Proinflammatory cytokines, microRNAs and schizophrenia

Epstein–Barr virus (EBV) has been identified as a putative trigger of multiple sclerosis (MS). We hypothesized that latent EBV infection alters the immune response to a second stimulus thereby exacerbating autoimmunity. Previously, we reported that mice latently infected with murine gamma herpesvirus 68 (gammaHV-68), the murine homolog to EBV, were induced for experimental autoimmune encephalomyelitis (EAE), they developed an enhanced neuroinflammatory disease more reminiscent of MS with lesions developing in the brain with both CNS infiltrating CD4 and CD8 T cells as well as focal demyelination. In this report, we demonstrate that when gammaHV-68 establishes latency a persistent upregulation of CD40 on dendritic cells is observed. We show that this upregulation of CD40 on DCs from latently infected mice is required to drive the priming of the strong TH1 response as well as the significant drop in Treg frequencies observed in latently infected mice before and during EAE. Further, virus latency is established in memory B cells and not dendritic cells and importantly, virus reactivation and/or replication is not observed post EAE induction. In addition, upregulation of CD40 on DCs accompanies and persists with viral latency for over 5 months post infection retaining the ability to enhance autoimmunity. We demonstrate that latent virus infection of memory B cells indirectly facilitates DC regulation of the immune response and most likely does this through changes in the balance of type I interferons. Clearly, latent gammaherpesvirus infection leaves a long-lasting immune impact that enhances subsequent immune responses leading to enhanced neuroinflammation and CNS pathology. This represents a novel mechanism by which EBV acts to influence MS.