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

Bräuninger, Andreas; Spieker, Tilmann; Mottok, Anja; Baur, Audrey S.; Küppers, Ralf; Hansmann, Martin‐Leo

doi:10.1002/eji.200323765

Cited by 56 publications

(56 citation statements)

References 37 publications

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“…19 Interest in viral infection of GC cells was reawakened by the observation that EBV-positive PTLD tumors, many of which had full latent antigen expression, often arise from B cells with atypical, even nonfunctional, IgH alleles. [8][9][10] The present work provides strong evidence that EBV infection in vitro can indeed rescue the failed products of GC reactions, leading to the outgrowth of surface immunoglobulin-negative LCLs with functionally inactivated IgH alleles; we recently learned of similar findings in 2 other laboratories. 20,21 Such activity likely reflects not just the well-documented growth-transforming function of EBV but also the ability of certain EBV latent proteins to protect B cells from apoptosis.…”

Section: Resultssupporting

confidence: 65%

“…[5][6][7] Recent studies have found that most PTLD tumors carry hypermutated immunoglobulin sequences, many of which are atypical of conventional antigenselected memory cells. [8][9][10] Indeed, some tumors lacked surface immunoglobulin and had functionally inactivated immunoglobulin sequences, 8 highlighting parallels with another EBV-associated B-cell malignancy, Hodgkin lymphoma (HL), in which the tumor cells are again surface immunoglobulin negative and often carry similarly "crippled" immunoglobulin genes. 11 These findings suggest that EBV infection can promote the survival of atypical post-germinal center (GC) B cells carrying unfavorable or even inactivating immunoglobulin gene mutations.…”

Section: Introductionmentioning

confidence: 99%

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Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes

Chaganti

Bell

Pastor

et al. 2005

Blood

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IntroductionEpstein-Barr virus (EBV) has B-cell growth-transforming ability and is linked to a range of B-cell malignancies. 1,2 Of these, posttransplantation lymphoproliferative disease (PTLD) is pathogenetically the least complex. Thus, PTLD tumors arising early after transplantation, when immunosuppression is greatest, resemble EBV-positive in vitro-transformed lymphoblastoid cell lines (LCLs) in cellular phenotype and in expressing the full range of EBV-latent proteins. 3,4 Here, viral transformation appears to be sufficient for tumor growth, whereas in certain late-onset PTLD lesions, viral gene expression is more restricted and tumor evolution has involved additional cellular genetic changes. [5][6][7] Recent studies have found that most PTLD tumors carry hypermutated immunoglobulin sequences, many of which are atypical of conventional antigenselected memory cells. [8][9][10] Indeed, some tumors lacked surface immunoglobulin and had functionally inactivated immunoglobulin sequences, 8 highlighting parallels with another EBV-associated B-cell malignancy, Hodgkin lymphoma (HL), in which the tumor cells are again surface immunoglobulin negative and often carry similarly "crippled" immunoglobulin genes. 11 These findings suggest that EBV infection can promote the survival of atypical post-germinal center (GC) B cells carrying unfavorable or even inactivating immunoglobulin gene mutations. Such cells, arising as failed products of the somatic hypermutation process that occurs during GC transit, normally die by apoptosis 12 ; however, if rescued by EBV, they might form a pool of cells particularly prone to tumor development. Here we ask whether EBV infection of GC B cells in vitro leads to the outgrowth of LCLs with crippled immunoglobulin genes. Study design Target cell transformationFresh tonsils were obtained with informed consent from 3 adult patients after tonsillectomy. Mononuclear cells were isolated by Ficoll-Isopaque centrifugation and then T-depleted using CD3 Dynabeads (Dynal Biotech, Bromborough, United Kingdom). The resultant B-cell population was stained for the CD10 marker of GC origin 13 using phycoerythrin (PE)-Cy5-labeled anti-CD10 (BD Pharmingen, Oxford, United Kingdom) monoclonal antibody (mAb) and CD10 ϩ cells collected by fluorescence-activated cell sorter (FACS) on a Mo-Flo sorter (Dako Cytomation, Ely, United Kingdom). In parallel experiments involving different adult donors, naive, and memory B cells were isolated from peripheral blood B cells by FACS sorting of immunoglobulin D ϩ (IgD ϩ )CD27 Ϫ and IgD Ϫ CD27 ϩ subsets, respectively, after staining with FITC-labeled anti-IgD (Caltag, Buckingham, United Kingdom) and RPE (R-phycoerythrin)-labeled anti-CD27 (BD Pharmingen) mAbs. Target B cells were exposed to B95.8 EBV for 1 hour at 37°C and then were seeded at limiting dilutions onto wells containing a human fibroblast feeder layer. Cells were maintained in RPMI 1640 medium supplemented with 2 mM glutamine and 10% vol/vol fetal calf serum (FCS) for 3 to 4 weeks, at which time isolated wel...

