The Role Of IL-17A In The Pathogenesis Of Sarcoidosis And Propionibacterium Acnes Induced Fibrosis Following Granulomatosis In Mice

Background Sarcoidosis is a multisystem, multi-organ disorder characterized by non-caseating granulomata. And the pulmonary tract is the most frequently involved, which up to 90% sarcoidosis patients. Although most cases can resolve spontaneously, about 30% sarcoidosis patients progress into chronic disease with irreversible pulmonary fibrosis eventually and lack of effective treatment. The etiology and pathogenesis of the disease are elusive. It is regard as an disease with immune disorder, mainly induced by macrophages and T-helper type 1 cells. The mechanisms of granulomata formation especially progressive granulomatous course and progression towards the fibrotic phase have not been determined, what’s the most important, lack of animal disease model. Recent researches indicated that IL-17 A may play role in granulomatous formation and pulmonary fibrosis.Objective This project based on the hypothesis “ IL-17 A plays a central role in granulomata formation in sarcoidosis”. Through the establishment of pulmonary sarcoidosis animal model in mice, studying the role of IL-17 A in the pathogenesis of sarcoidosis, and the significance of IL-17 A level detection of sarcoidosis in clinical practice. Based on the hypothesis “ antigen booster challenge could induce chronic inflammation and fibrosis following granulomatosis”, we gave booster antigen challenge to sarcoidosis mice and establish fibrotic sarcoidosis models. Investigating the mechanisms of immune responses in granulomatosis transition to fibrosis in the lung.Materials and MethodsPulmonary sarcoido-granlomata were induced by Propionibacterium acnes(PA) in IL-17 A knockout and wild-type mice model. Lung tissues and alveolar lavage fluid were collected, and histopathology, flow cytometry, ELISA methods were used to detect, the immune responses levels and pulmonary pathological changes. Anti-IL-17 A antibody were given to antagonism in WT mice. These researches were tried to confirm IL- 17 A a key role in the course of sarcoid granulomas formation. Prolonging the antigen stimulus, evaluating the wild type mice by histopathology, ELISA, real-time PCR methods, observing the pathological physiology change of lung tissue in mice, in order to verify the sarcoidosis animal model of pulmonary fibrosis. This animal disease model is established for investigating the immunological changes during granulomatous inflammation progress into pulmonary fibrosis, determined that the role of IL-17 A in the progression of sarcoidosis especially pulmonary fibrosis.Results IL-17 A were determined higher expression in mouse lungs with granulomata. Given PA challenge to IL-17 A knockout mice induced enhanced Th1-type immune response, however it failed to induce any granuloma in the lung and decreased the amount of inflammatory cells. Giving anti-IL-17 A antibody treatment after PA challenging to wild-type mice, effectively reduced the expression of IL-17 A and ameliorates granulomatosis. Repeated PA challenge through treachea induce chronic inflammation and finally progress into pulmonary fibrosis. An enhancement of Th1-type immune response and expression of IL-17 A and TGF-βwere detected during the pulmonary fibrosis course.Conclusions This research suggested that IL-17 A is a key factor in granulomata formation and inflammatory cell influx in the lung. Persistent antigen stimulation could inducechronic disease course. And continuous high expression of IL-17 A may involve in the pathogensis of lung fibrosis. IL-17 A could be a new target in sarcoidosis.