Benign Lymphoepithelial Lesion of Lacrimal Gland:Macrophage Migration Inhibitory Factor Is Overexpre

来源 :北京工业大学 | 被引量 : 0次 | 上传用户:tw2008hr
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Despite the decades that have elapsed since the discovery of benign lymphoepithelial lesion(BLEL)the exact etiology,and mechanisms of its pathogenesis are still elusive.There is,however,a consensus that BLEL is an inflammatory disease,but the mediators of this inflammatory response and their role in the pathogenesis of the disease are unknown.The main objective of this thesis was,therefore,to provide a fundamental understanding of the cellular and molecular processes that regulate the pathogenesis of BLEL.These objectives were achieved by using advanced histological and molecular biology techniques such as in vitro and in vivo assays,gene and cytokine profiling,immunohistochemistry and immunoblotting.Genes and cytokines profiling identified MIF as the most overexpressed cytokine in BLEL.We identified a Th-2 and Th17 cell-type related immune response,Toll-like receptors signaling,and MIF overexpression in BLEL.It had also provided evidence that MIF is the most overexpressed and that its expression positively correlated with that of numerous cytokines in BLEL.Moreover,downstream signalization molecules such as MAPKs and PI3K/Akt pathways were found activated in BLEL together with an enhanced cell proliferation and resistance to apoptosis.We have also identified B cell receptor signaling pathway,NF-kappa B signaling pathway,pathways in cancer,Fc gamma R-mediated phagocytosis,Fc epsilon RI signaling pathway,and Epstein-Barr virus infection significantly associated with the occurrence of malignant lymphoma in BLEL.MIF plays key functions in the pathogenesis of BLEL.Through exposition or inhibition of MIF,we showed that MIF plays fundamental roles in the pathogenesis of BLEL.We identified MIF to stimulate proliferation,induce resistance to apoptosis and regulate MAPK and PI3K/Akt pathways in BLEL.We also found that MIF played a role in fibrosis in BLEL through its ability to induce fibroblast differentiation into myofibroblasts and to enhance their proliferation and resistance to apoptosis.Furthermore,MIF stimulated the synthesis of extracellular matrix components from BLEL fibroblasts and myofibroblasts.TLR7/8 regulate MIF expression in BLEL.In vitro,we showed that TLR7/8 induced and differently regulated MIF expression in BLEL depending on the cell type and identified lymphocytes to be the main source of the circulating MIF in response to TLR7/8 activation.In addition,by using in vitro(retinal,blood,brain,nasopharynx,and liver cells)and in vivo(orbital,brain,liver,and spleen tissues collected from C57BL/6J mice)experimental models different from BLEL models,we confirmed the findings from the BLEL cells experiments and provided evidence that the expression and regulation of MIF by TLR7/8 were not specific to BLEL and could be also observed in any conditions where TLR7/8 are activated.Overall,this study has linked MIF to the pathogenesis of BLEL and provided supports for future research that will aim to find effective therapeutic targets and strategies against BLEL.
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