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Allanach, Jessica R.

University of British Columbia

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of the central nervous system (CNS) caused by environmental triggers in genetically susceptible individuals. Previous infection with Epstein-Barr virus (EBV) is a strong risk factor for the development of MS, however, studying the mechanisms underlying this association is experimentally challenging because of the latent virus’ narrow host tropism for human B cells and subsequent lack of experimental models that support EBV infection directly. To evaluate the immunomodulatory effects of EBV infection in a murine model of MS, we induced experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein in humanized mice reconstituted with peripheral blood mononuclear cells (PBMC) from individuals with or without a history of EBV infection and/or a diagnosis of relapsing MS (RRMS). EAE-induced humanized PBMC (HuPBMC) mice recapitulate key clinical and immunopathological aspects of the disease more closely than regular EAE models. In the HuPBMC EAE model, we observed clinical symptoms typical of EAE in regular mice, including ascending paralysis and weight loss. Our findings indicate that demyelination of the brain and spinal cord in this model occurs through the coordinated cytotoxic actions of human IFN𝝲⁺CD4⁺ (Th1) and IFNg⁺GzmB⁺CD8⁺ cytotoxic T cells, in conjunction with the phagocytic activity of murine macrophages. HuPBMC EAE mice generated from EBV⁻ healthy donor samples were less susceptible to developing clinical symptoms than EBV⁺ healthy donor and EBV⁺ RRMS recipient cohorts, with reduced disease severity and delayed symptom onset. The EBV and RRMS status of the PBMC donors did not affect the degree of human B cell infiltration of the CNS in recipient HuPBMC EAE cohorts, though significant T cell immunomodulation was observed. Donor EBV seropositivity and RRMS diagnosis led to a significant incremental increase in the number of CNS infiltrating effector T cells, in the absence of viral reactivation, due to enhanced proliferation of proinflammatory T cells and reduced expansion of regulatory T cells. 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.

Text

2024-01-12

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87228

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/