Identification of the missing link between Epstein-Barr-Virus (EBV) infection and increased risk of acquiring multiple sclerosis: Investigation of myelin-reactive T cells and myelin-reactive B cells in mouse models mimicking EBV infection

• Applicants: Professor Dr. Klaus Rajewsky; Privatdozent Dr. Volker Siffrin
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452527779

This project is dedicated to tackle an unresolved issue concerning the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS). It has been known for a long time that the overt clinical manifestation of human B cell-transforming Epstein-Barr-Virus (EBV) infection, i.e. infectious mononucleosis, significantly increases the risk to acquire MS later in life. EBV employs basic mechanisms of immune regulation to establish an optimal way of co-existence with its human host in terms of viral maintenance and spread in the human population. The human immune system has in parallel developed efficient adaptive immune mechanisms resulting in efficient T cell memory responses to keep EBV in check. A potential causative role for EBV to promote or induce autoimmune processes has been postulated but could not be proven so far. We have now the unique chance to investigate a potential causative link between EBV related immune responses and autoimmune neuroinflammation by combining our expertise. We model EBV infection and pathologies in mice (which are not a natural host of EBV) by expressing latent memprane protein 1 (LMP1), a crucial EBV encoded protein, in B cells at various stages of differentiation. These transgenic mice undergo similar processes as humans upon primary and/or chronic EBV infection. We use these models of EBV infection in mice expressing transgenic myelin specific B and/or T cell receptors.In this way we will reconstruct key elements of EBV-induced immune mechanisms in the context of potential CNS directed autoimmunity. We will specifically test the hypothesis that LMP1-induced co-stimulation triggers autoimmune T cells in absence of (auto)antigen and the alternative hypothesis that LMP1-induced presentation of autoantigens presented on MHC molecules triggers autoimmune T cells. This is of prominent clinical importance as the results may identify new therapeutic targets to treat the disease specifically. Currently, total B cell depletion is one of the most effective ways of stopping MS. However, this treatment has the inherent problem of promoting immunosuppression as B cell protective responses are largely abolished. Our work may open up more specific approaches, leading to disease control without interfering with protective B cell functions.

• DFG Programme: Research Grants