RESUMO
Myelin reactive T cells are central in the development of the autoimmune response leading to CNS destruction in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis (EAE). Investigations on the mechanisms underlying the activation and expansion of myelin reactive T have stressed the importance of non-autoimmune conditions impinging the autoimmune repertoire potentially involved in the disease. Here, we show that CNS injury caused by the toxic cuprizone results in the generation of immunoreactivity towards several myelin components. Paradoxically, exposure to CNS injury does not increase the susceptibility to develop EAE, but render mice protected to the pathogenic autoimmune response against myelin antigens.
Assuntos
Cuprizona/toxicidade , Encefalomielite Autoimune Experimental/imunologia , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Bainha de Mielina/imunologia , Linfócitos T/imunologia , Animais , Especificidade de Anticorpos/imunologia , Antígenos/imunologia , Quelantes/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Glicoproteínas/toxicidade , Tolerância Imunológica/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas da Mielina/imunologia , Bainha de Mielina/patologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/toxicidade , Linfócitos T/efeitos dos fármacosRESUMO
To elucidate the role of innate immunity in susceptibility to the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we induced EAE by immunization with spinal cord homogenate (SCH) plus complete Freund adjuvant or carbonyl iron in 3 inbred rat strains. Lewis are considered "susceptible," PVG/c-Rt7a (PVG) as "semisusceptible," and Brown Norway (BN) as "resistant" to EAE. Immunization with SCH-carbonyl iron resulted in clinical disease in all 3 strains, but the pathologic features of EAE in the resistant BN and the semisusceptible PVG rats differed from those in the Lewis and PVG model of EAE induced with SCH-complete Freund adjuvant. In BN and PVG rats, there were numerous inflammatory lesions with prominent involvement of microglia and, to a lesser extent, perivascular macrophages. These data suggest that different levels of activation of the innate immune system by different adjuvants determine whether EAE will or will not develop. Accordingly, the widely accepted scale of susceptibility to EAE development (Lewis > PVG > BN) should be revised because it does not take into account the important contribution of the composition of the adjuvant to the quality and quantity of the innate immune response and, consequently, to the generation and extent of the pathogenic T-cell-mediated, that is, adaptive, autoimmune disease.
Assuntos
Adjuvantes Imunológicos/farmacologia , Autoantígenos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Predisposição Genética para Doença , Imunidade Inata , Animais , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Adjuvante de Freund/farmacologia , Imuno-Histoquímica , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Interferon gama/biossíntese , Compostos de Ferro/farmacologia , Ativação de Macrófagos/imunologia , Óxido Nítrico/biossíntese , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/imunologia , Medula Espinal/patologia , Linfócitos T/imunologiaRESUMO
EAE development in SJL/J mice is age and sex dependent: young males are EAE resistant; females and adult males are EAE susceptible. By studying splenocytes' IFNgamma and NO production and the induction or the suppression of actively induced EAE by manipulating NO systemic levels, we provide evidence that the failure of young male SJL/J mice to develop EAE lies in the activation of the innate immune system by the immunising stimulus.
