Epstein-Barr virus (EBV)-positive lymphoproliferations in post-transplant patients show immunoglobulin V gene mutation patterns suggesting interference of EBV with normal B cell differentiation processes.
In a model for persistent infection, Epstein-Barr virus (EBV) uses the germinal center (GC) reaction to establish persistence in memory B cells. To study whether EBV adopts to normal B cell differentiation processes also in EBV-associated lymphoproliferative diseases, we micromanipulated EBV(+) cells from biopsies of five patients with post-transplantation lymphoproliferative disease (PTLD) and one unusual Hodgkin lymphoma with many small EBV(+) cells, and analyzed rearranged V genes of single cells. In all cases clonal expansions of EBV(+) B cells were identified. The vast majority of these clones carried mutated V gene rearrangements and a fraction of clones showed ongoing hypermutation. Hence, PTLD likely derive from GC and/or post-GC B cells. In two clones hypermutation occurred in the absence of follicular dendritic and CD4(+) T cells, important interaction partners of normal GC B cells. Furthermore, in one case sustained somatic hypermutation occurred without expression of a functional antigen receptor. Hence, EBV(+) B cells in PTLD can retain or acquire features of GC B cells in an unphysiological setting and may continue to undergo somatic hypermutation uncoupled from normal selection processes, suggesting that EBV interferes with normal B cell differentiation and selection processes in PTLD.
Bräuninger
Andreas
A
Department of Pathology, University of Frankfurt, Germany. braeuninger@em.uni-frankfurt.de
Spieker
Tilmann
T
Mottok
Anja
A
Baur
Audrey Sylvia
AS
Küppers
Ralf
R
Hansmann
Martin-Leo
ML
D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation; D019070:Cell Lineage; D017637:Clonal Deletion; D002999:Clone Cells / Q000473:pathology; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D015322:Gene Rearrangement, B-Lymphocyte; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000472:pathogenicity* / Q000502:physiology; D006689:Hodgkin Disease / Q000276:immunology / Q000821:virology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007165:Immunosuppression Therapy / Q000009:adverse effects; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000821:virology*; D008969:Molecular Sequence Data; D016377:Organ Transplantation; D011183:Postoperative Complications / Q000276:immunology / Q000821:virology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D014412:Tumor Virus Infections / Q000276:immunology*; D014775:Virus Activation
D007135:Immunoglobulin Variable Region