Surface Immunoglobulin-Deficient Epstein-Barr Virus-Infected B Cells in the Peripheral Blood of Pediatric Solid-Organ Transplant Recipients

Schauer, Elizabeth; Webber, Steven A.; Green, Michael; Rowe, David

doi:10.1128/jcm.42.12.5802-5810.2004

Cited by 16 publications

(12 citation statements)

References 35 publications

(40 reference statements)

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“…Moreover, EBV load directly correlated with EBV-lytic–specific CD8 + T cells in HVL patients. Although our previous published data highlighted the accumulation of EBV latently infected B cells with high viral DNA copy number in HVL carriers (37, 38), our results in this study indicate for the first time, to our knowledge, that asymptomatic chronic HVL carrier state after pediatric thoracic organ transplantation may entail active lytic viral replication (identified by TMR staining) in addition to the accumulation of EBV latently infected cells in peripheral blood. Thus, future studies are required to clarify the nature of the life cycle of the virus in immunosuppressed children.…”

Section: Discussioncontrasting

confidence: 61%

EBV-Specific CD8+ T Cells from Asymptomatic Pediatric Thoracic Transplant Patients Carrying Chronic High EBV Loads Display Contrasting Features: Activated Phenotype and Exhausted Function

Macedo

Webber

Donnenberg

et al. 2011

The Journal of Immunology

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Serial EBV load monitoring of clinically asymptomatic pediatric thoracic organ transplant patients has identified three groups of children who exhibit undetectable (<100 copies/ml), chronic low (100–16,000 copies/ml), or chronic high (>16,000 copies/ml) EBV loads in peripheral blood. Chronic high EBV load patients have a 45% rate of progression to late-onset posttransplant lympho-proliferative disorders. In this article, we report that asymptomatic patients carrying EBV loads (low and high) expressed increased frequencies of EBV-specific CD8+ T cells, as compared with patients with undetectable EBV loads. Although patients with low viral load displayed EBV-specific CD8+ T cells with moderate signs of activation (CD38+/−/CD127+/−), programmed death 1 upregulation and effective IFN-γ secretion, high EBV load carriers showed significant CD38+ upregulation, features of cellular exhaustion (programmed death 1+/CD127−) accompanied by a decline in IFN-γ release. Immunopolarization of EBV-specific CD8+ T cells was skewed from the expected type 1 (IFN-γ) toward type 0 (IFN-γ/IL-5) in patients, and Tr1 (IL-10) in high load carriers. These results indicate the importance of chronic EBV load and of the levels of antigenic pressure in shaping EBV-specific memory CD8+ T cells. Concomitant phenotypic and functional EBV monitoring is critical for identifying the complex “functional” versus “exhausted” signature of EBV-specific CD8+ T cells, with implications for immunologic monitoring in the clinic.

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Section: Discussioncontrasting

confidence: 61%

EBV-Specific CD8+ T Cells from Asymptomatic Pediatric Thoracic Transplant Patients Carrying Chronic High EBV Loads Display Contrasting Features: Activated Phenotype and Exhausted Function

Macedo

Webber

Donnenberg

et al. 2011

The Journal of Immunology

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“…Thus, prosurvival functions have now been demonstrated for EBNA3 proteins, 22 for LMP1 through mimicry of CD40 signaling, 23 and for LMP2 through mimicry of surface immunoglobulin engagement. 24 The present work, and the recent detection of EBV in a population of CD19 ϩ surface immunoglobulinnegative cells in the blood of patients after transplantation, 25 strengthen the view that virus-mediated rescue of aberrant GC products contributes directly to the pathogenesis of PTLD. The relevance of these findings to the pathogenesis of HL, an EBVassociated tumor similarly derived from atypical post-GC B cells often carrying crippled immunoglobulin genes, 11 is less clear.…”

Section: Resultsmentioning

confidence: 48%

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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“…Irrespective of the mechanism of BCR loss, immunosuppression may allow the survival of BCR-deficient B-cells, as detected in recipients of solid organ allografts [64]. In EBVþ PTLD, the virus itself may rescue B-cell clones, which lack evidence of antigen selection or have crippling Ig mutations [2,7,8], a hypothesis supported by recent in vitro experiments [11].…”

Section: B-cell Receptor Abnormalities In Ptld Have a Multifactorial mentioning

confidence: 96%

Genetic and phenotypic analysis of B‐cell post‐transplant lymphoproliferative disorders provides insights into disease biology

Vakiani

Basso

Klein

et al. 2008

Hematological Oncology

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B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6 +/- MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed 'crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV- PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions.

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Surface Immunoglobulin-Deficient Epstein-Barr Virus-Infected B Cells in the Peripheral Blood of Pediatric Solid-Organ Transplant Recipients

Abstract: Epstein-Barr virus (EBV),

Cited by 16 publications

References 35 publications

EBV-Specific CD8+ T Cells from Asymptomatic Pediatric Thoracic Transplant Patients Carrying Chronic High EBV Loads Display Contrasting Features: Activated Phenotype and Exhausted Function

EBV-Specific CD8+ T Cells from Asymptomatic Pediatric Thoracic Transplant Patients Carrying Chronic High EBV Loads Display Contrasting Features: Activated Phenotype and Exhausted Function

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

Genetic and phenotypic analysis of B‐cell post‐transplant lymphoproliferative disorders provides insights into disease biology

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