Reactivity Profiles of Memory-B Cells Infected With The Epstein-Barr Virus.
Epstein-Barr Virus (EBV) is a gamma herpesvirus that is highly prevalent worldwide.
Primary infection with EBV typically occurs during childhood and follows a subclinical
course, but infection later in life can result in the transient lymphoproliferative
disease infectious mononucleosis (IM). By the time they reach adulthood, more than 90%
of all humans have become infected. Once ... read moreit has achieved primary infection, EBV persists
within memory-B cells for the lifetime of the host. Our group has proposed a germinal
center (GC)-dependent lifecycle model of EBV infection. In our model, EBV+ memory-B
cells derive from naïve B cells that were infected and then driven, by virally
encoded proteins, to enter or initiate GC reactions. These EBV+ GC B cells are then
driven by further viral signaling to differentiate into long-lived memory-B cells. Once
infected cells have reached this stage, the virus persists in a quiescent state,
allowing it to avoid immunosurveillance efforts. EBV accomplishes these steps by
activating a series of viral gene transcription programs that are sensitive to the
various differentiation states of the host B cell during its ontological development.
Notably, evidence suggests that expression of particular viral proteins in GC B cells
may affect the susceptibility of these infected cells to GC selection pressures. If so,
this represents a mechanism by which viral actions may affect the reactivity of
surviving memory-B cells. Notably, this may result in the differentiation of
autoreactive memory-B cells, which is one mechanism that has been proposed to account
for the associations of EBV with autoimmune disease. To determine how EBV affects the
reactivity of host cells, we have cloned rAbs from single infected memory-B cells,
acquired from donors experiencing IM. The sequence characteristics and reactivity
patterns of these rAbs were then profiled using several assays. Our results reveal that
EBV+ memory-B cells have features similar to normal, uninfected memory-B cells acquired
from the same donors. This implies that instead of extensively manipulating B cell
differentiation pathways, EBV often directly infects memory-B cells during IM, a finding
that requires updating of the GC-dependent model to encompass this phenomenon. This work
also finds no evidence to support the idea that EBV induces the persistence of
autoreactive memory-B cells, arguing against the idea that this mechanism can explain
the associations of EBV and autoimmune
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Immunology.
Advisors: Erik Selsing, and David Thorley-Lawson.
Committee: Thereza Imanishi-Kari, Alexander Poltorak, David Stollar, and Ann Marshak-Rothstein.
Keywords: Immunology, and Virology.read less