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Blood. 2019 Jun 13;133(24):2597-2609. doi: 10.1182/blood.2018880138. Epub 2019 Apr 8.

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

Author information

1
Research Unit Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Munich, Germany.
2
Department for Experimental and Laboratory Animal Pathology, Medical University Vienna, Vienna, Austria.
3
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
4
Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Vienna, Austria.
5
CBMed Core Lab2, Medical University of Vienna, Vienna, Austria.
6
Research Unit Analytical Pathology, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Munich, Germany.
7
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
8
Experimental Hematology, TranslaTUM, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; and.
9
German Cancer Research Center, German Cancer Consortium, Heidelberg, Germany.

Abstract

CD30 is expressed on a variety of B-cell lymphomas, such as Hodgkin lymphoma, primary effusion lymphoma, and a diffuse large B-cell lymphoma subgroup. 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+ 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 expressed higher levels of CD30 than B2 cells and that CD30 was upregulated in IRF4+ plasmablasts (PBs). Furthermore, we generated and analyzed mice expressing a constitutively active CD30 receptor in B lymphocytes. These mice displayed an increase in B1 cells in the peritoneal cavity (PerC) and secondary lymphoid organs as well as increased numbers of plasma cells (PCs). TI-2 immunization resulted in a further expansion of B1 cells and PCs. We provide evidence that the expanded B1 population in the spleen included a fraction of PBs. CD30 signals seemed to enhance PC differentiation by increasing activation of NF-κB and promoting higher levels of phosphorylated STAT3 and STAT6 and 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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