Characterizing the Role of Epstein-Barr Virus (EBV) B Cell Transformation and Molecular Mimicry in Multiple Sclerosis (MS)

• Applicant: Dr. Friederike Held
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 543971973

Epstein-Barr virus (EBV) infection precedes Multiple Sclerosis (MS) diagnosis, but the mechanisms of how EBV contributes to MS pathogenesis are poorly understood. In the proposed research project, we will systematically explore how EBV augments autoimmunity, induces neuroinflammation, and facilitates the development of MS. MS is characterized by a B-cell-driven chronic inflammation of the central nervous system (CNS) with compartmentalized intrathecal oligoclonal antibody synthesis. EBV, a B lymphotropic double-stranded DNA gamma herpesvirus, infects naïve B cells and establishes lifelong latency in human memory B cells. Intermittently, EBV reactivates and infects new B cells. In healthy individuals, the virus stays almost exclusively in low latency stages. Recent data suggest that EBV-infected B cells of autoimmune patients are in an unstable latency state, prone to activate higher-latency and lytic programs. Epidemiological data provide evidence for an association between EBV and MS as nearly 100% of MS patients are seropositive and infection with EBV predisposes to the subsequent development of MS. Various theories have been proposed to explain EBV's involvement in autoimmunity, including dysregulation of the immune response through B cell transformation, molecular mimicry, and impaired control of EBV-infected B cells by CD8+ T cells. In this proposal, we suggest comprehensively characterizing the impact of EBV on CNS B cell autoreactivity (Aim 1), molecular mimicry (Aim 2), and the dynamic interactions of EBV-infected B cells with CNS infiltrating T cells (Aim 3). We aim to identify dysregulated transcriptional pathways and unique antibody repertoires in EBV-transformed B cells from MS patients and healthy individuals, characterize antigen specificities of BCRs from EBV-infected B cells in MS patients, and test the ability of EBV-infected B cells to activate CNS T cells. This project is to understand EBV's involvement in the pathogenesis of MS, one of the fundamental questions in MS research, and likely identify novel molecular targets for MS therapies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Tobias Lanz