Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation
Epstein-Barr virus (EBV)-driven B cell neoplasms arise from the reactivation of latently infected B cells. In a subset of patients, EBV was seen to drive a polymorphous lymphoproliferative disorder (LPD) in which B cell differentiation was retained. In this work, spontaneous EBV reactivation followi...
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MDPI AG
2023-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/12/3083 |
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| author | Matthew A. Care Sophie Stephenson Roger Owen Gina M. Doody Reuben M. Tooze |
| author_facet | Matthew A. Care Sophie Stephenson Roger Owen Gina M. Doody Reuben M. Tooze |
| author_sort | Matthew A. Care |
| collection | DOAJ |
| description | Epstein-Barr virus (EBV)-driven B cell neoplasms arise from the reactivation of latently infected B cells. In a subset of patients, EBV was seen to drive a polymorphous lymphoproliferative disorder (LPD) in which B cell differentiation was retained. In this work, spontaneous EBV reactivation following B cell mitogen stimulation was shown to provide a potential model of polymorphic EBV-driven LPD. Here, we developed an in vitro model of plasma cell (PC) differentiation from peripheral blood memory B cells. To assess the frequency and phenotypes of EBV-associated populations derived during differentiation, we analysed eight differentiations during the PC stage with a targeted single-cell gene expression panel. We identified subpopulations of EBV-gene expressing cells with PC and/or B cell expression features in differentiations from all tested donors. EBV-associated cells varied in frequency, ranging from 3–28% of cells. Most EBV-associated cells expressed PC genes such as <i>XBP1</i> or <i>MZB1,</i> and in all samples these included a quiescent PC fraction that lacked cell a cycle gene expression. With increasing EBV-associated cells, populations with B cell features became prominent, co-expressing a germinal centre (GC) and activating B cell gene patterns. The presence of highly proliferative EBV-associated cells was linked to retained <i>MS4A1/CD20</i> expression and <i>IGHM</i> and <i>IGHD</i> co-expression, while <i>IGHM</i> class-switched cells were enriched in quiescent PC fractions. Thus, patterns of gene expression in primary EBV reactivation were shown to include features related to GC B cells, which was also observed in EBV-transformed lymphoblastoid cell lines. This suggests a particular association between spontaneously developing EBV-expansions and IgM+ IgD+ non-switched B cells. |
| first_indexed | 2024-03-11T02:39:55Z |
| format | Article |
| id | doaj.art-986b90f7194b44ada23cf80426cd7386 |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T02:39:55Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-986b90f7194b44ada23cf80426cd73862023-11-18T09:40:26ZengMDPI AGCancers2072-66942023-06-011512308310.3390/cancers15123083Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven LymphoproliferationMatthew A. Care0Sophie Stephenson1Roger Owen2Gina M. Doody3Reuben M. Tooze4Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UKDivision of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UKHaematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UKDivision of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UKDivision of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UKEpstein-Barr virus (EBV)-driven B cell neoplasms arise from the reactivation of latently infected B cells. In a subset of patients, EBV was seen to drive a polymorphous lymphoproliferative disorder (LPD) in which B cell differentiation was retained. In this work, spontaneous EBV reactivation following B cell mitogen stimulation was shown to provide a potential model of polymorphic EBV-driven LPD. Here, we developed an in vitro model of plasma cell (PC) differentiation from peripheral blood memory B cells. To assess the frequency and phenotypes of EBV-associated populations derived during differentiation, we analysed eight differentiations during the PC stage with a targeted single-cell gene expression panel. We identified subpopulations of EBV-gene expressing cells with PC and/or B cell expression features in differentiations from all tested donors. EBV-associated cells varied in frequency, ranging from 3–28% of cells. Most EBV-associated cells expressed PC genes such as <i>XBP1</i> or <i>MZB1,</i> and in all samples these included a quiescent PC fraction that lacked cell a cycle gene expression. With increasing EBV-associated cells, populations with B cell features became prominent, co-expressing a germinal centre (GC) and activating B cell gene patterns. The presence of highly proliferative EBV-associated cells was linked to retained <i>MS4A1/CD20</i> expression and <i>IGHM</i> and <i>IGHD</i> co-expression, while <i>IGHM</i> class-switched cells were enriched in quiescent PC fractions. Thus, patterns of gene expression in primary EBV reactivation were shown to include features related to GC B cells, which was also observed in EBV-transformed lymphoblastoid cell lines. This suggests a particular association between spontaneously developing EBV-expansions and IgM+ IgD+ non-switched B cells.https://www.mdpi.com/2072-6694/15/12/3083Epstein-Barr virusB-cellgerminal centreplasma celllatencyreactivation |
| spellingShingle | Matthew A. Care Sophie Stephenson Roger Owen Gina M. Doody Reuben M. Tooze Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation Cancers Epstein-Barr virus B-cell germinal centre plasma cell latency reactivation |
| title | Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation |
| title_full | Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation |
| title_fullStr | Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation |
| title_full_unstemmed | Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation |
| title_short | Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation |
| title_sort | spontaneous ebv reactivation during b cell differentiation as a model for polymorphic ebv driven lymphoproliferation |
| topic | Epstein-Barr virus B-cell germinal centre plasma cell latency reactivation |
| url | https://www.mdpi.com/2072-6694/15/12/3083 |
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