Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event

Abstract

Key Points• CD191 CD27 1 memory B cells are detectable at supranormal frequencies in patients with high-level EBV DNAemia following allogeneic HSCT.• These memory B cells are frequently positive for EBV genomes and bear many of the hallmarks of lymphoblastoid transformation.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 1 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 1 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 1 memory B cells. Analysis of sorted CD27 1 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 1 B lymphoblasts in the peripheral blood. (Blood. 2015;126(25):2665-2675

Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection

“…The GC model posits that EBV infection of naïve B cells promotes B cell maturation mimicking the GC reaction to access the long-lived memory B cell compartment and thus persisting for the lifetime of the host (Burns et al, 2015; Roughan and Thorley-Lawson, 2009). Our data support this model in that early infection of B cells by EBV promotes MCL-1 as a critical apoptotic regulator similar that observed for GC B cells in the mouse (Vikstrom et al, 2010).…”

Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection

“…96,106,107 Moreover, although the number of total B cells may reach levels comparable to adult controls, most of the reconstituting B cells in the first year after HCT are comprised primarily of transitional and na€ ıve subsets, while the recovery of memory B cells occurs much later. 108,109 One exception is EBV reactivation, which leads to preferential expansion of IgGC or IgAC class-switched memory B cells. 108 Different graft sources have differential impacts on the tempo of B cell reconstitution.…”

“…108,109 One exception is EBV reactivation, which leads to preferential expansion of IgGC or IgAC class-switched memory B cells. 108 Different graft sources have differential impacts on the tempo of B cell reconstitution. For instance, the number of total B cells, na€ ıve and memory B cells are 10-20-fold higher in PBSC grafts compared to BM.…”

Lymphocyte subset at time of Epstein‐Barr viremia post‐allogeneic hematopoietic stem cell transplantation in children may predict development of post‐transplant lymphoproliferative disease: CD8:CD20 ratio as a sensitive predictor

“…Different EBV viral load cutoffs have been proposed to predict development of PTLD including 1000 copies/mL, 10 000 copies/mL, and 40 000 copies/mL, though there is a lack of a standard assay and control among different laboratories. There has been increasing evidence that monitoring of EBV viral load may not be sufficient to promptly predict the development of, and allow, appropriate intervention to prevent PTLD …”

“…There has been increasing evidence that monitoring of EBV viral load may not be sufficient to promptly predict the development of, and allow, appropriate intervention to prevent PTLD. [16][17][18] Quantitative reduction in CD3 + and CD4 + T cells and qualitative impairment of CD8 + T cells have been reported to increase risk of development of PTLD. 12,19 Moreover, utilizing both CD3 + T-cell number and EBV viral load to trigger preemptive rituximab therapy was shown to be an effective strategy.…”