Target cells of Epstein-Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma.
BACKGROUND
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) encompasses a histologically broad range of lesions, arising from the expanded pool of EBV-infected B cells in the immunocompromised host. Identification of the precise cellular origin of these tumours could clarify their pathogenesis.


METHODS
Of 13 cases of EBV-positive cases of PTLD characterised by histological analysis, pattern of EBV gene expression, and clinical course, 11 had monoclonal or biclonal lesions in which we determined the progenitor B cell by immunoglobulin heavy chain (IgH) genotyping.


RESULTS
Two tumours had a naive B cell genotype and two showed patterns of IgH somatic mutation typical of antigen-selected (post-germinal-centre) memory cells. All four arose early post-transplant and expressed the markers of EBV transformation--Epstein-Barr nuclear antigen (EBNA) 2 and latent membrane protein (LMP) 1. However, seven tumours, either of early or late onset and including some with downregulated EBNA 2 and LMP 1, arose from post-germinal cells with randomly mutated or sterile IgH genotypes usually incompatible with B-cell survival in vivo.


CONCLUSIONS
PTLD can arise from a broad range of target B cells and not only from the pool of antigen-selected memory cells that EBV generally colonises in immunocompetent individuals. Tumour development seems frequently associated with the EBV-induced rescue and expansion of B cells that have failed the physiological process of germinal centre selection into memory. This finding shows an unexpected connection between pathogenesis of PTLD and that of EBV-positive Hodgkin's lymphoma, another B-cell malignancy of atypical post-germinal-centre cell origin.
Timms
Judith M
JM
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK.
Bell
Andrew
A
Flavell
Joanne R
JR
Murray
Paul G
PG
Rickinson
Alan B
AB
Traverse-Glehen
Alexandra
A
Berger
Françoise
F
Delecluse
Henri-Jacques
HJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D005838:Genotype; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity; D006689:Hodgkin Disease / Q000821:virology*; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000473:pathology / Q000821:virology*; D008969:Molecular Sequence Data; D016377:Organ Transplantation; D011183:Postoperative Complications / Q000821:virology*