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A central role for CD4(+) T cells and RANTES in virus-induced central nervous system inflammation and demyelination
1Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, California. tlane@uci.edu
Abstract:
Infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in a demyelinating encephalomyelitis characterized by mononuclear cell infiltration and white matter destruction similar to the pathology of the human demyelinating disease multiple sclerosis. The contributions of CD4(+) and CD8(+) T cells in the pathogenesis of the disease were investigated. Significantly less severe inflammation and demyelination were observed in CD4(-/-) mice than in CD8(-/-) and C57BL/6 mice (P < or = 0.002 and P < or = 0.001, respectively). Immunophenotyping of central nervous system (CNS) infiltrates revealed that CD4(-/-) mice had a significant reduction in numbers of activated macrophages/microglial cells in the brain compared to the numbers in CD8(-/-) and C57BL/6 mice, indicating a role for these cells in myelin destruction. Furthermore, CD4(-/-) mice displayed lower levels of RANTES (a C-C chemokine) mRNA transcripts and protein, suggesting a role for this molecule in the pathogenesis of MHV-induced neurologic disease. Administration of RANTES antisera to MHV-infected C57BL/6 mice resulted in a significant reduction in macrophage infiltration and demyelination (P < or = 0.001) compared to those in control mice. These data indicate that CD4(+) T cells have a pivotal role in accelerating CNS inflammation and demyelination within infected mice, possibly by regulating RANTES expression, which in turn coordinates the trafficking of macrophages into the CNS, leading to myelin destruction.
Insights
CD4(+) T cells accelerate central nervous system (CNS) inflammation and demyelination in mouse hepatitis virus (MHV)-infected mice. This may involve regulating RANTES, a chemokine that attracts macrophages, leading to myelin destruction.
Area of Science:
- Neuroimmunology
- Virology
- Pathology
Background:
- Mouse hepatitis virus (MHV) infection in C57BL/6 mice causes demyelinating encephalomyelitis, mirroring human multiple sclerosis pathology.
- Investigating the roles of CD4(+) and CD8(+) T cells in the disease pathogenesis is crucial.
Purpose of the Study:
- To elucidate the specific contributions of CD4(+) and CD8(+) T cells in MHV-induced demyelinating encephalomyelitis.
- To explore the role of RANTES (a C-C chemokine) in the disease process and its regulation by T cells.
Main Methods:
- Comparative analysis of inflammation and demyelination severity in CD4(-/-), CD8(-/-), and wild-type C57BL/6 mice infected with MHV.
- Immunophenotyping of central nervous system (CNS) infiltrates to quantify immune cell populations.
- Measurement of RANTES mRNA transcripts and protein levels.
- Administration of RANTES antisera to assess its impact on disease progression.
Main Results:
- CD4(-/-) mice exhibited significantly less severe inflammation and demyelination compared to CD8(-/-) and C57BL/6 mice.
- A reduction in activated macrophages/microglial cells was observed in the CNS of CD4(-/-) mice.
- Lower levels of RANTES mRNA and protein were detected in CD4(-/-) mice.
- RANTES antisera administration significantly reduced macrophage infiltration and demyelination in infected mice.
Conclusions:
- CD4(+) T cells play a pivotal role in exacerbating CNS inflammation and demyelination during MHV infection.
- CD4(+) T cells may regulate RANTES expression, influencing macrophage trafficking into the CNS and subsequent myelin destruction.
- RANTES is implicated as a key mediator in MHV-induced demyelinating disease pathogenesis.