Epstein–Barr virus–associated lymphoproliferative diseases (also abbreviated EBV-associated lymphoproliferative diseases or EBV+ LPD) are a group of disorders in which one or more types of lymphoid cells (a type of white blood cell), i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.
EBV-associated LPDs are a subcategory of EBV-associated diseases. Non-LPD that have significant percentages of cases associated with EBV infection (see Epstein–Barr virus infection) include the immune disorders of multiple sclerosis and systemic lupus erythematosus; malignancies such as stomach cancers, soft tissue sarcomas, leiomyosarcoma, and undifferentiated nasopharyngeal cancer; the childhood disorders of Alice in Wonderland syndrome; and acute cerebellar ataxia.
About 50% of all five-year-old children and 90% of adults have evidence of previous infection with EBV. During the initial infection, the virus may cause infectious mononucleosis, only minor non-specific symptoms, or no symptoms. Regardless of this, the virus enters a latency phase in its host and the infected individual becomes a lifetime asymptomatic carrier of EBV. Weeks, months, years, or decades thereafter, a small percentage of these carriers, particularly those with an immunodeficiency, develop an EBV+ LPD. Worldwide, EBV infection is associated with 1% to 1.5% of all cancers. The vast majority of these EBV-associated cancers are LPD. The non-malignant, premalignant, and malignant forms of EBV+ LPD have a huge impact on world health.
The classification and nomenclature of the LPD reported here follow the revisions made by the World Health Organization in 2016. This classification divides EBV+ LPD into five categories: EBV-associated reactive lymphoid proliferations, EBV-associated B cell lymphoproliferative disorders, EBV-associated NK/T cell lymphoproliferative disorders, EBV-associated immunodeficiency-related lymphoproliferative disorders, and EBV-associated histiocytic-dendritic disorders.
Pathophysiology Lymphoid cells involved in EBV+ LPD In the "germinal center model" for the normal maturation of B cells, naive B cells enter the germinal centers of lymph nodes and other lymphoid tissues and in the process of becoming competent for producing functional antibodies, mature into lymphoblasts, centroblasts, centrocytes, memory B cells, and ultimately plasma cells. During this maturation, the B cells rearrange their immunoglobulin genes at multiple sites. The first lymphoid cell type invaded by EBV is the naïve B cell. Following this invasion, the virus express genes that control this cell's advance through these maturation stages; it can force the naïve B cell that it infects to: arrest maturation at any of these stages; become undetectable as an infected cell by the host's immune system; proliferate excessively; and develop into a B cell-based LPD. The virus may also exit the B cell it initially infects; invade T- or NK cells; and cause these cells to avoid detection by the immune system, proliferate, and progress to a T- or NK cell-based LPD. The T cells that may become infected by EBV are natural killer T cells (NK cells), Gamma delta T cells (γδ T cells), cytotoxic T cells (CTL), helper T cells (Th cells), and follicular B helper T cells (TFH cells). The means by which EBV establishes a dendritic-histiocytic cell (i.e. follicular dendritic cell) infection are unclear. Follicular dendritic cells are connective tissue rather than lymphoid cells. They do, however, have a surface membrane receptor, CD21 (also known as complement receptor type 2), which EBV uses to enter B cells. EBV may escape their infected B cell to invade follicular dendritic cells through this CD21 entry pathway. However, it is also thought possible that the EBV may direct its infected lymphoid cell to mature into an apparent follicular dendritic cell.
Epstein–Barr virus infection
The Epstein–Barr virus (also termed human herpesvirus 4) belongs to the Herpes family of Group I double-stranded DNA viruses. It is spread by transfer from the oral/nasal secretions of an infected individual to the oral cavity of an uninfected individual. Once in the oral cavity, the virus invades, reproduces in, establishes its lytic phase in, and lyses (i.e. bursts open) epithelial cells that line the oral mucosa of the newly infected individual. The freed virus then invades naïve B cells located in submucosal lymphoid tissue e.g. tonsils or adenoids. Here, it establishes either a lytic phase that allows it to infect other lymphoid cells or expresses genes that suppress the lytic cycle and impose one of four latency phases. Initially, the virus establishes latency III by expressing nuclear proteins encoded by its EBNA-1, -2, -3A, -3B, -3C, LP, LMP-1, -2A, and -2B and BART genes; cell surface membrane proteins encoded by its LMP-1, -2A, and 3A genes; and microRNAs encoded by its EBER-1 and EBER-2 genes. The products of these genes immortalize, promote the growth and survival, and regulate the maturation of the infected B cell. However, products of some latency III genes (particularly the viral cell surface proteins) make the infected cell susceptible to attack by the host's immune system. The virus avoids this by limiting expression of its latency genes to EBNA-1, LMP-1, -2A, -2B, some BARTs, and the two EBERs. This Latency II pattern of gene expression continues the infected cells' immortalization and proliferation, helps the cells escape the immune surveillance, and forces them to differentiate (i.e. mature) into memory B cells. EBV may establish and maintain a Latency I state in its infected memory B cells by expressing only EBNA1 and the two EBER genes. The products of the latter genes keep the virus in a mostly dormant state. Finally, EBV may establish and maintain a Latency 0 phase by expressing only EBER genes. In latency 0, EBV is in memory B cells as fully dormant, non-reproductive viruses but in this, as in all of the other latency phases, it can revert to its lytic phase. The following table gives more information on the actions of the EBV latency genes.
