Epstein-Barr virus, the germinal centre and the development of Hodgkin's lymphoma

Abstract

The relationship between Epstein-Barr virus (EBV) and the germinal centre (GC) of the asymptomatic host remains an enigma. The occasional appearance of EBV-positive germinal centres in some patients, particularly those with a history of immunosuppression, suggests that EBV numbers in the GC are subject to immune control. The relationship, if any, between lymphoid hyperplasia with EBV-positive germinal centres and subsequent or concurrent lymphomagenesis remains to be clarified. As far as the development of EBV-associated Hodgkin's lymphoma is concerned, the suppression of virus replication, mediated by LMP1 on the one hand, and the loss of B-cell receptor signalling on the other, appears to be an important pathogenic mechanism. A further important emerging concept is that alterations in the microenvironment of the EBV-infected B-cell may be important for lymphomagenesis.

Fig. 1.

Different forms of EBV latency. EBV, Epstein-Barr virus; EBNA, EBV nuclear antigen; LMP, latent membrane protein; EBER, EBV-encoded RNAs; miRNA, microRNA.

Fig. 2.

The fate of EBV-infected GC B-cells. The normal fate of the non-malignant EBV-infected GC B-cell is unclear but like normal GC B-cells they are thought to be able to differentiate into either plasma cells or memory cells. This could be important for the normal viral life cycle because differentiation to memory cells is associated with latency and long-term persistence, whereas differentiation to plasma cells has been shown to induce the lytic cycle and is probably important for the replication of EBV in the oropharynx.

Fig. 3.

Rare cases of reactive lymphadenopathy harbouring EBV-positive germinal centres. (a) EBER-positive cells in a GC with some scattered interfollicular EBER-positive cells in an enlarged cervical lymph node (case 1; see Table 1). The number of EBER-positive cells per GC was highly variable, including completely negative germinal centres. (b) Interfollicular EBER-positive cells express LMP1, while EBER-positive cells in GCs are LMP1-negative. A similar pattern was observed for LMP2A.

Fig. 4.

Model in which LMP1 blocks plasma cell differentiation. BLIMP1α is required for plasma cell differentiation. Plasma cell differentiation of EBV-infected B-cell leads to induction of the virus lytic cycle. LMP1 can suppress BLIMP1α expression, thereby preventing terminal differentiation to plasma cells. LMP1 can also presumably drive cells into the memory B-cell pool.