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Demyelination induced by murine hepatitis virus JHM strain (MHV-4) is immunologically mediated
F I Wang1, S A Stohlman, J O Fleming
1Department of Neurology, School of Medicine, University of Southern California, Los Angeles 90033.
Abstract:
The neurotropic mouse hepatitis viruses (MHV), in particular strain JHM (JHMV or MHV-4), cause experimental central nervous system demyelination that pathologically resembles multiple sclerosis, an important human demyelinating disease. The mechanism of JHMV-induced demyelination remains unclear, though its tropism for oligodendrocytes had led to the belief that JHMV causes demyelination by direct lysis of these myelin-producing cells. However, several studies have also implicated the involvement of immune responses in the demyelinating process. In this communication, we present evidence that generalized immunosuppression with gamma irradiation prevents JHMV-induced demyelination, a finding that was not limited to a particular strain of JHMV or to one strain of mouse. In addition, significant paralytic-demyelinating disease was restored to infected, irradiated mice after the adoptive transfer of nylon wool nonadherent splenic cells and appeared to be restricted by the major histocompatibility complex (MHC). These observations indicate that the principal mechanisms of JHMV-induced demyelination are most likely immunopathological.
Insights
Mouse hepatitis virus (MHV) causes demyelination resembling multiple sclerosis. Immunosuppression prevents this, suggesting immune responses, not direct viral attack, drive the disease.
Area of Science:
- Neurovirology
- Immunopathology
- Demyelinating diseases
Background:
- Neurotropic mouse hepatitis viruses (MHV), particularly strain JHM (JHMV), induce experimental demyelination mirroring human multiple sclerosis.
- The precise mechanism of JHMV-induced demyelination is debated, with theories including direct oligodendrocyte lysis versus immune-mediated damage.
Purpose of the Study:
- To investigate the role of the immune system in JHMV-induced central nervous system demyelination.
- To determine if immunosuppression can prevent JHMV-induced demyelination and if immune cell transfer can restore disease.
Main Methods:
- Generalized immunosuppression was induced using gamma irradiation in mice infected with JHMV.
- Adoptive transfer of splenic cells was performed in infected, irradiated mice to assess disease restoration.
- The role of the major histocompatibility complex (MHC) in disease pathogenesis was examined.
Main Results:
- Gamma irradiation significantly prevented JHMV-induced demyelination across different JHMV strains and mouse models.
- Adoptive transfer of specific splenic immune cells restored paralytic-demyelinating disease in irradiated mice.
- Disease restoration appeared to be MHC-restricted, indicating a specific immune response.
Conclusions:
- JHMV-induced demyelination is primarily an immunopathological process.
- Immune responses, rather than direct viral lysis of oligodendrocytes, are the main drivers of demyelination in this model.
- This finding has implications for understanding and potentially treating multiple sclerosis.