Studies on the aetiology/mechanisms of autoimmunity associated with Epstein Barr Virus infection

Epstein Barr Virus (EBV) is a member of the herpesvirus family that latently infects B cells and is known to cause mononucleosis and lymphoid and epithelial cancer. Epidemiological studies suggest EBV infection is an obligate step for the development of multiple sclerosis (MS), but its role in pathology remains unclear, and autoantigen mimics have been unreproducible. Development of autoimmunity is the product of polygenic and environmental influences, and infection with EBV induces an immune response that is believed to possibly be the driving force of MS. Our aim is to elucidate the key EBV autoimmune triggers and the corresponding human encoded mimetic antigens that could be behind this immune response. Here, we propose to generate recombinant human antibody libraries from the peripheral blood mononuclear cells (PBMC) from EBV-positive people with MS and to select against a recombinant EBV-displayed polypeptide library and against healthy/diseased human brain transcriptomic libraries using ribosome display technology. This novel approach will therefore be "using a library against a library" in a completely in-vitro-based selection platform to identify the cognate antibody-antigen pairings in an unbiased and exhaustive way. Once we have identified the anti-EBV antigen antibodies and human open reading frame (ORF) antibodies, these will also be used to pan a random, typically 12mer peptide library to generate consensus binding motifs. The consensus motifs will then be used to search the predicted human ORFs to identify likely candidate molecular mimics involved in EBV-binding and potential cross-reactivity with human ORFs, to identify targets for MS or potentially other autoimmune diseases. The approach could be applied to other research elements with the group and the project provides a basis for studies that can be developed further by the student over the course of a PhD.