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Blood. 2019 Apr 8. pii: blood.2018880138. doi: 10.1182/blood.2018880138. [Epub ahead of print]

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

Author information

1
AGV, Helmholtz Zentrum München, Germany.
2
Helmholtz Zentrum München, Germany.
3
Gene Vectors, Helmholtz Zentrum München, Germany.
4
BSL BIOSERVICE Scientific Laboratories Munich GmbH, Germany.
5
Department of Pathology, Medical University Vienna, Austria.
6
Clinical Institute of Pathology, Medical University of Vienna, Austria.
7
HMGU, Germany.
8
Max Delbrueck Center for Molecular Medicine, Germany.
9
Experimental Hematology, TranslaTUM, Klinikum rechts der Isar, Technische Universität München, Germany.
10
Technische Universität München, Germany.
11
Department of Gene Vectors, Helmholtz Zentrum München, Germany.
12
Research Unit Gene Vectors, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Germany strobl@helmholtz-muenchen.de.

Abstract

CD30 is expressed on a variety of B-cell lymphomas such as Hodgkin's lymphoma, primary effusion lymphoma, and a subgroup of diffuse large B-cell lymphoma. In normal tissues, CD30 is expressed on some activated B and T lymphocytes. However, the physiological function of CD30-signaling and its contribution to the generation of CD30-positive lymphomas are still poorly understood. To gain a better understanding of CD30-signaling in B cells, we studied the expression of CD30 in different murine B-cell populations. We show that B1 cells express higher levels of CD30 than B2 cells and that CD30 is upregulated in IRF4+ plasmablasts (PB). Furthermore, we generated and analyzed mice expressing a constitutively active CD30-receptor in B lymphocytes. These mice displayed an increase of B1 cells in the peritoneal cavity (PerC) and in secondary lymphoid organs as well as increased numbers of plasma cells (PC). TI-2-immunization resulted in a further expansion of B1 cells and PC. We provide evidence that the expanded B1 population in the spleen includes a fraction of PB. CD30 signals appeared to enhance PC-differentiation by increasing activation of NF-κB, higher levels of phosphorylated STAT3 and STAT6 and of nuclear IRF4. In addition, chronic CD30-signaling led to B-cell lymphomagenesis in aged mice. These lymphomas were localized in the spleen and PerC and had a B1-like/plasmablastic phenotype. We conclude that our mouse model mirrors chronic B cell activation with increased numbers of CD30+ lymphocytes and provides experimental proof that chronic CD30-signaling increases the risk of B-cell lymphomagenesis.

PMID:
30962205
DOI:
10.1182/blood.2018880138

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