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Section: Resultssupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes

Chaganti

Bell

Pastor

et al. 2005

Blood

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“…52 Also, EBV infection is found in many post-transplant lymphoproliferative disorders with crippled IGV genes. 24,50,51 Overall, these observations support a central role of EBV in the pathogenesis of lymphomas with impaired B-cell receptor.…”

Section: Discussionsupporting

confidence: 58%

“…These features are at variance with those observed in other lymphomas associated with immunodeficiency, namely post-transplant lymphoproliferative disorders, whose molecular features suggest a minor role for antigen stimulation. 24,50,51 In particular, the different role exerted by B-cell receptor stimulation in the pathogenesis of HIV-NHL and posttransplant lymphoproliferative disorders is indicated by the presence of IGV inactivation by crippling mutations introduced by somatic hypermutation in nearly a quarter of post-transplant lymphoproliferative disorders, 24,50,51 whereas crippling mutations of IGV rearrangements are a very rare finding among HIV-NHL (3%; this study). Interestingly, each case of HIV-NHL carrying IGV inactivation by crippling mutations was positive for EBV infection of the tumor clone.…”

Section: Discussionmentioning

confidence: 67%

Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis

Capello¹,

Martini²,

Gloghini³

et al. 2008

Haematologica

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“…Among more than 50 cases of classical HL, 11 of 12 cases in which such crippling mutations have been identified were EBVinfected, while 19 of 43 cases lacking evidence for crippling muta- Cases without crippling mutations 19 24 This overview is based on data from refs. 3,4,6,11,62,63,65,66,68,[90][91][92][93][94]. Not included is an EBV-negative case in which only a subclone of the HRS cells is crippled (case 3), 92 and 1 case lacking crippling mutations in which a subclone of the HRS cells is EBVinfected.…”

mentioning

confidence: 99%

Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma

Bräuninger

Schmitz

Bechtel

et al. 2005

Intl Journal of Cancer

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169

116

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Hodgkin's and Reed/Sternberg (HRS) cells, the tumour cells in classical Hodgkin's lymphoma (HL), represent transformed B cells in nearly all cases. The detection of destructive somatic mutations in the rearranged immunoglobulin (Ig) genes of HRS cells in classical HL indicated that they originate from preapoptotic germinal centre (GC) B cells that lost the capacity to express a highaffinity B-cell receptor (BCR). Several aberrantly activated signalling pathways and transcription factors have been identified that contribute to the rescue of HRS cells from apoptosis. Among the deregulated signalling pathways, activation of multiple receptor tyrosine kinases in HRS cells appears to be a specific feature of HL. In about 40% of cases of classical HL the HRS cells are infected by Epstein-Barr virus (EBV), indicating an important role of EBV in HL pathogenesis. Interestingly, nearly all cases of HL with destructive Ig gene mutations eliminating BCR expression (e.g. nonsense mutations) are EBV-positive, suggesting that EBV-encoded genes have a particular function to prevent apoptosis of HRS-cell precursors that acquired such crippling mutations. This idea is further supported by the recent demonstration that isolated human GC B cells harbouring crippled Ig genes can be rescued by EBV from cell death, giving rise to lymphoblastoid cell lines. The molecular analysis of composite Hodgkin's and nonHodgkin's lymphomas indicated that many cases develop from a common GC B-cell precursor in a multistep transformation process with both shared and distinct oncogenic events. 2-6 Nearly all cases of classical and lymphocyte-predominance HL carry somatically mutated V genes, suggesting an origin from (post) germinal centre (GC) B cells, as somatic hypermutation of Ig V genes specifically takes place in GC B cells.7 In lymphocyte-predominance HL, the detection of intraclonal V gene diversity and several phenotypic features suggest an origin of the L&H cells from mutating and selected GC B cells. 2,4,5 In classical HL, crippling mutations that destroyed the coding capacity of originally functional rearrangements were detected in about a quarter of cases.3,8 Such obviously crippling mutations happen in mutating GC B cells, but represent only a small fraction of all disadvantagous mutations that normally result in apoptosis of the respective GC B cells. In the GC, there is a stringent selection for B cells acquiring affinity-increasing mutations, so also many GC B cells that still express a B-cell receptor (BCR) but which fails to bind to the cognate antigen with improved affinity will undergo apoptosis.9,10 Thus, we speculated that the vast majority of HRS cells in classical HL are derived from preapoptotic GC B cells. 3 In rare cases (about 2%) HRS cells originate from T cells. 11,12 Although HRS cells are usually transformed B cells, global gene expression analysis of HRS cell lines using microarrays revealed that the HRS cells have lost the expression of most B-cell markers to an extent that is unique among B-cell lymphomas. 13 As t...

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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

Cited by 56 publications

References 37 publications

Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes

Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes

Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis

Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma

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