B cells reappear less mature and more activated after their anti-CD20–mediated depletion in multiple sclerosis

Abstract

B cell depletion via anti-CD20 antibodies is a highly effective treatment for multiple sclerosis (MS). However, little is known about the maturation/activation stage of the returning B cell population after treatment cessation and the wider effects on other immune cells. In the present study, 15 relapsing-remitting MS patients receiving 1,000 mg of rituximab were included. B, T, and myeloid cells were analyzed before anti-CD20 administration and in different time intervals thereafter over a period of 24 mo. In comparison to the phenotype before anti-CD20 treatment, the reappearing B cell pool revealed a less mature and more activated phenotype: 1) reappearing B cells were significantly enriched in transitional (before: 10.1 ± 1.9%, after: 58.8 ± 5.2%) and mature naive phenotypes (before: 45.5 ± 3.1%, after: 25.1 ± 3.5%); 2) the frequency of memory B cells was reduced (before: 36.7 ± 3.1%, after: 8.9 ± 1.7%); and 3) reappearing B cells showed an enhanced expression of activation markers CD25 (before: 2.1 ± 0.4%, after: 9.3 ± 2.1%) and CD69 (before: 5.9 ± 1.0%, after: 21.4 ± 3.0%), and expressed significantly higher levels of costimulatory CD40 and CD86. T cells showed 1) a persistent increase in naive (CD4+: before: 11.8 ± 1.3%, after: 18.4 ± 3.4%; CD8+: before: 12.5 ± 1.4%, after: 16.5 ± 2.3%) and 2) a decrease in terminally differentiated subsets (CD4+: before: 47.3 ± 3.2%, after: 34.4 ± 3.7%; CD8+: before: 53.7 ± 2.1%, after: 49.1 ± 2.7%).

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20—Yet Progress Continues

“…Recent research has improved the understanding on immunological characteristics of repleting CD20 + cells. A lately published study indicates that the reappearing pool of B cells after depletion with RTX mainly consists of naïve and transitional B cells, while memory B cells are diminished [103]. The same holds true for patients treated with RTX for various autoimmune diseases and for CD20 depletion in EAE induced with MOG peptide [102,[104][105][106].…”

“…Since memory B cells are thought to be more pathogenic than naïve B cells, the observation of a more naïve repleting B cell pool seems to be a promising observation. However, repleting naïve B cells in patients with MS and RA were found to possess a more pro-inflammatory phenotype with variations of repopulation kinetics and patterns at an individual level [102][103][104]. More research is needed to find out whether rebound effects could occur after cessation of longterm anti-CD20 treatment.…”

B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders

“…In most patients, absolute blood B cell counts are still low six to nine months after infusion [ 127 , 128 ]. Interestingly, it was recently shown that in the reappearing B cell pool, the frequency of immature B cells and the expression of activation markers was found to be increased [ 129 , 130 ]. Mature plasmablasts and plasma cells are largely preserved as they lack CD20 expression [ 127 ].…”

Toll-Like Receptor Homolog CD180 Expression Is Diminished on Natural Autoantibody-Producing B Cells of Patients with Autoimmune CNS Disorders

“…In addition to antibody production, B cells are important in antigen presentation and proinflammatory cytokine secretion [10]. The clinical success of anti-CD20 antibodies in the treatment of MS and NMOSD [11,12] underlines the important role of B cells in disease initiation and progression. Studies focusing on B cell subpopulations in MS and NMOSD are limited, and the precise role and changes in naïve and memory B cell distribution are still unclear in the development of MS and NMOSD.…”