Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease

Häusler, Darius; Häusser‐Kinzel, Silke; Feldmann, Linda; Torke, Sebastian; Lepennetier, Gildas; Bernard, Carole; Zamvil, Scott S.; Brück, Wolfgang; Lehmann‐Horn, Klaus; Weber, Martin

doi:10.1073/pnas.1810470115

Cited by 77 publications

(97 citation statements)

References 32 publications

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“…In context with our phenotypical analysis above, we do not believe that the higher expression of CD25 is due to an elevated frequency of memory B cells in the repleting pool, but reflective of the fact that naive, regrowing B cells are being activated in the process of repopulation. This general observation confirms our earlier experimental study showing that in the context of peripheral activation, B cells reappear with an enhanced proinflammatory molecular arsenal (21). Jointly, these data point to a shift toward a less differentiated state, yet with enhanced proliferation, activation, and costimulatory capacities.…”

Section: Discussionsupporting

confidence: 90%

“…Of note and in contrast to T cells, these changes were not determined by the preexisting B cell phenotype. Most likely, these alterations, which confirm our earlier observations in mice (21) and men (28) represent the concomitant loss of B cell regulatory properties (29)(30)(31), which likely occurs upon nonselective depletion of CD20-positive B cells.…”

Section: Discussionsupporting

confidence: 89%

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

Nissimov

Hajiyeva²,

Torke

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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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%).

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

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

Nissimov

Hajiyeva²,

Torke

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The fact that B cells play a critical role during the onset and course of inflammatory processes is indisputable and has been demonstrated in many studies in both mice and humans. However, these studies focused on the production of autoantibodies with B cells being understood as the cause for the development of inflammation, e.g., multiple sclerosis (MS) (1)(2)(3). Nevertheless, it is important to discriminate between the versatile functions of B cells.…”

Section: Introductionmentioning

confidence: 99%

Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

et al. 2020

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B cells fulfill multifaceted functions that influence immune responses during health and disease. In autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, depletion of functional B cells results in an aggravation of disease in humans and respective mouse models. This could be due to a lack of a pivotal B cell subpopulation: regulatory B cells (Bregs). Although Bregs represent only a small proportion of all immune cells, they exhibit critical properties in regulating immune responses, thus contributing to the maintenance of immune homeostasis in healthy individuals. In this study, we report that the induction of Bregs is differentially triggered by the immunogenicity of the host microbiota. In comparative experiments with low immunogenic Bacteroides vulgatus and strong immunogenic Escherichia coli, we found that the induction and longevity of Bregs depend on strong Toll-like receptor activation mediated by antigens of strong immunogenic commensals. The potent B cell stimulation via E. coli led to a pronounced expression of suppressive molecules on the B cell surface and an increased production of anti-inflammatory cytokines like interleukin-10. These bacteria-primed Bregs were capable of efficiently inhibiting the maturation and function of dendritic cells (DCs), preventing the proliferation and polarization of T helper (Th)1 and Th17 cells while simultaneously promoting Th2 cell differentiation in vitro. In addition, Bregs facilitated the development of regulatory T cells (Tregs) resulting in a possible feedback cooperation to establish immune homeostasis. Moreover, the colonization of germfree wild type mice with E. coli but not B. vulgatus significantly reduced intestinal inflammatory processes in dextran sulfate sodium (DSS)-induced colitis associated with an increase induction of immune suppressive Bregs. The quantity of Bregs directly correlated with the severity of inflammation. These findings may provide new insights and therapeutic approaches for B cell-controlled treatments of microbiota-driven autoimmune disease.

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“…Anti-CD20-mediated B-cell depletion has been shown to be a very efficient therapy in MS, [14][15][16][17] however, treatment cessation may lead to a recovery of highly differentiated pathogenic B cells, 30 and long-term treatment may lower immunoglobulin production, possibly raising the risk of infections over time. 31 Our data support the concept that GA could act as a suitable maintenance therapy after cessation of anti-CD20 treatment by fostering regulatory properties in repopulating B cells.…”

Section: Discussionmentioning

confidence: 99%

Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS

Häusler

Hajiyeva

Traub

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveWe examined the effect of glatiramer acetate (GA) on B-cell maturation, differentiation, and antigen presentation in MS and experimental autoimmune encephalomyelitis (EAE).MethodsA cross-sectional study of blood samples from 20 GA-treated and 18 untreated patients with MS was performed by flow cytometry; 6 GA-treated patients with MS were analyzed longitudinally. GA-mediated effects on B-cell antigen-presenting function were investigated in EAE, or, alternatively, B cells were treated with GA in vitro using vehicle as a control.ResultsIn MS, GA diminished transitional B-cell and plasmablast frequency, downregulated CD69, CD25, and CD95 expression, and decreased TNF-α production, whereas IL-10 secretion and MHC Class II expression were increased. In EAE, we observed an equivalent dampening of proinflammatory B-cell properties and an enhanced expression of MHC Class II. When used as antigen-presenting cells for activation of naive T cells, GA-treated B cells promoted development of regulatory T cells, whereas proinflammatory T-cell differentiation was diminished.ConclusionsGA immune modulates B-cell function in EAE and MS and efficiently interferes with pathogenic B cell–T cell interaction.

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Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease

Cited by 77 publications

References 32 publications

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

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

Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS

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