RESUMEN
Os receptores do tipo Toll compreendem a família de receptores de reconhecimento de padrões melhor caracterizados, que podem ativar diferentes respostas imunes, dependendo de quais receptores e conjuntos de adaptadores são utilizados. Os TLRs, como TLR2, TLR4 e TLR9, e sua sinalização foram implicados no reconhecimento de P. brasiliensis e na regulação da resposta imune, no entanto, o papel do TLR3 ainda não está claro. Assim, a compreensão da função endossomal do TLR3 na PCM experimental é crucial. Utilizamos modelos in vitro e in vivo de infecção por P. brasiliensis, camundongos C57Bl/6 e TLR3-/-, para avaliar a contribuição da TLR3 no desenvolvimento da infecção. Mostramos que ausência de TLR3 leva o aumento de óxido nítrico e a capacidade fagocítica por macrófagos nas primeiras 4 horas de interação com leveduras P. brasiliensis. Mostramos ainda que os camundongos TLR3-/- desempenham papel protetor após 30 dias de infecção intratraqueal com P. brasiliensis, mostrando diminuição do aumento de CFU, perfil de resposta Th1 e Th17, bem como aumento de células citotóxicas T CD8+ produtoras de IFN-γ e IL-17. As células citotóxicas T CD8+ mostraram ser essenciais para o controle da infecção nos camundongos TLR3-/-, uma vez que a depleção dessas células levou a progressão da doença. Em estágios iniciais, 3 e 5 dias de infecção, observamos aumento do recrutamento de neutrófilos para o pulmão. Estudos recentes indicam que o TLR3 é um receptor importante para a resposta imune na micose e sua ausência favorece a infecção por fungos. Em contraste, nossos resultados mostram que, no caso do PCM, o TLR3 é prejudicial ao hospedeiro, sugerindo que a ativação do TLR3 pode ser um possível mecanismo de escape de P. brasiliensis
Toll-like receptors comprise the best-characterized pattern-recognition receptor family that can activate different immune responses, depending on which receptor and adaptor set are utilized. TLRs, such as TLR2, TLR4 and TLR9, and their signaling have been implicated in the recognition of P. brasiliensis and regulation of the immune response, however, the role of TLR3 remains unclear. Thus, understanding the endosomal function of TLR3 in experimental PCM is crucial. We used in vitro and in vivo models of infection by P. brasiliensis, C57Bl/6 and TLR3-/- mice, to assess the contribution of TLR3 on development of infection. We show that absence of TLR3 leads to increased nitric oxide and phagocytic capacity by macrophages in the first 4 hours of interaction with yeasts P. brasiliensis. We also showed that TLR3-/- mice play a protective role after 30 days of intratracheal infection with P. brasiliensis, showing a decrease in the CFU increase, Th1 and Th17 response profile, as well as an increase in cytotoxic CD8+ cells producing IFN-γ and IL-17. The cytotoxic T CD8+ cells were shown to be essential for the control of infection in TLR3-/- mice, since the depletion of these cells led to the progression of the disease. In the initial stages, 3 and 5 days of infection, we observed increased recruitment of neutrophils to the lung. Recent studies indicate that TLR3 is an important receptor for the immune response in mycosis and its absence favors fungal infection. In contrast, our results show that in the case of PCM, TLR3 is detrimental to the host, suggesting that TLR3 activation may be a possible escape mechanism of P. brasiliensis
Asunto(s)
Animales , Femenino , Ratones , Paracoccidioidomicosis/prevención & control , Receptor Toll-Like 3/análisis , Paracoccidioides/patogenicidad , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Pruebas de Enzimas/métodos , Citometría de Flujo/métodosRESUMEN
BACKGROUND/AIMS: Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblast-like synoviocytes (FLS). METHODS: FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry. RESULTS: The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-kappaB), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS. CONCLUSIONS: Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-kappaB signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.
Asunto(s)
Humanos , Artritis Reumatoide/tratamiento farmacológico , Células Cultivadas , Fibroblastos/metabolismo , Interleucina-8/análisis , FN-kappa B/fisiología , Neovascularización Patológica/etiología , ARN Mensajero/análisis , Membrana Sinovial/citología , Receptor Toll-Like 3/análisis , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
Tras una encefalitis herpética (EH), una cuarta parte de los pacientes con EH tiene una recaída de la enfermedad que, excepcionalmente, se manifiesta como un síndrome extrapiramidal de tipo coreoatetósico. La base fisiopatológica de este tipo de recaída es desconocida, pero se hipotetiza que puede ser un cuadro inmunitario mediado. Se presenta el caso de un niño de 8 meses con EH por virus del herpes simple tipo 1 que en la tercera semana de evolución tuvo una recaída caracterizada por un síndrome extrapiramidal con coreoatetosis y balismo. El cuadro se interpretó como postinfeccioso, inmunitario mediado. Se trató al paciente con corticoides en altas dosis e inmunoglobulinas, además de un nuevo ciclo de aciclovir. La coreoatetosis fue tan grave y resistente a los fármacos que obligó a sedorrelajar al paciente inicialmente. Posteriormente, se ensayó tratamiento con tetrabenazina. Se estudió a escala molecular una mutación en el receptor tipo Toll 3, que se ha relacionado con la susceptibilidad de presentar la enfermedad, que resultó ser negativa (AU)
After Herpes simplex encephalitis, 25% of cases may have a relapse, rarely as a choreoathetosic movement disorder. The anatomic basis for herpes simplex virus encephalitis-associated movement disorders remains poorly understood, but the hypothesis is that it may be due to a post-infectious immune-mediated process. We report an 8-month-old boy, with herpes simplex encephalitis type 1, who started with an extrapyramidal Syndrome, presenting with choreoathetosis and ballistic movements, three weeks after onset. These new symptoms were attributed to a post-infectious immune-mediated process. We treated our patient with corticosteroids at high dose and gamma-globulins, in addition to a new course of Acyclovir. Sedation was required to control the intense choreoathetosic movements. Tetrabenazine was also tried, unsuccessfully. We studied a mutation on the toll like receptors (TLR3), which has been related to susceptibility for the disease, which was negative (AU)