Page 864 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 54

INFECTIOUS MONONUCLEOSIS AND OTHER EPSTEIN-BARR

VIRUS–ASSOCIATED DISEASES

Carl Allen, Cliona M. Rooney, and Stephen Gottschalk

The initial clinical descriptions of primary Epstein-Barr virus (EBV) antigens 2 and 3 (EBNA2 and EBNA3). However, using polymor-
infections are credited to Filatov and Pfeiffer at the end of the 19th phisms in the latent membrane protein 1 (LMP1), further subtypes
century. Pfeiffer coined the term glandular fever, which described an have been described. EBV strains vary by geography and have not
illness consisting of fever, malaise, sore throat, and lymphadenopathy. been linked to a particular EBV-associated disease.
In 1920, Sprunt and Evans introduced the term infectious mononucleo-
sis (IM) to describe a series of patients with fatigue, fever, lymphade-
nopathy, and prominent mononuclear lymphocytosis (Fig. 54.1). PRIMARY EPSTEIN-BARR VIRUS INFECTION
Serologic diagnosis of IM became available in the 1930s with the
heterophile agglutination test developed by Paul and Bunnel and later Primary EBV infection usually occurs through the oropharynx, where
modified by Davidson. mucosal epithelial cells and/or B cells become productively infected
The identification of EBV as the causative agent of IM was (Fig. 54.2). Infection of B cells by EBV is initiated by binding of the
impeded for many years by the inability to transmit the disease to dominant viral glycoprotein gp350/220 to CD21, the C3d comple-
animals or to grow the virus ex vivo. In 1958 Burkitt described a ment receptor; subsequent cell entry is mediated by a complex of
lymphoma in African children and investigators suspected an infec- three viral glycoproteins, gH, gL, and gp42. Gp42 binds to HLA
tious etiology because the lymphoma’s geographic distribution pattern class II, which functions as a coreceptor, and gH is most likely
1
coincided with the African mosquito belt. In 1964 Epstein, Achong, involved in virus-cell fusion. The entry of EBV into epithelial cells
and Barr described herpesvirus-like particles in tumor biopsies from may occur through multiple mechanisms because the majority of
patients with Burkitt lymphoma (BL). Werner and Gertrude Henle epithelial cells are CD21 negative. After viral entry, the capsid is
developed an indirect immunofluorescent antibody assay to this new dissolved and the EBV genome is transported into the nucleus where
virus, now called Epstein-Barr virus, and showed that patients with it circularizes. Infection of epithelial cells results in lytic or abortive
BL, as well as 90% of American adults, had antibodies against EBV. infection, whereas B-cell infection results predominantly in latency,
In 1965 the Henles documented seroconversion to EBV of an indi- the lytic infection also occurs, resulting in the release of infectious
vidual who presented with clinical symptoms of IM. This initial virus into the saliva and other secretions. During primary infection,
observation was corroborated by larger studies confirming the asso- EBV establishes lifelong latency in B cells and it is estimated that 1
6
ciation of EBV and IM. to 50 cells per 1 × 10 B cells in the peripheral circulation are infected
Since then, EBV has been linked to a heterogeneous group of with EBV. The number of latently infected B cells within a person
2
diseases (see box on EBV-Associated Clinical Syndromes). EBV was remains stable over years; however, intermittent reactivation of EBV
the first human virus implicated in oncogenesis, and the biology of in B cells into the lytic cycle at mucosal sites is probably responsible
the virus has been studied extensively on a cellular and molecular for the observed shedding of infectious virus into the saliva of asymp-
2
level. Because primary EBV infection is a self-limiting disease in tomatic carriers (Fig. 54.2).
almost all individuals, therapeutic strategies have focused on the Although EBV can infect any B cell and express the full spectrum
treatment of rare, potentially fatal EBV-associated diseases. Over the of latency proteins, studies suggest that only infection of naive B cells
last two decades, successful immunotherapeutic approaches have results in persistent infection (Fig. 54.2). EBV infection pushes the
been developed for EBV-associated malignancies, using either mono- naive B cell into a memory state independent of an antigen-dependent
clonal antibodies or the adoptive transfer of EBV-specific T cells. 3,4 germinal center (GC) reaction by upregulation of cytosine deaminase,
which induces both class switching and somatic hypermutation. The
former also requires the expression of EBV-encoded LMP1, a con-
BIOLOGY OF EPSTEIN-BARR VIRUS stitutively activated CD40 molecule, or CD40 ligation, most likely
provided by GC T helper (Th)3 cells that can provide T-cell help for
EBV belongs to the family of herpesviruses, which has almost 100 B-cell differentiation by provision of CD40 ligand, interleukin (IL)-4,
members. Membership is based on the architecture of the virion that and IL-10 while preventing antigen-dependent effector T-cell–medi-
is 120 to 300 nm in size and contains (a) a core of linear, double- ated B-cell elimination by expression of transforming growth factor
stranded DNA, (b) an icosadeltahedral capsid with 162 capsomers, (TGF)-β. This reaction occurs within the lymph node (see E-Slide
(c) an amorphous material between the capsid and envelope desig- VM03965) and also involves downregulation of latency proteins and
nated tegument, and (d) an envelope containing viral glycoproteins. expression of latency type II. On exit from the lymph node, expres-
Besides EBV, designated human herpesvirus 4, seven other herpesvi- sion of latency proteins is completely inhibited. In this way infected
ruses have been isolated from humans: herpes simplex viruses 1 and B cells can evade immune elimination. By contrast, primarily infected
2, cytomegalovirus (CMV), varicella-zoster virus, human herpesvirus memory B cells enter and remain in latency type III and are rapidly
6, human herpesvirus 7, and the Kaposi sarcoma–associated herpes- eliminated by effector T cells and therefore do not contribute to virus
virus (KSHV, human herpesvirus 8). Herpesviruses are further persistence.
divided into subfamilies to reflect evolutionary relatedness and similar
biologic properties. EBV and KSHV belong to the human gamma
herpesvirus subgroup and have a limited tissue tropism to B and T LATENT EPSTEIN-BARR VIRUS INFECTION
lymphocytes and certain types of epithelial cells. Several variants of
EBV have been identified by genomic polymorphisms. Initially, two During latent infection, EBV persists episomally in resting memory
EBV types were distinguished by sequence changes in EBV nuclear B cells. Initially, it was thought that EBNA1 and LMP2 were

747