scholarly journals Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 788
Author(s):  
Monika A. Zelazowska ◽  
Kevin McBride ◽  
Laurie T. Krug
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Adaptive Immune Response ◽  
Kaposi Sarcoma ◽  
Lymphoid Tissues ◽  
Barr Virus ◽  
Sequencing Technologies ◽  
Biologic Property ◽  
Epstein Barr ◽  
Immunoglobulin Repertoire

A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins and non-coding RNAs to reprogram lymphocytes for proliferative expansion. Within lymphoid tissues, the germinal center (GC) reaction is a hub of B cell proliferation and death. The goal of a GC is to generate and then select for a pool of immunoglobulin (Ig) genes that will provide a protective humoral adaptive immune response. B cells infected with GHVs are detected in GCs and bear the hallmark signatures of the mutagenic processes of somatic hypermutation and isotype class switching of the Ig genes. However, data also supports extrafollicular B cells as a reservoir engaged by GHVs. Next-generation sequencing technologies provide unprecedented detail of the Ig sequence that informs the natural history of infection at the single cell level. Here, we review recent reports from human and murine GHV systems that identify striking differences in the immunoglobulin repertoire of infected B cells compared to their uninfected counterparts. Implications for virus biology, GHV-associated cancers, and host immune dysfunction will be discussed.

Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4345-4350 ◽  
Author(s):  
Dörte Bechtel ◽  
Julia Kurth ◽  
Claus Unkel ◽  
Ralf Küppers
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Classic Hodgkin Lymphoma ◽  
Epstein Barr

In classic Hodgkin lymphoma (HL) and posttransplantation lymphoproliferative disease (PTLD), 2 malignancies frequently associated with Epstein-Barr virus (EBV), the tumor cells often appear to derive from B-cell receptor (BCR)–deficient and therefore preapoptotic germinal center (GC) B cells. To test whether EBV can rescue BCR-less GC B cells, we infected human tonsillar CD77+ GC B cells in vitro with EBV. More than 60 monoclonal lymphoblastoid cell lines (LCLs) were established. Among these, 28 cell lines did not express surface immunoglobulin (sIg). Two of the sIg-negative cell lines carry obviously destructive mutations that have been introduced into originally functional VH gene rearrangements during the process of somatic hypermutation. Quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) showed that in most other lines the sIg deficiency was not simply the result of transcriptional down-regulation, but it was rather due to posttranscriptional defects. These findings strongly support the idea that EBV plays a central role in the pathogenesis of classic HL and PTLD by rescuing BCR-deficient, preapoptotic GC B cells from apoptosis, and that EBV infection renders the cells independent from survival signals normally supplied by a BCR. The monoclonal LCLs represent valuable models for early stages of lymphoma development in classic HL and PTLD.

scholarly journals LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1448-1455 ◽  
Author(s):  
Julia Rastelli ◽  
Cornelia Hömig-Hölzel ◽  
Jane Seagal ◽  
Werner Müller ◽  
Andrea C. Hermann ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Cd40 Ligand ◽  
Barr Virus ◽  
Class Switch ◽  
Epstein Barr

AbstractThe Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell–specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.

scholarly journals Epstein-Barr virus nuclear protein EBNA3C directly induces expression of AID and somatic mutations in B cells

2016 ◽  
Vol 213 (6) ◽  
pp. 921-928 ◽  
Author(s):  
Jens S. Kalchschmidt ◽  
Rachael Bashford-Rogers ◽  
Kostas Paschos ◽  
Adam C.T. Gillman ◽  
Christine T. Styles ◽  
...  
Keyword(s):  
B Cells ◽  
Epstein Barr Virus ◽  
Nuclear Protein ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Regulatory Elements ◽  
Definitive Evidence ◽  
Barr Virus ◽  
Activation Induced Cytidine Deaminase ◽  
Epstein Barr

Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma. Using various Epstein-Barr virus (EBV) recombinants, we provide definitive evidence that the viral nuclear protein EBNA3C is essential in EBV-infected primary B cells for the induction of AID mRNA and protein. Using lymphoblastoid cell lines (LCLs) established with EBV recombinants conditional for EBNA3C function, this was confirmed, and it was shown that transactivation of the AID gene (AICDA) is associated with EBNA3C binding to highly conserved regulatory elements located proximal to and upstream of the AICDA transcription start site. EBNA3C binding initiated epigenetic changes to chromatin at specific sites across the AICDA locus. Deep sequencing of cDNA corresponding to the IgH V-D-J region from the conditional LCL was used to formally show that SHM is activated by functional EBNA3C and induction of AID. These data, showing the direct targeting and induction of functional AID by EBNA3C, suggest a novel role for EBV in the etiology of B cell cancers, including endemic Burkitt lymphoma.

scholarly journals Epstein-Barr Virus–induced Molecule 1 Ligand Chemokine Is Expressed by Dendritic Cells in Lymphoid Tissues and Strongly Attracts Naive T Cells and Activated B Cells

1998 ◽  
Vol 188 (1) ◽  
pp. 181-191 ◽  
Author(s):  
Vu N. Ngo ◽  
H. Lucy Tang ◽  
Jason G. Cyster
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Epstein Barr Virus ◽  
Cell Receptor ◽  
Lymphoid Tissues ◽  
Barr Virus ◽  
Epstein Barr ◽  
Activated B Cells

Movement of T and B lymphocytes through secondary lymphoid tissues is likely to involve multiple cues that help the cells navigate to appropriate compartments. Epstein-Barr virus– induced molecule 1 (EBI-1) ligand chemokine (ELC/MIP3β) is expressed constitutively within lymphoid tissues and may act as such a guidance cue. Here, we have isolated mouse ELC and characterized its expression pattern and chemotactic properties. ELC is expressed constitutively in dendritic cells within the T cell zone of secondary lymphoid tissues. Recombinant ELC was strongly chemotactic for naive (L-selectinhi) CD4 T cells and for CD8 T cells and weakly attractive for resting B cells and memory (L-selectinlo) CD4 T cells. After activation through the B cell receptor, the chemotactic response of B cells was enhanced. Like its human counterpart, murine ELC stimulated cells transfected with EBI-1/CC chemokine receptor 7 (CCR7). Our findings suggest a central role for ELC in promoting encounters between recirculating T cells and dendritic cells and in the migration of activated B cells into the T zone of secondary lymphoid tissues.

scholarly journals Robust T-cell stimulation by Epstein-Barr virus–transformed B cells after antigen targeting to DEC-205

Blood ◽  
2013 ◽  
Vol 121 (9) ◽  
pp. 1584-1594 ◽  
Author(s):  
Carol S. Leung ◽  
Michael A. Maurer ◽  
Sonja Meixlsperger ◽  
Anne Lippmann ◽  
Cheolho Cheong ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Cell Stimulation ◽  
Barr Virus ◽  
T Cell Stimulation ◽  
Key Points ◽  
Epstein Barr ◽  
Mhc Presentation ◽  
Activated B Cells

Key Points B cells contribute to MHC presentation of DEC-205–targeted antigen. Activated B cells present DEC-205–targeted antigen efficiently, because they retain it longer.

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