Unknown,Transcriptomics,Genomics,Proteomics

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Comparative gene expression analysis upon stimulation of the human BCR or an inducible LMP2A in EBV immortalized lymphoblastoid cell lines

ABSTRACT: Survival of all B cells depends on signals from the B-cell receptor (BCR). In BCRnegative B cells the latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) replaces this survival signal and might play a role in the development of EBV-positive Hodgkin lymphomas and posttransplantation lymphoproliferative disease. In these BCR-negative cells LMP2A provides a ‘tonic’ signal similar to BCR’s constitutive expression in the absence of antigen in order to maintain activating signaling pathways common to both receptor molecules. In most latently EBV-infected B cells LMP2A and BCR are co-expressed but it is largely unclear what LMP2A contributes with respect to B-cell activation, proliferation and viral latency in these BCR-positive cells. A common model suggests that LMP2A maintains herpesviral latency by blocking BCR-mediated signals but how LMP2A could serve both antithetical ends in BCRnegative and BCR-positive cells is elusive. Our comparative analysis of BCR and LMP2A now indicates that LMP2A is a true BCR mimic that dominates BCR-operated signaling pathways in EBV-infected, BCR-positive cells to provide activation signals, support stable infections in vivo and allow exit from latency. These findings suggest that LMP2A co-opts the situation in anergic B cells, where continuous BCR signaling results in maintenance of the anergic state accompanied by unresponsiveness to acute BCR stimulation. The microarray experiment was used to compare effects of BCR and LMP2A on gene expression regulation. EBV's LMP2A and the human BCR activate similar cellular target genes; some genes are regulated solely by BCR or LMP2A, no gene is counter regulated A 12 chip study using cDNA from three separate 2525 LMP2A knockout LCL cultures and three separate 3696.10 LMP2A:mCD69 LCL cultures; each culture tested before and after 90 min stimulation of the BCR and LMP2A:mCD69, respectively.

ORGANISM(S): Homo sapiens

SUBMITTER: Wolfgang Hammerschmidt

PROVIDER: E-GEOD-25434 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Abstract: Epstein-Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells sometimes cause B cell malignancies in humans with T- or NK-cell deficiency. We now find EBV-encoded Latent Membrane Protein 2A (LMP2A) to mimic B cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B cell differentiation in mice that conditionally express LMP2A in GC B cells, or all B-lineage cells, found LMP2A expression enhanced not only BCR signals but also plasma-cell differentiation, in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody–producing B-cells despite apparently normal GC formation. GC B cell-specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the Zbtb20 locus. We conclude that LMP2A reduces the stringency of GC B cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with pro-survival signals. Significance Statement: Epstein-Barr virus (EBV) is a human herpesvirus that establishes persistent infection of the B-cell compartment. EBV is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). However, the molecular mechanisms by which EBV contributes to autoimmunity remain unclear. We used transgenic mouse models to study the role of EBV-encoded Latent membrane protein 2A (LMP2A), which mimics B-cell receptor signaling.　Interestingly, LMP2A not only enhanced B-cell survival, but also upregulated the transcription factor Zbtb20 and promoted plasma cell differentiation. When expressed late in B-cell development, LMP2A also caused prominent features of SLE, including autoantibody production with kidney immune complex deposition. Our findings suggest that LMP2A has important roles in B cell activation, differentiation and the development of EBV-associated autoimmune diseases.

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Comparative gene expression analysis upon stimulation of the human BCR or an inducible LMP2A in EBV immortalized lymphoblastoid cell lines

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