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Theiler's virus-mediated autoimmunity: local presentation of CNS antigens and epitope spreading
S Mark Tompkins1, Kevin G Fuller, Stephen D Miller
1Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Abstract:
Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a neurotropic picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to those of chronic-progressive multiple sclerosis. Upon infection, TMEV-specific CD4+ T cells target persistent viral antigens in the CNS and initiate myelin damage. Later in the disease, myelin-specific CD4+ T cells are primed by epitope spreading, and these autoimmune T cells contribute to the pathogenesis of the chronic-progressive disease. This review focuses upon aspects of the initiation of a virally induced CD4+ T cell-mediated autoimmune response. First, the steps involved in the hierarchical activation of non-cross-reactive myelin-specific T cells in the SJL/J mouse after CNS infection with TMEV and the role of these autoreactive T cells in chronic myelin damage are discussed. Second, the process of epitope spreading and the role of CNS antigen presenting cells in the temporal presentation of self-antigens is considered. Finally, we will discuss aspects of T cell activation and antigen presentation, and how they can impact autoimmune disease.
Insights
Theiler's murine encephalomyelitis virus (TMEV) triggers CD4+ T cell responses, causing chronic demyelination similar to multiple sclerosis. This review explores how viral infections initiate autoimmune responses targeting the central nervous system (CNS).
Area of Science:
- Neuroimmunology
- Virology
- Autoimmunity
Background:
- Theiler's murine encephalomyelitis virus (TMEV) is a neurotropic picornavirus causing chronic demyelinating disease in mice.
- This disease shares similarities with chronic-progressive multiple sclerosis (MS).
- Viral antigens in the CNS activate CD4+ T cells, initiating myelin damage.
Purpose of the Study:
- To review the initiation of virally induced CD4+ T cell-mediated autoimmune responses.
- To discuss the hierarchical activation of myelin-specific T cells and their role in chronic myelin damage.
- To examine epitope spreading and the role of CNS antigen-presenting cells in self-antigen presentation.
Main Methods:
- Review of existing literature on TMEV infection models.
- Analysis of CD4+ T cell activation pathways.
- Examination of antigen presentation by central nervous system cells.
Main Results:
- TMEV infection leads to the activation of myelin-specific CD4+ T cells via epitope spreading.
- Autoreactive T cells contribute significantly to chronic demyelination.
- Central nervous system antigen-presenting cells play a critical role in temporal self-antigen presentation.
Conclusions:
- Viral infections can initiate autoimmune responses targeting the CNS.
- Understanding T cell activation and antigen presentation is crucial for autoimmune disease pathogenesis.
- This model provides insights into mechanisms underlying chronic-progressive multiple sclerosis.