EBV making Memory B cell

Styles CT, Bazot Q, Parker GA, White RE, Paschos K, Allday MJ. EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency. PLoS Biol. 2017 Aug;15(8):e2001992.

Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. 

Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes. EBNA3B is not necessary to establish Lymphoblastoid lines, but EBNA3A and EBNA3C are required to sustain proliferation, in part, by repressing the expression of tumour suppressor genes. 

Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C can be conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that-after a phase of rapid proliferation-infected primary B cells express elevated levels of factors associated with plasma cell (PC) differentiation. 

These include the cyclin-dependent kinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of plasma cell differentiation B lymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38 and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in lymphoblastoid cell lines inhibition of CDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding of EBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming. Consistent with the binding of EBNA3A and/or EBNA3C, cells become committed to a B-blast fate in less than 12 days post-infection and are unable to de-repress p18INK4c or BLIMP-1-in either newly infected cells or lymphoblastoid cells by inactivating EBNA3A and EBNA3C. 

In vitro, about 20 days after infection with EBV lacking functional EBNA3A and EBNA3C, cells develop a plasma cell-like phenotype. Together, these data suggest that EBNA3A and EBNA3C have evolved to prevent differentiation to plasma cells after infection by EBV, thus favouring long-term latency in Memory B Cells and asymptomatic persistence.

EBNA3A and EBNA3C inhibit the differentiation of Epstein-Barr virus (EBV)-activated B cells to plasma cells.

Upon EBV infection, mature human B cells become activated, grow and proliferate. In vivo, in the presence of T cells or T cell–derived factors, infected cells can enter the germinal centre and differentiate into memory B cells, the site of long-term EBV latency and persistence. However, it has not been established what happens if T cell help is unavailable (Th-ve). Usually in the absence of T cell help, antigen-activated B cells can enter the default plasma cell differentiation pathway, resulting in antibody-producing plasma cells. We suggest EBV has evolved to prevent default plasma cell differentiation, thus favouring latency in memory B cells, through specific repression of the plasma cell differentiation factors p18INK4c and B lymphocyte-induced maturation protein-1 (BLIMP-1), by the viral transcription factors EBNA3A and EBNA3C that act in vitro to support the activated B-blast population in establishing continuously proliferating lymphoblastoid cell lines (LCLs). Since the repression of the p18INK4c and BLIMP-1 genes utilizes the polycomb system (PRC2) and is stable and heritable, continuous expression of functional EBNA3A and EBNA3C is unnecessary to favour memory cell rather than plasma cell differentiation.

We have been arguing that drugs that target memory B cells are important for control of MS. One potential reason is because they are removing Epstein Bar Virus. This study looks to see what happens when B cells are infected with the virus. It appears that some viral gene elements stop the B cells differentiating into antibody producing plasma cells and instead makes them form memory B cells where the virus can become latent and avoid immune destruction, but at the same time this will help virus and importantly memory B cells persist. Therefore does this cause immune memory to persist and so create an advantage to most infected humans.

So would a vaccine to kill EBV be a good thing.

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    • In a world of antibiotics, vaccines maybe not but historically when life expectancy was very short we don't know. This would be where the importance lies.

      Sickle cell anaemia is a consequence of protection against malaria, the sickle gene is not much use in UK, but its background is biology

  • You are assuming that the infected immortalised memory B cells remember anything of importance and that the infected cells function correctly, is there evidence that they do/do not.

    A number of genetic diseases survive without any advantage because they do not kill at an early enough stage (the people still breed) eg Huntington's disease, so something does not have to be useful to survive. Also Small Pox was around for a very long time and we have not seen a disadvantage from vaccinating against that.

  • Sorry, is the argument that without ebv we cannot produce memory B cells? Do people with no ebv have no B memory cells?

    • No the idea may be that ebv may make memory persist longer, but people without ebv will make memory B cells just like a mouse does

  • The Epstein Barr Virus is very "smart," it does not "kill you first," but it may leave you with sequelae as in the case of MS, or when it "bumps" into a host in which it ends up "awakening" but it can be deadly.

    Now the sequelae of MS are nothing "cool, easy to solve" and can kill yes, when you get to EDSS 9, unfortunately.
    Then if EBV is involved in it all, a vaccine against it's essential.

  • Thank-you for your interest in our paper. To address a couple of the questions that have been asked above:
    EBV is not essential for making memory B cells. EBV activates cells that it infects, and then controls the changes they undergo. The paper describes some aspects of how EBV makes sure that the infected cell turns into a memory B cell, in which it hides, rather than a plasma cell.
    I do not know if EBV-positive people live longer or less long than EBV negative (good question). What we do know is that mice latently infected with a related virus (MHV68) are more resistant to certain other diseases, so the relationship between EBV and health/disease may not be straightforward.
    Vaccinating against EBV has the potential to reduce harm in several ways. However, no herpesvirus (the virus family to which EBV belongs) has a vaccine that prevents infection. The Zoster (Chickenpox) vaccine only prevents disease, not infection. This may also be true of an EBV vaccine, but we won't know until we try.
    The other therapeutic strategy is to produce drugs that interfere with virus latency. For MS, we do not know how EBV is involved (the evidence is strong that it usually is), but there are some universal features of the EBV lifecycle that could possibly be targeted in all of its diseases.

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