 mAbs) inhibit the formation or retention of meningeal ectopic lymphoid tissue (mELT) in a murine model of multiple sclerosis (MS).

Methods: We used a spontaneous chronic experimental autoimmune encephalomyelitis (EAE) model of mice with mutant T-cell and B-cell receptors specific for myelin oligodendrocyte glycoprotein (MOG), which develop meningeal inflammatory infiltrates resembling those described in MS. ɑCD20 mAbs were administered in either a preventive or a treatment regimen. The extent and cellular composition of mELT was assessed by histology and immunohistochemistry.

Results: ɑCD20 mAb, applied in a paradigm to either prevent or treat EAE, did not alter the disease course in either condition. However, ɑCD20 mAb depleted virtually all B cells from the meningeal compartment but failed to prevent the formation of mELT altogether. Because of the absence of B cells, mELT was less densely populated with immune cells and the cellular composition was changed, with increased neutrophil granulocytes.

Conclusions: These results demonstrate that, in CNS autoimmune disease, meningeal inflammatory infiltrates may form and persist in the absence of B cells. Together with the finding that ɑCD20 mAb does not ameliorate spontaneous chronic EAE with mELT, our data suggest that mELT may have yet unknown capacities that are independent of B cells and contribute to CNS autoimmunity.

About the author

Neuro Doc Gnanapavan


  • Is eae not a T cell disease therefore the role of B cells in those models don’t recapitulate the human model of disease adequately ?

  • Lucky NDG got there first…on this one..maybe I can comment on this without giving it an altmetric:-)

    • I think it would be best if you avoid commenting on this one MD 😉

      I would like to read future posts by the current Mouse Doctor…..not the scientist formally known as MD! Your voice is probably still a few octaves higher, since your recent “procedure”

  • thank you for all your post, although most of the content is way over my head sometimes I can extract a bit of info. Question is this just in relation to PPMS, would CD20 B-cell DMT’s be effective for RRMS?

    • “would CD20 B-cell DMT’s be effective for RRMS?”

      Yes…they would keep relapses away..but the point of this
      is that….over longer time…it wouldn’t stop rr from turning
      into progressive ms…called spms.

  • Have to say although evidence is drawn on EAE but still much more convincing than posts from Prof G.

  • So is the takeaway point that those on anti CD20 therapies should switch to something else (HSCT or Alemtuzumab) if they want to reduce the risk of unrelenting progressive disease?

    “The major finding of this work is that depleting B cells alone using anti-CD20s doesn’t get rid of all inflammation in the neuronal tissue.” Is the aim of the Sizomus trial to see if the drug being tested works against the inflammation (smouldering MS) in the neuronal tissue?

    Thanks to Team G for all the recent posts. I get the sense that the understanding of what drives MS is rapidly improving so hopefully therapies to treat the real disease will follow.

    • Hi SID,

      You raise a very important point, we need to look at the whole picture. If an individual is failing treatment a change of strategy based on the individuals disease process and biology is key. SIZOMUS is based on Ixazomib a proteosome inhibitor that targets B cells and plasma cells, and yes that is an aim we’re looking at, but it is too early to say! It is a change in direction for MS drugs (may work or fail -you can never tell). In the RRMS group it’s an add onto their existing treatment, but de novo in the progressive group.

    • The take away point Sid, is that you shouldn’t do these type of studies in mice because in mice, EAE is undoubtedly a T cell mediated disease whereas in MS, the undeniable effectiveness of anti-CD20 DMTs suggests that extrapolation from the mouse to human in this respect is very silly. Yet, so many continue to don their exclusive T cell blinkers.
      In my opinion, it’s high time these sort of studies are rejected as unethical.



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