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Updated: Apr 4, 2026
Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Latent virus infection upregulates CD40 expression facilitating enhanced autoimmunity in a model of multiple
Costanza Casiraghi1, Ana Citlali Márquez1, Iryna Shanina1
1Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
Abstract:
Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS) by multiple groups working worldwide. Previously, we reported that when experimental autoimmune encephalomyelitis (EAE) was induced in mice latently infected with murine γ-herpesvirus 68 (γHV-68), the murine homolog to EBV, a disease more reminiscent of MS developed. Specifically, MS-like lesions developed in the brain that included equal numbers of IFN-γ producing CD4(+) and CD8(+) T cells and demyelination, none of which is observed in MOG induced EAE. Herein, we demonstrate that this enhanced disease was dependent on the γHV-68 latent life cycle and was associated with STAT1 and CD40 upregulation on uninfected dendritic cells. Importantly, we also show that, during viral latency, the frequency of regulatory T cells is reduced via a CD40 dependent mechanism and this contributes towards a strong T helper 1 response that resolves in severe EAE disease pathology. Latent γ-herpesvirus infection established a long-lasting impact that enhances subsequent adaptive autoimmune responses.
Insights
Latent Epstein-Barr virus (EBV) infection in mice enhances experimental autoimmune encephalomyelitis (EAE) by reducing regulatory T cells. This viral latency promotes a strong T helper 1 response, leading to severe disease resembling multiple sclerosis (MS).
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Epstein-Barr virus (EBV) is a suspected environmental trigger for multiple sclerosis (MS).
- Murine gammaherpesvirus 68 (γHV-68), the mouse homolog of EBV, was used to model latent viral infection.
- Previous studies showed γHV-68 infection altered experimental autoimmune encephalomyelitis (EAE) in mice.
Purpose of the Study:
- To investigate the role of γHV-68 latent infection in the development of MS-like disease.
- To elucidate the mechanisms by which latent γHV-68 infection enhances autoimmune responses.
Main Methods:
- Induction of EAE in mice with latent γHV-68 infection.
- Analysis of immune cell populations, including CD4(+) and CD8(+) T cells, and regulatory T cells.
- Assessment of molecular markers such as STAT1 and CD40 on dendritic cells.
Main Results:
- Latent γHV-68 infection led to MS-like brain lesions with demyelination and mixed CD4(+) and CD8(+) T cell infiltrates.
- Enhanced EAE severity was dependent on the γHV-68 latent life cycle.
- STAT1 and CD40 upregulation was observed on uninfected dendritic cells.
- Latent infection reduced regulatory T cell frequency through a CD40-dependent mechanism, promoting a T helper 1 response.
Conclusions:
- Latent γHV-68 infection establishes a long-lasting impact, enhancing subsequent adaptive autoimmune responses.
- The reduction of regulatory T cells via CD40 signaling contributes to severe EAE pathology.
- Latent herpesvirus infection can significantly influence the development and severity of autoimmune diseases like MS.
