Rescue of "crippled" germinal center B cells from apoptosis by Epstein-Barr virus.
Epstein-Barr virus (EBV) is associated with B-cell lymphomas such as Hodgkin lymphoma, Burkitt lymphoma, and post-transplantation lymphoma, which originate from clonal germinal center (GC) B cells. During the process of somatic hypermutation, GC B cells can acquire deleterious or nonsense mutations in the heavy and light immunoglobulin genes. Such mutations abrogate the cell surface expression of the B-cell receptor (BCR), which results in the elimination of these nonfunctional B cells by immediate apoptosis. EBV encodes several latent genes, among them latent membrane protein 1 (LMP1) and LMP2A, which are regularly expressed in EBV-positive Hodgkin lymphoma and posttransplantation lymphomas. Since LMP1 and LMP2A mimic the function of 2 key receptors on B cells, CD40 and BCR, respectively, we wanted to learn whether EBV infection can rescue proapoptotic GC B cells with crippling mutations in the heavy chain immunoglobulin locus from apoptosis. We show here that BCR-negative GC B cells readily enter the cell cycle upon infection with EBV in vitro and yield clonal lymphoblastoid cell lines that are incapable of expressing a functional BCR because the rearranged and formerly functional heavy chain immunoglobulin alleles carry deleterious mutations. Our findings imply an important role for EBV in the process of lymphomagenesis in certain cases of Hodgkin lymphoma and posttransplantation lymphomas.
Mancao
Christoph
C
GSF-National Research Center for Environment and Health, Department of Gene Vectors, Marchioninistr 25, D-81377 Munich, Germany.
Altmann
Markus
M
Jungnickel
Berit
B
Hammerschmidt
Wolfgang
W
D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D002478:Cells, Cultured; D018858:Germinal Center / Q000737:chemistry / Q000276:immunology / Q000473:pathology*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics