Chronic CD30 signaling in B cells results in lymphomagenesis by driving the expansion of plasmablasts and B1 cells

Sperling, Stefanie; Fiedler, Petra; Lechner, Markus; Pollithy, Anna; Ehrenberg, Stefanie; Schiefer, Ana‐Iris; Kenner, Lukas; Feuchtinger, Annette; Kühn, Ralf; Swinerd, Gene W.; Schmidt-Supprian, Marc; Strobl, Lothar J.; Zimber-Strobl, Ursula

doi:10.1182/blood.2018880138

Cited by 14 publications

(22 citation statements)

References 62 publications

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“…For example, genes for MYC, the key factor for proliferation, differentiation, and apoptosis are increased in CD30 + reactive cells, as well as genes important for the interaction between B- and T-cells, known for HRS-cells [29]. Attention should be drawn to recently published work of Sperling et al who proved that chronic CD30 signaling of activated B-cells in mice increases the risk of B-cell lymphomagenesis [30]. Therefore, CD30 + cells may be precursors of HRS-cells under special conditions.…”

Section: Discussionmentioning

confidence: 99%

3D image analysis reveals differences of CD30 positive cells and network formation in reactive and malignant human lymphoid tissue (classical Hodgkin Lymphoma)

et al. 2019

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AimsThe examination of histological sections is still the gold standard in diagnostic pathology. Important histopathological diagnostic criteria are nuclear shapes and chromatin distribution as well as nucleus-cytoplasm relation and immunohistochemical properties of surface and intracellular proteins. The aim of this investigation was to evaluate the benefits and drawbacks of three-dimensional imaging of CD30+ cells in classical Hodgkin Lymphoma (cHL) in comparison to CD30+ lymphoid cells in reactive lymphoid tissues.Materials and resultsUsing immunoflourescence confocal microscopy and computer-based analysis, we compared CD30+ neoplastic cells in Nodular Sclerosis cHL (NScCHL), Mixed Cellularity cHL (MCcHL), with reactive CD30+ cells in Adenoids (AD) and Lymphadenitis (LAD). We confirmed that the percentage of CD30+ cell volume can be calculated. The amount in lymphadenitis was approx. 1.5%, in adenoids around 2%, in MCcHL up to 4,5% whereas the values for NScHL rose to more than 8% of the total cell cytoplasm. In addition, CD30+ tumour cells (HRS-cells) in cHL had larger volumes, and more protrusions compared to CD30+ reactive cells. Furthermore, the formation of large cell networks turned out to be a typical characteristic of NScHL.ConclusionIn contrast to 2D histology, 3D laser scanning offers a visualisation of complete cells, their network interaction and spatial distribution in the tissue. The possibility to differentiate cells in regards to volume, surface, shape, and cluster formation enables a new view on further diagnostic and biological questions. 3D includes an increased amount of information as a basis of bioinformatical calculations.

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Section: Discussionmentioning

confidence: 99%

3D image analysis reveals differences of CD30 positive cells and network formation in reactive and malignant human lymphoid tissue (classical Hodgkin Lymphoma)

et al. 2019

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“…NP-specific antibody titers were measured in ELISA, following the procedure described by Sperling at el., Blood 2019 (51). The absorbance was determined with a microplate ELISA reader (Photometer Sunrise RC, Tecan) at an optical density (OD) at 405 nm.…”

Section: Methodsmentioning

confidence: 99%

Notch2 signaling guides B cells away from germinal centers towards marginal zone B cell and plasma cell differentiation

Babushku

Rane

Lechner

et al. 2022

Preprint

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Notch2 signaling has a profound role in driving the development of marginal zone B (MZB) cells. We could show recently that FoB cells act as precursors for MZB cells in mice, however, the mechanism of this differentiation is still elusive. Our current study revealed that Venus expression in CBF:H2B-Venus reporter mice, which is a proxy for Notch signaling, increases progressively with B cell maturation and is highest in MZB cells, suggesting that most peripheral B cells receive a Notch signal and cells with the highest signal preferably develop into MZB cells. Interestingly, Venus expression is heterogeneous in the MZB pool, indicating a loss of Notch signaling over time. Our data also revealed an interplay of antigen induced activation with Notch2 signals, in which FoB cells that turn off the Notch pathway enter GC reactions, whereas B cells with high Notch2 signals undergo MZB and plasmablast differentiation. While Notch2 signaling is dispensable for the initiation of the GC reaction, it supports switching to IgG1+ cells in the GC. Integration of our experimental data into a mathematical modelling framework revealed that antigen activation induces a binary cell-fate decision in FoB cells, to differentiate into either GC or MZB cells. The newly generated MZB cells have a short life span and are sustained by influx of antigen activated B cells. Our findings demonstrate that MZB cell generation is a systematic response to TD immunization and provide for the first time a detailed quantitative map of their dynamics during an ongoing TD immune response.One-sentence summaryIn antigen-activated FoB cells, ablation of Notch2 does not interfere with GC formation, but obstructs the production of IgG1+ GC B cells, whereas induction of Notch2IC inhibits the GC reaction and drives MZB and plasmablast differentiation instead.

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“…For antigen-specific ELISpot, 96-well plates for ELISpots (Millipore) were coated with NP 4 -or NP 16 -bovine serum albumin (Biosearch Technologies). ELISpot analyzes were performed as described (48,49). Spots were analyzed and counted with the ImmunoSpot Series 5 UV Analyzer (CTL Europe).…”

Section: Elisa and Elispotmentioning

confidence: 99%

ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation

et al. 2021

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Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal–regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell–specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence of Raf-1 and B-Raf was mediated by multiple RAF-independent pathways, with phosphoinositide 3-kinase (PI3K) playing an important role. Furthermore, we found that ERK phosphorylation strongly increased during the transition from activated B cells to pre-plasmablasts. This increase in ERK phosphorylation did not occur in B cells lacking both Raf-1 and B-Raf, which most likely explains the partial block of plasma cell differentiation in mice lacking both RAFs. Collectively, our data indicate that B-Raf and Raf-1 are not necessary to mediate ERK phosphorylation in naïve or activated B cells but are essential for mediating the marked increase in ERK phosphorylation during the transition from activated B cells to pre-plasmablasts.

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Chronic CD30 signaling in B cells results in lymphomagenesis by driving the expansion of plasmablasts and B1 cells

Cited by 14 publications

References 62 publications

3D image analysis reveals differences of CD30 positive cells and network formation in reactive and malignant human lymphoid tissue (classical Hodgkin Lymphoma)

3D image analysis reveals differences of CD30 positive cells and network formation in reactive and malignant human lymphoid tissue (classical Hodgkin Lymphoma)

Notch2 signaling guides B cells away from germinal centers towards marginal zone B cell and plasma cell differentiation

ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation

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