RESUMO
Endosymbiotic Wolbachia bacteria that infect the filarial nematode Onchocerca volvulus were previously found to have an essential role in the pathogenesis of river blindness. The current study demonstrates that corneal inflammation induced by Wolbachia or O. volvulus antigens containing Wolbachia is completely dependent on expression of myeloid differentiation factor 88.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Infecções Oculares Bacterianas/imunologia , Ceratite/imunologia , Onchocerca volvulus/imunologia , Oncocercose Ocular/imunologia , Wolbachia/imunologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Modelos Animais de Doenças , Infecções Oculares Bacterianas/genética , Ceratite/genética , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide , Neutrófilos/imunologia , Oncocercose Ocular/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/fisiologia , Wolbachia/patogenicidadeRESUMO
Although production of specific Ab is a critical element of host defense, the presence of Ab in tissues leads to formation of immune complexes, which can trigger a type III Arthus reaction. Our studies on a mouse model of river blindness showed that Ab production is essential for recruitment of neutrophils and eosinophils to the cornea and for development of corneal opacification. In the current study, we determined the relative contribution of complement and FcgammaR interactions in triggering immune complex-mediated corneal disease. FcgammaR(-/-) mice, C3(-/-) mice, and immunocompetent control (B6/129Sj) mice were immunized s.c. and injected intrastromally with Onchocerca volvulus Ags. Slit lamp examination showed that control mice, C3(-/-) mice, and control mice injected with cobra venom factor developed pronounced corneal opacification, whereas corneas of FcgammaR(-/-) mice remained completely clear. Furthermore, recruitment of neutrophils and eosinophils to the corneal stroma was significantly impaired in FcgammaR(-/-) mice, but not in C3(-/-) mice or cobra venom factor-treated mice. We therefore conclude that FcgammaR-mediated cell activation, rather than complement activation, is the dominant pathway of immune complex disease in the cornea. These findings demonstrate a novel role for FcgammaR interactions in mediating ocular inflammation.
Assuntos
Anticorpos Anti-Helmínticos/fisiologia , Substância Própria/imunologia , Substância Própria/patologia , Ceratite/imunologia , Ceratite/patologia , Receptores de IgG/fisiologia , Animais , Anticorpos Anti-Helmínticos/biossíntese , Antígenos de Helmintos/imunologia , Complemento C3/deficiência , Complemento C3/genética , Modelos Animais de Doenças , Venenos Elapídicos/administração & dosagem , Isotipos de Imunoglobulinas/biossíntese , Injeções Intraperitoneais , Ceratite/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Onchocerca volvulus/imunologia , Oncocercose Ocular/genética , Oncocercose Ocular/imunologia , Oncocercose Ocular/patologia , Receptores de IgG/biossíntese , Receptores de IgG/deficiência , Receptores de IgG/genéticaRESUMO
Infiltration of neutrophils and eosinophils into the mammalian cornea can result in loss of corneal clarity and severe visual impairment. To identify mediators of granulocyte recruitment to the corneal stroma, we determined the relative contribution of chemokine receptors CXC chemokine receptor (CXCR)-2 (IL-8R homologue) and CCR1 using a murine model of ocular onchocerciasis (river blindness) in which neutrophils and eosinophils migrate from peripheral vessels to the central cornea. CXCR2(-/-) and CCR1(-/-) mice were immunized s.c. and injected into the corneal stroma with Ags from the parasitic helminth Onchocerca volvulus. We found that production of macrophage-inflammatory protein (MIP)-2, KC, and MIP-1 alpha was localized to the corneal stroma, rather than to the epithelium, which was consistent with the location of neutrophils in the cornea. CCR1 deficiency did not inhibit neutrophil or eosinophil infiltration to the cornea or development of corneal opacification. In marked contrast, neutrophil recruitment to the corneas of CXCR2(-/-) mice was significantly impaired (p < 0.0001 compared with control, BALB/c mice) with only occasional neutrophils detected in the central cornea. Furthermore, CXCR2(-/-) mice developed only mild corneal opacification compared with BALB/c mice. These differences were not due to impaired KC and MIP-2 production in the corneal stroma of CXCR2(-/-) mice, which was similar to BALB/c mice. Furthermore, although MIP-1 alpha production was lower in CXCR2(-/-) mice than BALB/c mice, eosinophil recruitment to the cornea was not impaired. These observations demonstrate the critical role for CXCR2 expression in neutrophil infiltration to the cornea and may indicate a target for immune intervention in neutrophil-mediated corneal inflammation.
Assuntos
Quimiocinas CC/metabolismo , Córnea/imunologia , Ceratite/imunologia , Infiltração de Neutrófilos/imunologia , Onchocerca volvulus/imunologia , Oncocercose Ocular/imunologia , Receptores de Quimiocinas/biossíntese , Receptores de Interleucina-8B/biossíntese , Animais , Anticorpos Anti-Helmínticos/biossíntese , Movimento Celular/genética , Movimento Celular/imunologia , Quimiocina CCL4 , Quimiocina CXCL1 , Quimiocina CXCL2 , Quimiocinas/biossíntese , Quimiocinas CC/biossíntese , Quimiocinas CXC , Córnea/metabolismo , Córnea/parasitologia , Córnea/patologia , Opacidade da Córnea/genética , Opacidade da Córnea/imunologia , Opacidade da Córnea/parasitologia , Citocinas/biossíntese , Eosinófilos/imunologia , Eosinófilos/metabolismo , Epitélio Corneano/imunologia , Epitélio Corneano/metabolismo , Epitélio Corneano/parasitologia , Imunoglobulina G/biossíntese , Ceratite/genética , Ceratite/parasitologia , Ceratite/patologia , Proteínas Inflamatórias de Macrófagos/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oncocercose Ocular/genética , Oncocercose Ocular/patologia , Receptores CCR1 , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Receptores de Interleucina-8B/deficiência , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/fisiologia , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/parasitologiaRESUMO
Invasion of the corneal stroma by neutrophils and eosinophils and subsequent degranulation disrupts corneal clarity and can result in permanent loss of vision. In the current study, we used a model of helminth-induced inflammation to demonstrate a novel role for Ab in mediating recruitment of these inflammatory cells to the central cornea. C57BL/6 and B cell-deficient (microMT) mice were immunized s. c. and injected intrastromally with Ags from the parasitic helminth Onchocerca volvulus (which causes river blindness). C57BL/6 mice developed pronounced corneal opacification, which was associated with an Ag-specific IL-5 response and peripheral eosinophilia, temporal recruitment of neutrophils and eosinophils from the limbal vessels to the peripheral cornea and subsequent migration to the central cornea. In contrast, the corneas of microMT mice failed to develop keratitis after intrastromal injection of parasite Ags unless Ags were injected with immune sera. Eosinophils were recruited from the limbal vessels to the peripheral cornea in microMT mice, but failed to migrate to the central cornea, whereas neutrophil recruitment was impaired at both stages. With the exception of IL-5, T cell responses and peripheral eosinophils were not significantly different between C57BL/6 and microMT mice. Taken together, these findings not only demonstrate that Ab is required for the development of keratitis, but also show that recruitment of neutrophils to the cornea is Ab-dependent, whereas eosinophil migration is only partially dependent upon Ab interactions.