title: Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event.
abstract: Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B-cell system. Although many allo-HSCT recipients maintain low or undetectable levels of EBV DNA posttransplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated posttransplant lymphoproliferative disease. Intriguingly, this high-level EBV reactivation typically arises in the first 3 months posttransplant, at a time when the peripheral blood contains low numbers of CD27+ memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B-cell reconstitution in a cohort of allo-HSCT patients for up to 12 months posttransplant. In patients with low or undetectable levels of EBV, the circulating B-cell pool consisted predominantly of transitional and naive cells, with a marked deficiency of CD27+ memory cells which lasted >12 months. However, among patients with high EBV loads, there was a significant increase in both the proportion and number of CD27+ memory B cells. Analysis of sorted CD27+ memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B-cell growth transformation, had a plasmablastic phenotype, and frequently expressed the proliferation marker Ki-67. These findings suggest that high-level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27+ B lymphoblasts in the peripheral blood.
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: David M
authors.initials: DM
authors.lastname: Burns
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Rose
authors.initials: R
authors.lastname: Tierney
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Shannon-Lowe
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Jo
authors.initials: J
authors.lastname: Croudace
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Inman
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Ben
authors.initials: B
authors.lastname: Abbotts
authors.affiliation: Centre for Clinical Haematology, University Hospitals Birmingham National Health Service Trust, Birmingham, United Kingdom; and.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Nagra
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospitals National Health Service Trust, Nottingham, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Fox
authors.affiliation: Centre for Clinical Haematology, University Hospitals Birmingham National Health Service Trust, Birmingham, United Kingdom; and.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Chaganti
authors.affiliation: Centre for Clinical Haematology, University Hospitals Birmingham National Health Service Trust, Birmingham, United Kingdom; and.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Craddock
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
authors.affiliation: School for Cancer Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Bell
mesh_terms: D000328:Adult; D000368:Aged; D016175:B-Lymphocyte Subsets / Q000821:virology; D001402:B-Lymphocytes / Q000821:virology*; D002472:Cell Transformation, Viral / Q000502:physiology*; D004279:DNA, Viral / Q000097:blood; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000821:virology; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D019562:Viral Load / Q000276:immunology; D014775:Virus Activation / Q000276:immunology*
chemical_list: D004279:DNA, Viral; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7