Molecular characterisation of Epstein-Barr virus-specific B cell response

Abstract

Primary Epstein-Barr virus (EBV) infection causes infectious mononucleosis (IM) in 50% of infected adolescents and young adults. It has long been known that IM is associated with the aberrant expansion of EBV-specific CD8+ T cells and can cause rare but serious complications, including airway obstruction, splenic rupture, and haemolytic anaemia. IM is also associated with an increased incidence of EBV-associated Hodgkin’s Lymphoma and autoimmune diseases like multiple sclerosis. Despite significant research, it is not clear why some individuals are more likely than others to develop clinical symptoms. In seeking an explanation, we studied immune control during the early stages of EBV infection, before cell-mediated immune responses come into play. We hypothesized that there is a defect in immune control during the early stages of EBV infection. EBV infection induces a strong humoral immune response and the antibodies produced against EBV are used as diagnostic markers in the detection of EBV infection. While considerable knowledge has been accumulated on T cell response during acute IM, we have little understanding of virus-specific B cell immunity during primary EBV infection. Cross-sectional and longitudinal analyses of humoral immune responses in this project revealed that patients with acute IM have a severe deficiency of anti-EBV neutralizing antibodies, which was associated with a lack of gp350-specific B cell responses and a significant reduction in total memory B cells in peripheral blood. Furthermore, these patients also showed dysregulation of tumour necrosis factor (TNF)-family members BAFF and APRIL and increased expression of FAS on circulating B cells. This impairment of anti-viral B cell responses was coincident with a dramatic loss of circulating myeloid and plasmacytoid DC numbers during acute IM, which recovered to baseline following convalescence. The loss of plasmacytoid dendritic cells was found to be much greater than that of myeloid DCs, with slower recovery upon disease resolution. This is consistent with earlier published findings of an absence of IFN-α in the plasma of IM patients, since plasmacytoid dendritic cells are the main producers of IFN-α. A number of possible causes for the loss of blood DCs were also explored in this project. Finally, using in vitro studies, we demonstrated that the loss of circulating DCs is intrinsically linked to the impaired activation and maturation of antibody-secreting B cells. These observations delineate new mechanistic insight into immune dysregulation during acute IM and its impact on anti-viral B cell responses that will help us to design better therapeutic/prophylactic strategies to prevent acute IM symptoms.