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.
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
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.