EBV product Latency Function EBNA-1 III, II, I Promote replication of the viral genome; controls the infected cell's expression of nuclear and surface membrane proteins that regulate the virus's latency phases. EBNA-2 III Induces expression of the virus's LMP gene and ~300 genes of the infected cell (e.g. the MYC proto-oncogene) which promote this cell's proliferation, survival, and malignancy; required for the malignant transformation of this cell. EBNA-3A III Represses expression of the infected cell's p16INK4a protein thereby promoting its proliferation; represses expression the infected cell's BCL2L11 protein thereby inhibiting apoptosis to promote this cell's survival. EBNA-3B III Inhibits the infected cell's proliferation; attracts lymphoid cells to its infected cell; inactivates promoters of its infected cell's genes possibly thereby causing this cell more able to evade the host's immune system and to become malignant. EBNA-3C III Required for the malignant transformation of infected cells; along with EBNA-3A, represses the infected cell's p16INK4a and BCL2L11 proteins thereby promoting, respectively, this cell's proliferation and repressing its apoptosis; disturbs cell cycle checkpoints in the infected cell to promote its proliferation or locking it in the non-reproductive cell cycle state of G1. EBNA-LP III Overcomes the innate immune responses of infected cells to promote the virus's survival; acts with EBNA-2 to promote the malignant transformation of its infected cells. LMP-1 III, II Induces the expression of the infected cell's NF-κB and BCL2 proteins thereby blocking this cells apoptosis and stimulating its proliferation; regulates the infected cell's maturation. LMP-2A III, II Prevents the establishment of EBV's lytic cycle; stimulates the infected cell's AKT and B cell receptor proteins thereby blocking this cell's apoptosis and promoting its survival and proliferation. LMP-2B III, II Inhibits the ability of the virus's LMP-2A protein to establish EBV's lytic cycle; stimulates the infected host cell's AKT and B cell receptor proteins thereby blocking this cell's apoptosis and promoting its survival and proliferation. BART microRNAs III, II, I While abundantly expressed, the functions of BART microRNAs are unclear; may help evade the infected cell avoid attack by uninfected T- and NK-cells or modify the infected cell's notch signaling pathway to promote its proliferation; not required for EBV-induced B cell immortalization or malignant transformation. EBER1/2 nuclear RNAs III, II, I, 0 Abundantly expressed by EBV-infected cells in all latency stages; causes infected cell to produce interleukin 10 which may promote this cell to proliferate and avoid attack by host cytotoxic T cells; may block apoptosis in the infected cell.
EBV-associated reactive lymphoid proliferations EBV-associated reactive lymphoid proliferations are a set of disorders in which B cells or NK/T cells proliferate as an apparent reaction to EBV infection. They are usually self-limiting, non-malignant disorders but have a variable possibility of progressing to a malignant lymphoproliferative disease.
Epstein–Barr virus-positive reactive lymphoid hyperplasia EBV-positive reactive lymphoid hyperplasia (or EBV-positive reactive lymphoid proliferation) is a benign form of lymphadenopathy, i.e. swollen, often painful lymph nodes. The disorder is based on histologic findings that occur in the lymphoid tissue of mainly older individuals who were infected with EBV many years earlier. Immunodeficient individuals of any age may also have the disorder. In immunologically normal individuals, histologic findings include the presence of small B cells located in the extrafollicular or, rarely, the follicular area of normal or minimally hyperplastic lymph nodes. These cells are commonly EBV+, express EBER viral genes, and carry the virus in its latency I or II phase. These cells may also occur in the bone marrow. Individuals who are immunodeficient because of disease, immunosuppressive drugs, or old age immunosenescence may exhibit a more pronounced hyperplasia of affected nodes, higher numbers of EBV+ cells, and a more disseminated disorder termed polymorphic lymphoproliferative disorder. These disorders almost always resolve spontaneously but in very rare cases progress over months or years to EBV+ Hodgkin lymphoma or EBV+ diffuse large B-cell lymphoma of the elderly.
Epstein–Barr virus-positive infectious mononucleosis