RESUMEN
Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG(1-125)) in CD4(-/-) and CD8(-/-) DBA/1 mice. Both gene-deleted mice developed clinical signs of EAE, albeit milder than in wild-type mice, suggesting that both CD4(+) and CD8(+) cells participate in disease development. Demyelination and inflammation in the central nervous system was reduced in the absence of CD8(+) T cells. Antibody depletion of CD4(+) cells completely protected CD8(-/-) mice from MOG-induced EAE while depletion of CD8(+) cells in CD4(-/-) mice resulted in fewer EAE incidence compared to that in control antibody-treated mice. Antibody depletion of CD4(+) cells in wild-type mice protected from EAE, but not depletion of CD8(+) cells, although demyelination was reduced on removal of CD8(+) T cells. Immunization with immunodominant MOG(79-96) peptide led to EAE only in the presence of pertussis toxin (PT) in the inoculum. PT also triggered an earlier onset and more severe EAE in CD8(-/-) mice. We interpret our findings such that in an ontogenic lack of CD4(+) T cells, EAE is mediated by CD8(+) and elevated levels of alphabetaCD4(-)CD8(-) cells, and that CNS damage is partly enacted by the activity of CD8(+) T cells.
Asunto(s)
Antígenos CD4/genética , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/genética , Linfocitos T CD8-positivos/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Eliminación de Gen , Animales , Autoanticuerpos/biosíntesis , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/patología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/patología , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/inmunología , Enfermedades del Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/prevención & control , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Incidencia , Inyecciones Intradérmicas , Depleción Linfocítica , Linfopenia/genética , Linfopenia/inmunología , Linfopenia/patología , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunologíaRESUMEN
Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.