RESUMEN
It has been reported recently that the bacterial respiratory pathogen Chlamydia pneumoniae is present in the cerebrospinal fluid of a subset of multiple sclerosis (MS) patients. However, it is not known whether this organism is a causative agent of MS, or merely an opportunistic pathogen that takes advantage of a disease process initiated by some other means. We report identification of a 20-mer peptide from a protein specific to C. pneumoniae which shares a 7-aa motif with a critical epitope of myelin basic protein, a major CNS Ag targeted by the autoimmune response in MS. This bacterial peptide induces a Th1 response accompanied by severe clinical and histological experimental autoimmune encephalomyelitis in Lewis rats, a condition closely reflective of many aspects of MS. Studies with peptide analogues suggest that different populations of encephalitogenic T cells are activated by the C. pneumoniae and myelin basic protein Ags. Mild experimental autoimmune encephalomyelitis was also observed when rats were immunized with sonicated C. pneumoniae in CFA.
Asunto(s)
Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/inmunología , Chlamydophila pneumoniae/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Sustitución de Aminoácidos/inmunología , Animales , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Células Cultivadas , Chlamydophila pneumoniae/genética , Encefalomielitis Autoinmune Experimental/microbiología , Femenino , Regulación Bacteriana de la Expresión Génica , Cobayas , Inyecciones Subcutáneas , Datos de Secuencia Molecular , Proteína Básica de Mielina/química , Proteína Básica de Mielina/inmunología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Isoformas de Proteínas/administración & dosificación , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Ratas , Ratas Endogámicas Lew , Homología de Secuencia de Aminoácido , Linfocitos T/inmunología , Linfocitos T/microbiología , Células Tumorales Cultivadas/inmunología , Células Tumorales Cultivadas/microbiología , Células Tumorales Cultivadas/trasplanteRESUMEN
Lewis (LEW) and DA rats are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with guinea pig myelin basic protein (MBP), but respond to different epitopes. The dominant epitope for LEW rats is MBP73-86, and disease is mediated primarily by Vbeta8.2 Th1 cells. DA rats lack conventional Vbeta8.2 T cells and do not respond to MBP73-86. Rather, DA rats respond to the cryptic epitope MBP63-81, which is not encephalitogenic for LEW rats. Responses to these neuroantigens were investigated in (DAxLEW) F1 hybrids to determine if experimental findings in inbred rats remain valid in more genetically complex models. Surprisingly, MBP63-81, a cryptic epitope for DA rats, induced moderate-to-severe EAE in F1 hosts, whereas MBP73-86, the dominant LEW epitope, was only weakly encephalitogenic in F1 hosts. The poor clinical response to MBP73-86 appears to be a consequence of an inability to expand Vbeta8.2 T cells. These results suggest that parental responses to neuroantigens are poor predictors for determining encephalitogenicity in F1 progeny.
Asunto(s)
Presentación de Antígeno/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , División Celular/inmunología , Femenino , Citometría de Flujo , Predisposición Genética a la Enfermedad , Epítopos Inmunodominantes/inmunología , Técnicas In Vitro , Interferón gamma/metabolismo , Datos de Secuencia Molecular , Proteína Básica de Mielina/química , Proteína Básica de Mielina/inmunología , Ratas , Ratas Endogámicas Lew , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
This paper reports that DA rats develop experimental autoimmune encephalomyelitis (EAE) when immunized with encephalitogenic myelin basic protein (MBP) peptide (MBP63-81) in IFA. In contrast, most rodent strains are tolerized by this procedure. Doses as low as 5 micrograms peptide + IFA induced EAE in DA rats. Lewis (LEW) rats did not develop EAE, even after immunization with 100 micrograms encephalitogenic peptide (MBP68-86) + IFA, but were rendered tolerant to EAE. DA rat T cells proliferated to peptide, and proliferation was inhibited by CTLA4Ig, and by anti-B7.1 and anti-B7. 2 mAbs. This indicates that the ease of induction of EAE in this strain does not reflect a decreased requirement for T cell costimulation through the B7/CD28 costimulatory pathway. The inhibitory effect of CTLA4Ig was abrogated in the presence of anti-TGF-beta-neutralizing Ab. An encephalitogenic DA T cell line expressed mRNA for the Th1 cytokines IFN-gamma and TNF-alpha, as well as IL-10, and secreted these cytokines. In contrast, a T cell line from peptide + IFA-immunized LEW rats (which did not develop EAE) failed to secrete these cytokines. Although this line did not express TNF-alpha or IL-10 mRNA, IFN-gamma mRNA was detected, suggesting posttranscriptional regulation of IFN-gamma expression. Attempts to induce unresponsiveness in DA rats with encephalitogenic peptide-coupled splenocytes were also unsuccessful.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica , Lípidos , Secuencia de Aminoácidos , Animales , Reactivos de Enlaces Cruzados , Citocinas/biosíntesis , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/patología , Etildimetilaminopropil Carbodiimida/análogos & derivados , Femenino , Adyuvante de Freund/administración & dosificación , Inyecciones Intravenosas , Inyecciones Subcutáneas , Activación de Linfocitos , Masculino , Datos de Secuencia Molecular , Proteína Básica de Mielina/administración & dosificación , Proteína Básica de Mielina/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Ratas , Ratas Endogámicas Lew , Especificidad de la Especie , Bazo/citología , Bazo/trasplante , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
This brief review highlights investigations conducted over the past three decades concerning the role of suppressor T cells in the regulation of experimental autoimmune encephalomyelitis (EAE). In addition, more recent studies are summarized which suggest that apoptosis of autoreactive T cells is also involved in the regulation of EAE. The possibility that natural killer (NK) cells mediate apoptosis is also considered.