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Hodgkin's lymphoma (HL)

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Overview

Introduction

Hodgkin's lymphoma is a rare hematopoietic malignancy in which the neoplastic cells constitute only a minority (1-2%) of the total tumor mass. These are large mononucleated (Hodgkin) and multinucleated (Reed-Sternberg) cells amidst a non-neoplastic inflammatory infiltrate. Malignant HRS cells exhibit strong NF-kB overexpression. They also lost the expression of typical B cell lineage genes and instead show strong expression of signaling molecules and transcription factors of other cell types. Most cases of HL carry clonal somatically mutated Ig V (Variable)-gene re-arrangement. Up to 40% of HL cases are associated with Epstein-Barr Virus (EBV), and so far, it is the only candidate for the infectious agent causing HL. Along with Nasopharyngeal carcinoma (NPC) and peripheral T cell lymphoma, HRS cells exhibit latency II program (see EBV latency and persistence) with viral antigen expression limited to EBNA-1, LMP-1, LMP-2, and EBERs.

The large majority of Hodgkin lymphoma associated with Human Immunodeficiency Virus (HIV) infection are pathogenically linked to EBV, with rates of EBV positivity ranging from 80 to 100%.

Brief history

Hodgkin's disease was first described in 1832 by Thomas Hodgkin (1798-1866) who published his article "On some morbid appearances of the adsorbent glands and spleen" based on post-mortem examination of seven patients. More than 30 years later, based on some additional cases, Wilks published his article describing same type of disease naming it Hodgkin's disease. In 1994, Hodgkin's disease's currently accepted types and subtypes were listed in the Revised European-American Lymphoma classification. In 2001, the World Health Organization (WHO) lymphoma classification system renamed Hodgkin's disease to Hodgkin's lymphoma.

Types of Hodgkin's lymphoma

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Role of Epstein-Barr virus in evolution and maintenance of HL

Evidence linking EBV to etiology of EBV+ HL
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Contribution of EBV in HL development and pathogenesis

There are many potential mechanisms of EBV oncogenicity. Some of them are briefly outlined below. Much more detailed information can be found in reviews referenced listed in next section.

HRS cells are derived from preapoptotic postgerminal center B cells which escaped apoptosis. Analysis has shown that they have immunogobulin gene heavy chain rearrangements that abolish its transcription. Usually B cells that carry crippling somatic mutations are destined to die. Survival of HRS cells suggests that a transforming event such as EBV infection, has taken place.

LMP-1 expression was associated with multinuclearity in EBV- LMP-1 transfected cell line. Also, functional analysis of LMP-1 has found that EBV+ HRS-associated LMP-1 is more oncogenic than normal EBV+ B-cell-associated LMP-1. LMP-1 functions as a constitutively activated tumor necrosis factor (TNF) receptor and many of phenotyping and growth transforming effects of LMP-1 result from its ability to activate a variety of signaling pathways including, Nuclear Factor kB (NF-kB).

One EBV gene expressed at very high levels in HL, LMP-2A, carries an immunoreceptor tyrosine-based activation motif (ITAM) that resembles motif carried by immunoglobin molecules. When expressed at the cell membrane, LMP-2A provides anti-apoptotic signal.

Although no direct oncogenic activity of EBNA-1 has been observed in tissue culture assays, expression of EBNA-1 in transgenic mice induces B cell follicular lymphoma. This demonstration that EBNA-1 is oncogenic in vivo suggests that it may also play direct role in the pathogenesis of EBV-associated malignancies probably through dysregulation of JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathways.

EBNA-1 also plays prominent role in evasion of immune response. It is protected from processing and presentation via the conventional major histocompatibility complex (MHC) class I pathway by virtue of its internal Glycine-Alanine repeat (GAr) domain, which acts as cis-inhibitory signal to prevent ubiquitin/proteasome dependent protein degradation. It also appears to reduce its own synthesis.

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References