RESUMO
Uveitis (intraocular inflammation) is a leading cause of loss of vision. Although its aetiology is largely speculative, it is thought to arise from complex genetic-environmental interactions that break immune tolerance to generate eye-specific autoreactive T cells. Experimental autoimmune uveitis (EAU), induced by immunization with the ocular antigen, interphotoreceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing complete Freund's adjuvant (CFA), has many clinical and histopathological features of human posterior uveitis. Studies in EAU have focused on defining pathogenic CD4+ T cell effector responses, such as those of T helper type 17 (Th17) cells, but the innate receptor pathways precipitating development of autoreactive, eye-specific T cells remain poorly defined. In this study, we found that fungal-derived antigens possess autoimmune uveitis-promoting function akin to CFA in conventional EAU. The capacity of commensal fungi such as Candida albicans or Saccharomyces cerevisae to promote IRBP-triggered EAU was mediated by Card9. Because Card9 is an essential signalling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defence, we evaluated further the proximal Card9-activating CLRs. Using single receptor-deficient mice we identified Dectin-2, but not Mincle or Dectin-1, as a predominant mediator of fungal-promoted uveitis. Conversely, Dectin-2 activation by α-mannan reproduced the uveitic phenotype of EAU sufficiently, in a process mediated by the Card9-coupled signalling axis and interleukin (IL)-17 production. Taken together, this report relates the potential of the Dectin-2/Card9-coupled pathway in ocular autoimmunity. Not only does it contribute to understanding of how innate immune receptors orchestrate T cell-mediated autoimmunity, it also reveals a previously unappreciated ability of fungal-derived signals to promote autoimmunity.
Assuntos
Doenças Autoimunes/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Candida albicans/imunologia , Candidíase/imunologia , Lectinas Tipo C/imunologia , Saccharomyces cerevisiae/imunologia , Uveíte/imunologia , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/patologia , Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase/induzido quimicamente , Candidíase/patologia , Proteínas do Olho/toxicidade , Lectinas Tipo C/genética , Camundongos , Camundongos Mutantes , Proteínas de Ligação ao Retinol/toxicidade , Células Th17/imunologia , Células Th17/patologia , Uveíte/induzido quimicamente , Uveíte/genética , Uveíte/patologiaRESUMO
The amorphane sesquiterpenes, deoxyarteannuin B and dihydro-deoxyarteannuin B, were isolated from Artemisia annua and their structures mainly determined by two-dimensional NMR spectoscopic analyses. The irregular monoterpene, trans-5-hydroxy-2-isopropenyl-5-methylhex-3-en-1-ol, was also characterized in the same way, and its structure was confirmed by synthesis from lavandulol. All of these natural products are suggested to be formed by autoxidation reactions. Full assignments of the 1H and 13C resonances for the known natural products epi-deoxyarteannuin B and isoannulide, determined by the same methodology, are also reported.
Assuntos
Artemisia/química , Artemisininas , Monoterpenos , Sesquiterpenos/química , Terpenos/química , Sesquiterpenos/isolamento & purificação , Terpenos/isolamento & purificaçãoRESUMO
Nine new phenylpropanoids (2-7, 10, 12, and 14) and two compounds representing novel structural classes of 7-O-8' and 7-O-8'.8-O-7' lignans (8 and 9, respectively) have been isolated from Illicium verum and their structures established by two-dimensional NMR. Most of these compounds appear to be biogenetically derived from threo-anethole glycol: relative stereochemistries for some members of this series were established by NOESY; absolute stereochemistries of others were determined by formation of Mosher esters.
Assuntos
Lignanas/isolamento & purificação , Fenilpropionatos/isolamento & purificação , Plantas Medicinais/química , Sequência de Carboidratos , China , Lignanas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Dados de Sequência Molecular , Fenilpropionatos/química , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
Twelve novel (1, 2, 4, 5, 7-14) and two known (3, 6) abietane diterpenes and have been isolated from the aerial parts of Illicium angustisepalum. These diterpenes are unusual in that they are oxygenated at the axial C-19 position of the gem-dimethyl group rather than the equatorial C-18 position.
Assuntos
Diterpenos/isolamento & purificação , Plantas Medicinais/química , Sequência de Carboidratos , China , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Dados de Sequência Molecular , Extratos Vegetais/química , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
Tradition curriculum content and structure in health administration education programs have focused on the managing of individual institutions, the business function, and the hospital as the center of the health system. These assumptions are challenged by managed care, with its orientation on integrating the business and clinical functions; prevention and primary care; and the provision of services through integrated service networks. The design and process of curriculum change in response to new organization structures and management challenges are explored.