Postdoctoral Scholar Ohio State Univ. Wexner Med. Ctr., United States
Introduction/Rationale: Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. A recent longitudinal analysis of a large cohort revealed a 32-fold increased risk of developing MS following infection with Epstein-Barr Virus (EBV), confirming a viral risk factor for the disease. Traditional experimental autoimmune encephalomyelitis (EAE) models of MS don’t include this viral nature of disease initiation.
Methods: Our lab recently demonstrated that infection of transgenic mice expressing a myelin basic protein-specific T cell receptor (TCRMBP mice) with the murine EBV analogue, MHV68, induces demyelinating disease in a majority of infected mice. Clinical features in these mice are commonly observed in MS patients.
Results: Both EBV and MHV68 latently infect and reprogram B cells. Thus, we performed single-cell RNA sequencing (scRNA-seq) of splenic B cells of TCRMBP from MHV68 infected mice. We identified a cluster of B cells that is enriched only in MHV68 infected cells displaying expression of a variety of interferon-inducible genes that localizes closely with a cluster that has a signature related to age associated B cells (ABCs). Interestingly we could further show by flow that the size of the population of MBP-specific T cells (TCR-Valpha2beta8) is decreased the CNS and periphery in MHV68 infected mice. Upon infection, clones of T cells that share the same beta chain but a different alpha chain and are presumably not specific for MBP expand particularly in mice exhibiting more severe neurological symptoms.
Conclusion: Together we identified a B cell cluster that has characteristcs of a more generalized viral response and an increased T cell population that does not recognize myelin antigen despite the presence of neurological symptoms in these mice indicating a potential bystander activation. Our novel novel gammherpesvirus-dependent mouse model of EAE to can provide a useful tool to study MS in vivo.
