RESUMO
To reevaluate whether an association exists between the clinical course of multiple sclerosis (MS) and the activation of memory T cells, we investigated the phenotype of T cells in peripheral blood and cerebrospinal fluid (CSF) of patients with MS using five-color flow cytometry. A cross-sectional study with 39 relapsing-remitting MS patients demonstrated that the percentage of CD25(+)CD45RO(+)CD4(+)CD3(+) cells was significantly increased in peripheral blood as well as in CSF of active MS patients compared with inactive MS patients. A longitudinal study with 11 relapsing-remitting MS patients also showed a higher percentage of CD25(+)CD45RO(+)CD4(+)CD3(+) cells in peripheral blood at the phase of exacerbation than during remission. On the other hand, regardless of the disease activity, the percentage of CD25(+)CD45RO(+)CD8(+)CD3(+) cells in peripheral blood was significantly higher in patients with MS than in healthy control subjects. A lower percentage of CD25(+)CD45RO(+)CD8(+)CD3(+) cells in CSF was observed in active MS patients compared with inactive MS patients. These results suggest that the activation of memory CD4(+) T cells is associated with the exacerbation of MS and activation of memory CD8(+) T cells reflects systemic immunological dysregulation in MS patients. Transient as well as continuous activation of T cells by recall antigens may be involved in the disease course of MS.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Antígenos CD/análise , Antígenos CD/classificação , Antígenos CD/imunologia , Estudos Transversais , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Estudos Longitudinais , Ativação Linfocitária/fisiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Estatísticas não ParamétricasRESUMO
The elimination of T cells by apoptosis is considered to be one of the regulatory factors in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To address further the role of apoptotic T cell death in EAE, we investigated myelin oligodendrocyte glycoprotein (MOG)-induced EAE in transgenic mice overexpressing the anti-apoptotic gene, bcl-2, in T cells. During the acute phase of EAE, no significant difference was observed in the clinical course, pathology and T cell response to MOG between bcl-2 transgenic mice and wild-type littermates. While the recovery from the first attack of EAE was not impaired in the bcl-2 transgenic mice, a more severe disease was observed during the chronic phase of the disease even though T and B cell responses to MOG were comparable to those of wild-type littermates. A flow cytometric analysis by Annexin V showed a significant decrease of apoptotic T cells in the central nervous system (CNS) of the bcl-2 transgenic mice with EAE compared with controls during the chronic as well as the acute phase of disease. These results suggest that while T cell apoptosis in the CNS may play a regulatory role in EAE, the spontaneous recovery from acute EAE cannot solely be explained by T cell apoptosis.
Assuntos
Apoptose , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/imunologia , Doença Aguda , Animais , Células Cultivadas , Doença Crônica , Citocinas/biossíntese , Progressão da Doença , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/patologia , Genes bcl-2 , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Nitritos/análise , Medula Espinal/patologiaRESUMO
The role of p53, a pro-apoptotic protein, in experimental autoimmune encephalomyelitis (EAE) was investigated using p53-deficient C57BL/6J mice. p53-deficient mice immunised with myelin oligodendrocyte glycoprotein (MOG) exhibited a more severe clinical course of EAE with more severe inflammation in the central nervous system (CNS) compared to wild-type littermates. While T and B cell responses of p53-deficient mice to MOG were comparable to those of wild-type littermates, significantly higher production of IL-6, granulocyte macrophage colony-stimulating factor and IL-10 was observed in lymphocytes exposed to MOG from p53-deficient mice than those from wild-type littermates. Furthermore, a flow cytometric analysis of Annexin V staining showed that apoptosis of CNS-infiltrating cells was less in p53-deficient mice with EAE compared to wild-type littermates. These results suggest that p53 may be involved in the regulatory process of EAE through the control of cytokine production and/or the apoptotic elimination of inflammatory cells.
Assuntos
Encefalomielite Autoimune Experimental/etiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Apoptose , Citocinas/biossíntese , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Óxido Nítrico/fisiologia , Nitritos/metabolismoRESUMO
Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), is more prevalent in females than males. It is well documented that a significant gender difference exits in the susceptibility of mice to develop experimental autoimmune encephalomyelitis (EAE), a model of MS, induced by myelin basic protein or proteolipid protein. In contrast, we report here that no significant difference between female mice and male mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE was observed in the incidence of disease, clinical course, histological findings in the CNS, T cell response and cytokine production of spleen cells to MOG, and anti-MOG IgG level in serum. These results suggest that gender-related difference in EAE depends on the encephalitogen and/or the strain of animals used. Given that MOG is a putative pathogenic myelin antigen in MS, the present findings may have implications for the pathogenesis of this disease.