Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading
S D Miller1, C L Vanderlugt, W S Begolka
1Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Abstract:
Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.
Insights
Virus infections can trigger autoimmune diseases like multiple sclerosis (MS) by causing T cells to attack the nervous system. This study reveals that virus-specific T cells can lead to new T cell responses against myelin, driving chronic disease progression.
Area of Science:
- Neuroimmunology
- Virology
- Autoimmunity
Background:
- Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease.
- Theiler's murine encephalomyelitis virus (TMEV) infection in mice mimics chronic progressive MS.
- Demyelination in TMEV infection involves virus-specific CD4+ T cells targeting persistent virus in the CNS.
Purpose of the Study:
- To investigate the development of T cell responses to myelin autoepitopes following TMEV infection.
- To determine the mechanism driving the emergence of self-reactive T cells in chronic demyelinating disease.
Main Methods:
- Induction of demyelinating disease in mice using TMEV.
- Kinetic and functional analysis of T cell responses to viral and myelin antigens.
- Assessment of T cell priming to myelin autoepitopes.
Main Results:
- T cell responses to multiple myelin autoepitopes emerged in an ordered progression 3-4 weeks after disease onset.
- T cell responses to the PLP139-151 epitope were not due to molecular mimicry.
- Self-reactive T cells were primed de novo to sequestered autoantigens released after virus-specific T cell-mediated demyelination.
Conclusions:
- Epitope spreading, rather than molecular mimicry, is a key mechanism driving autoimmune responses in TMEV-induced demyelination.
- Epitope spreading provides an alternative explanation for the etiology of virus-induced organ-specific autoimmune diseases like MS.
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