Vorobeychik, G. | Search bioRxiv

bioRxiv2022

Epstein-Barr virus infection promotes Th1-mediated disease in a humanized immune mouse model of multiple sclerosis

Infection with the human-tropic Epstein-Barr virus (EBV) is a strong risk factor for multiple sclerosis (MS), though the underlying mechanisms remain unclear. To investigate the immunomodulatory effects of latent EBV infection, we induced experimental autoimmune encephalomyelitis (EAE) in immunocompromised mice humanized with peripheral blood mononuclear cells (PBMCs) from individuals with or without a history of EBV infection and/or a diagnosis of relapsing MS. HuPBMC EAE mice generated from EBV seronegative healthy donors were less susceptible to developing severe clinical disease than EBV seropositive healthy donor and RRMS cohorts. Donor EBV seropositivity and RRMS led to a significant incremental increase in the number of brain and spinal cord infiltrating effector T cells, in the absence of viral reactivation, due to enhanced proliferation of donor T cells and reduced regulatory T cell expansion. The data indicate that a history of EBV infection, further compounded by a diagnosis of RRMS, promotes T cell-mediated disease in a novel humanized mouse model of MS. SUMMARYIn a novel humanized mouse model of multiple sclerosis (MS), donor history of Epstein-Barr virus (EBV) infection exacerbates disease severity by skewing the balance of effector and regulatory T cells in the brain and spinal cord. These results reveal an immunomodulatory mechanism by which latent EBV infection could predispose to the development of autoimmune disease.

immunology↗

bioRxiv2021

Gammaherpesvirus infection licenses age-associated B cells for pathogenicity in MS and EAE

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Epstein-Barr virus (EBV) infection has long been implicated in multiple sclerosis (MS), and it is not known whether ABCs could play a role in mediating viral contribution to autoimmunity. Here, we show that the circulating ABC population is expanded in people with MS and that EBV infection and MS status differentially impact the circulating ABC phenotype. We then directly compared ABCs during viral infection and autoimmunity using mouse models of EBV, gammaherpesvirus 68 ({gamma}HV68), and MS, experimental autoimmune encephalomyelitis (EAE). We observed that splenic ABCs are expanded in a sex-biased manner during both latent virus infection and EAE, and each event drives the ABC population to opposing phenotypes. We have previously shown that latent{gamma} HV68 infection exacerbates EAE and here we show that mice lacking ABCs fail to display{gamma} HV68-enhanced disease. Collectively, these findings indicate that latent viral infection and central nervous system autoimmunity differentially impact the ABC population and suggests that viral infections such as EBV prime ABCs to contribute pathogenically in MS.

immunology↗