Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease
| Autor: | Daisuke Okuzaki, Benjamin E. Gewurz, Hufeng Zhou, Hiroshi Kida, Masanori Obana, Elliott Kieff, Atsushi Kumanogoh, Yasushi Fujio, Teruhito Yasui, Chao-Yuan Tsai, Takeharu Minamitani, Bo Zhao, Yijie Ma, Hitoshi Kikutani |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Epstein-Barr Virus Infections Herpesvirus 4 Human Lymphoma CD30 medicine.disease_cause Virus Proinflammatory cytokine 03 medical and health sciences hemic and lymphatic diseases Plasma cell differentiation otorhinolaryngologic diseases medicine Humans B cell Multidisciplinary CD40 biology Germinal center Biological Sciences Germinal Center Epstein–Barr virus Killer Cells Natural stomatognathic diseases 030104 developmental biology medicine.anatomical_structure Immunology Cancer research biology.protein |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:4751-4756 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Epstein-Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|