T-Cells with CD20 Protein Marker May Drive Early Multiple Sclerosis

While the cause of MS is unclear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells. Proposed causes for this include genetics and environmental factors, such as viral infections. MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.

A team of scientists led by the University of Pennsylvania (Philadelphia, PA, USA) conducted detailed analyses of the immune cells found in the blood of MS patients before and after starting on ocrelizumab for the first time. The cells of two patient groups were analyzed: a set of 23 individuals with either relapsing-remitting (RRMS) or primary progressive disease PPMS who had not received prior therapy, and another group of 35 patients with RRMS. Phenotypic and functional immune profiles were comprehensively assessed by multi-parametric flow cytometry in high-quality cryopreserved peripheral blood mononuclear cells (PBMC).

The investigators reported that the results from both sets of patients were generally similar, with the anti-CD20 therapy leading to a sharp decrease in numbers of B-cells, as expected. The treatment also had marked effects on T-cells, of which there are two main types. One, known as CD8⁺ T-cells, is a type of cell that is able to kill other cells, for example, cancer cells or cells infected with a virus. By contrast, CD4⁺ T-cells, the other type, mainly act by helping to coordinate the activity of other components of the immune system, including B-cells. By analyzing specific markers on and in the cells, the team deduced that both the CD4⁺ and the CD8⁺ T-cells removed by anti-CD20 therapies were generally pro-inflammatory.

Furthermore, the removed cells showed evidence of being able to get into the central nervous system or CNS, comprised of the brain and spinal cord. The body has several systems in place that normally tightly control which immune cells are able to get into the CNS. Additional analyses showed that most CD8⁺ T-cells that were removed by ocrelizumab treatment expressed CD20; in other words, it’s likely that the treatment was directly killing these cells. By contrast, CD4⁺ depletion was not fully explained by the direct effects of targeting CD20.

The authors concluded that their study provided novel insights into both the mode of action of anti-CD20 and mechanisms underlying MS relapse biology. They distinguished the impact of anti-CD20 on CD8⁺ T cells (largely direct removal of CD20-expressing cells), versus the impact of anti-CD20 on CD4⁺ T cells (a combination of direct removal, and indirect effects, presumably through depletion of B cells resulting in their diminished in vivo interactions with the CD4⁺ T cells). The strong inverse correlation with disease activity suggests that CD20-expressing CD8⁺ T cells leaving the circulation (possibly to the CNS) participate in early encephalitogenic events involved in MS relapse development. The study was presented at the Virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis held October 13-15, 2021 (ECTRIMS).

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