The role of Epstein–Barr virus in Richter syndrome: response to Nourse et al

We wish to thank Nourse et al for their valuable comments on our article, ‘Richter’s syndrome: A review of clinical, ocular, neurological and other manifestations’ (Omoti & Omoti, 2008), which helps to put some of the issues concerning the role of Epstein–Barr Virus (EBV) in the aetiology of Richter’s syndrome in the right perspective. Although several review and original articles have focussed on the aetiology of Richter’s syndrome, our article summarized some sections, such as aetiology, and focussed on the systemic manifestations that have not been reviewed by other articles. In summarizing the aetiology, certain aspects may have been simplified. Definitely, Richter’s transformation represents a complex multistep process and, although viral associations have been identified, integration of the available scientific data poses substantial questions. Concerning the cell type that is primarily infected by EBV, a model for EBV persistence has been proposed as follows (Hochberg et al, 2004): Virions enter the mucosal surface of the nasopharynx through saliva. The virus enters the lymphoid tissue of Waldeyer’s ring, where it infects resting naive B cells and drives them to become proliferating lymphoblasts through expression of nine latent proteins (the growth program). These blasts can then differentiate into resting memory cells through a process analogous to the germinal centre (GC) reaction by using the default program. Once in resting memory cells, all viral protein expression ceases (the latency program). Latently infected memory cells circulate in the periphery and return to the lymphoid tissue, where at some unknown rate, they differentiate into plasma cells and release infectious virus to initiate a new round of infection. Each stage of the cycle is subject to immunosurveillance (cytotoxic T lymphocytes against infected cells and antibody against virions), with the exception of the memory cells, which are invisible because they express no viral proteins. In the absence of an immune response, the cycle will amplify until the memory B compartment is filled with latently infected cells. Once the immune response is activated, the cycle is dramatically reduced or perhaps even completely blocked and the reservoir of latently infected memory cells decays. There are now recent studies that propose this model or something very similar (Klein & Dalla-Favera, 2008). However, other studies seem to differ from this model (Kurth et al, 2000, 2003). These studies on acute infectious mononucleosis tonsils have led to the suggestion that EBV may establish persistent infection in the memory compartment by direct infection. EBV-driven clonal expansion of naive B cells was not seen in these studies. In infectious mononucleosis, GC and/or memory B cells were found to be directly infected by EBV and expand without somatic hypermutation, whereas the GC passage of EBV-infected naive B cells does not contribute detectably to the generation of infected memory B cells, the main reservoir of EBV during persistence (Kurth et al, 2003). One limitation of several studies is that patients are only tested when they present to the clinic. It is possible that during the very early stages of the infection, before the onset of symptoms, multiple cell types are infected in the blood. Subsequently, the infection could become restricted to memory cells by the time of onset of symptoms, when the patients are first studied (Hochberg et al, 2004). Another limitation with immunohistochemical approaches to identify infected cells in vivo is that the lower threshold for detection is not known (Hochberg et al, 2004). Thus, it is impossible to know how many infected cells have been missed and how representative the identified cells are. It is clear that the precise role of EBV infection in Richter’s syndrome remains to be established. What is not in doubt however is that the memory cells are the site of long-term persistent infection. Advances in technology have allowed a more precise dissection of the phenotypes of GC B cells and the specific transcriptional programmes that are responsible for this phenotype, as well as understanding of the mechanism controlling the exit of B cells from the GC and the decision to become a memory B cell or plasma cell (Klein & Dalla-Favera, 2008). Further advances are required to fully establish the precise role of EBV in the aetiology of Richter’s syndrome.