RESUMO
Theiler's murine encephalomyelitis virus-induced demyelinating disease has been extensively studied as an attractive infectious model for human multiple sclerosis. Virus-specific inflammatory Th1 cell responses followed by autoimmune responses to myelin antigens play a crucial role in the pathogenic processes leading to demyelination. Antibody and cytotoxic T cells (CTL) responses to virus appears to be primarily protective from demyelinating disease. Although the role of Th1 and CTL responses in the induction of demyelinating disease is controversial, assessment of cytokines produced locally in the central nervous system (CNS) during the course of disease and the effects of altered inflammatory cytokine levels strongly support the importance of Th1 responses in this virus-induced demyelinating disease. Induction of various chemokines and cytokines in different glial and antigen presenting cells upon viral infection appears to be an important initiation mechanism for inflammatory Th1 responses in the CNS. Coupled with the initial inflammatory responses, viral persistence in the CNS may be a critical factor for sustaining inflammatory responses and consequent immune-mediated demyelinating disease.
Assuntos
Infecções por Cardiovirus/etiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/etiologia , Esclerose Múltipla/etiologia , Theilovirus/patogenicidade , Formação de Anticorpos , Citocinas/biossíntese , Modelos Animais de Doenças , Modelos Imunológicos , Linfócitos T/imunologiaRESUMO
Theiler's virus induces immune-mediated demyelinating disease similar to human MS in susceptible mice. Though the MHC class II-restricted T cell response is critical, susceptibility/resistance is also associated with a MHC class I haplotype. Here we report that perforin-deficient C57BL/6 mice (pKO) are susceptible to demyelination and develop clinical disease. The levels of primary demyelination, proliferation, Th1 responses, and viral load were also markedly enhanced. In addition, immunization of pKO mice with UV-inactivated virus further enhanced clinical incidence and accelerated the disease course. Thus, perforin is most likely involved in viral clearance, hence protection from the disease.
Assuntos
Glicoproteínas de Membrana/genética , Esclerose Múltipla/virologia , Poliomielite/genética , Theilovirus , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença/epidemiologia , Incidência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Perforina , Poliomielite/imunologia , Proteínas Citotóxicas Formadoras de Poros , Medula Espinal/imunologia , Medula Espinal/patologia , Medula Espinal/virologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologiaRESUMO
Intracerebral infection of susceptible mice with Theiler's murine encephalomyelitis virus results in immune-mediated inflammatory demyelination in the white matter and consequent clinical symptoms. This system has been utilized as an important virus model for human multiple sclerosis. Although the potential involvement of virus-specific Th cells has been studied extensively, very little is known about the nature of T cells infiltrating the CNS during viral infection and their role in the development of demyelinating disease. In this study, the clonal nature of T cells in the spinal cord during the disease course was analyzed using size spectratyping and sequencing of the TCR beta-chain CDR3 region. These studies clearly indicate that T cells are clonally expanded in the CNS after viral infection, although the overall TCR repertoire appears to be diverse. The clonal expansion appears to be Ag-driven in that it includes Th cells specific for known viral epitopes. Interestingly, such restricted accumulation of T cells was not detectable in the infiltrates of mice with proteolipid protein peptide-induced experimental autoimmune encephalomyelitis. The initial T cell repertoire (7-9 days postinfection) seems to be more diverse than that observed in the later stage (65 days) of virally induced demyelination, despite the more restricted utilization of Vbeta subfamilies. These results strongly suggest continuous stimulation and clonal expansion of virus-specific T cells in the CNS of Theiler's murine encephalomyelitis virus-infected mice during the entire course of demyelinating disease.