title: Identification of a sub-population of B cells that proliferates after infection with Epstein-Barr virus.
abstract: BACKGROUND
  Epstein-Barr virus (EBV)-driven B cell proliferation is critical to its subsequent persistence in the host and is a key event in the development of EBV-associated B cell diseases. Thus, inquiry into early cellular events that precede EBV-driven proliferation of B cells is essential for understanding the processes that can lead to EBV-associated B cell diseases.
  
  
  METHODS
  Infection with high titers of EBV of mixed, primary B cells in different stages of differentiation occurs during primary EBV infection and in the setting of T cell-immunocompromise that predisposes to development of EBV-lymphoproliferative diseases. Using an ex vivo system that recapitulates these conditions of infection, we correlated expression of selected B cell-surface markers and intracellular cytokines with expression of EBV latency genes and cell proliferation.
  
  
  RESULTS
  We identified CD23, CD58, and IL6, as molecules expressed at early times after EBV-infection. EBV differentially infected B cells into two distinct sub-populations of latently infected CD23+ cells: one fraction, marked as CD23hiCD58+IL6- by day 3, subsequently proliferated; another fraction, marked as CD23loCD58+, expressed IL6, a B cell growth factor, but failed to proliferate. High levels of LMP1, a critical viral oncoprotein, were expressed in individual CD23hiCD58+ and CD23loCD58+ cells, demonstrating that reduced levels of LMP1 did not explain the lack of proliferation of CD23loCD58+ cells. Differentiation stage of B cells did not appear to govern this dichotomy in outcome either. Memory or naïve B cells did not exclusively give rise to either CD23hi or IL6-expressing cells; rather memory B cells gave rise to both sub-populations of cells.
  
  
  CONCLUSIONS
  B cells are differentially susceptible to EBV-mediated proliferation despite expression of viral gene products known to be critical for continuous B cell growth. Cellular events, in addition to viral gene expression, likely play a critical role in determining the outcome of EBV infection. By indentifying cells predicted to undergo EBV-mediated proliferation, our study provides new avenues of investigation into EBV pathogenesis.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Megyola
authors.forename: Jianjiang
authors.initials: J
authors.lastname: Ye
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhaduri-McIntosh
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D005260:Female; D015870:Gene Expression; D004854:Herpesvirus 4, Human / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008297:Male; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology
chemical_list: D015850:Interleukin-6; D017455:Receptors, IgE