| Background:Sarcoidosis is a multisystemic granulomatous disease of unknown etiology,whose typical pathological feature is the formation of non-necrotizing granulomatous structures.The disease primarily affects the lungs,as well as mediastinal lymph nodes,with a proportion of nearly 90%.Patients with sarcoidosis are highly heterogeneous,with about 1/3 of them progressing to pulmonary fibrosis.The pathogenesis of sarcoidosis is unclear.It is likely to be that the individual with a genetic predisposition develops specific imbalanced immune response mediated by CD4+T cells,after environmental/occupational exposure or exogenous infection.Persistent inflammation induces granuloma formation,and repeated stimulation mediates the conversion of macrophages,from pro-inflammatory M1 to pro-fibrotic M2,inducing the formation of pulmonary fibrosis in sarcoidosis.Objective:To investigate the distribution frequency of CD4+effector T lymphocytes and immunoregulatory cell subsets and the phenotype transformation of macrophage,and decide their role in the pathogenesis of sarcoid granuloma and pulmonary fibrosis formation in patients with sarcoidosis.Content:The distribution of CD4+T lymphocyte subsets in peripheral blood or/and bronchoalveolar lavage fluid and the phenotypic differences of macrophages in bronchoalveolar lavage fluid of 76 patients with sarcoidosis were analyzed to evaluate their correlation with sarcoidosis onset,disease activity,pulmonary fibrogenesis and disease prognosis,compared with patients with hypersensitivity pneumonitis or idiopathic pulmonary fibrosis and healthy controls.By establishing a mouse model of pulmonary fibrosis in sarcoidosis,the phenotypic conversion of macrophage was evaluated to clarify their role in the formation of pulmonary fibrosis in sarcoidosis.Methods:Flow cytometry was applied to evaluate the distribution of CD4+T lymphocyte subsets in peripheral blood and bronchoalveolar lavage fluid and to decide the phenotype of macrophage in bronchoalveolar lavage fluid of patients with sarcoidosis.By establishing a mouse model of sarcoidosis characterized by formation of granuloma or pulmonary fibrosis,the phenotypic differences of macrophage in the lungs of mice at different disease stage were compared.Results:The distribution frequency of naive T lymphocytes from patients with extrapulmonary involvement sarcoidosis was lower than that from patients with pulmonary involvement sarcoidosis alone in bronchoalveolar lavage fluid,and showed decreasing trend in peripheral blood.The distribution frequency of Tregs in peripheral blood increased in active and fibrotic sarcoidosis patients,and positively correlated with serum ACE level and the ratio of CD4/CD8 in bronchoalveolar lavage fluid.It decreased in patients receiving immunoregulatory therapy.The distribution frequency of Tregs in peripheral blood of active sarcoidosis patients was higher than that of hypersensitivity pneumonitis patients or healthy controls.The distribution frequency of Tregs in peripheral blood of patients with fibrotic sarcoidosis was higher than that of patients with idiopathic pulmonary fibrosis.The distribution frequency of CD4+T lymphocytes and Th17.1 cells in bronchoalveolar lavage fluid in patients with sarcoidosis was higher than that in patients with hypersensitivity pneumonitis and idiopathic pulmonary fibrosis,and the distribution frequency of Tregs was lower than that in patients with idiopathic pulmonary fibrosis.Different from hypersensitivity pneumonitis and idiopathic pulmonary fibrosis,the distribution frequency of Th17.1 cells and the ratio of Th17.1 cells/Tregs in bronchoalveolar lavage fluid in patients with sarcoidosis were significantly higher than those in peripheral blood.In patients with sarcoidosis followed up for 1 year,the distribution frequency of CD4+T lymphocytes in peripheral blood decreased,naive T lymphocytes increased,Tregs did not change significantly,and activated Tregs decreased.The distribution frequency of Th17.1 cells in bronchoalveolar lavage fluid was reduced in patients developing chronic progressive sarcoidosis.The proportion of macrophages in bronchoalveolar lavage fluid and the mean fluorescence intensity of CD 163 and CD206 in patients with sarcoidosis were lower than those in patients with idiopathic pulmonary fibrosis.The mean fluorescence intensity of CD 163 and CD206 were negatively correlated with the distribution frequency of Th 17.1 cells and activated Tregs in bronchoalveolar lavage fluid,respectively.The concentration of IL-13 in serum and bronchoalveolar lavage fluid of sarcoidosis patients was lower than that of idiopathic pulmonary fibrosis patients.In the mouse model of sarcoidosis,M1 macrophage was prominent in the granulomatous stage and M2 macrophage in the pulmonary fibrosis stage.The transformation of macrophages from M1 to M2 mediated the formation of pulmonary fibrosis in mice.Conclusion:There was an imbalanced distribution of Tregs-Th17.1 cells in peripheral blood and bronchoalveolar lavage fluid of sarcoidosis patients.The distribution frequency of Tregs increased in peripheral blood and significantly related to disease activity,fibrotic process and prognosis.The distribution frequency of Th 17.1 cells in bronchoalveolar lavage fluid was increased and the increase was limited in the lungs.There was a decreased proportion of total macrophages and those acting as M2 in bronchoalveolar lavage fluid form patients with sarcoidosis.In a mouse model of sarcoidosis,the transformation of macrophages from M1 in the granuloma stage to M2 in the pulmonary fibrosis stage mediates the disease progression,leading to the formation of pulmonary fibrosis. |
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