| Abstract | 第5页 |
| Abbreviations | 第6-14页 |
| Chapter 1: Introduction | 第14-44页 |
| 1.1- Lacrimal gland: anatomy and histopathology | 第15-17页 |
| 1.2- Diseases of the lacrimal gland | 第17-19页 |
| 1.3- Benign lymphoepithelial lesion of lacrimal glands | 第19-22页 |
| 1.3.1- History and etiology of BLEL | 第19页 |
| 1.3.2- Clinical and histological characteristics of BLEL | 第19-21页 |
| 1.3.3- Cytokines in BLEL | 第21-22页 |
| 1.3.4- Malignant occurrence in BLEL | 第22页 |
| 1.4- Macrophage migration inhibitory factor | 第22-38页 |
| 1.4.1- Structural organization of MIF gene and protein | 第22-24页 |
| 1.4.2- Regulation of MIF gene and protein expression | 第24页 |
| 1.4.3- Biological functions of MIF | 第24-25页 |
| 1.4.4- MIF Receptors | 第25-27页 |
| 1.4.5- MIF signaling pathways | 第27-33页 |
| 1.4.5.1- MIF and MAPK signaling pathway | 第28-29页 |
| 1.4.5.2- MIF and PI3K/Akt signaling pathway | 第29-31页 |
| 1.4.5.3- MIF and p53 pathway | 第31-32页 |
| 1.4.5.4- MIF and JAB-1 signaling pathway | 第32页 |
| 1.4.5.5- MIF and G protein-couple receptors signaling pathway | 第32-33页 |
| 1.4.6- MIF in inflammation, tumorigenesis, and fibrosis | 第33-38页 |
| 1.4.6.1- MIF in inflammation | 第33-35页 |
| 1.4.6.2- MIF in tumorigenesis | 第35页 |
| 1.4.6.3- MIF and fibrosis | 第35-38页 |
| 1.5- Toll-like receptors signalization pathways and regulation | 第38-41页 |
| 1.6- Research context and objectives | 第41-42页 |
| 1.7- Research proposal | 第42-44页 |
| Chapter 2: Cellular and molecular features of the pathogenesis and malignant lymphoma occurrence in BLEL | 第44-88页 |
| 2.1- Materials and methods | 第45-49页 |
| 2.1.1- Biological materials | 第45页 |
| 2.1.2- Hematoxylin and eosin and Masson trichrome staining | 第45-46页 |
| 2.1.3- Microarray analysis | 第46-47页 |
| 2.1.4- Cytokines profiling | 第47页 |
| 2.1.5- TUNEL apoptosis assays | 第47-48页 |
| 2.1.6- Western blotting | 第48页 |
| 2.1.7- Immunohistochemistry and immunofluorescence assays | 第48页 |
| 2.1.8- Statistical analysis | 第48-49页 |
| 2.2- Results | 第49-83页 |
| 2.2.1- Clinical and histological features in BLEL | 第49-55页 |
| 2.2.1.1 Clinical features | 第49-50页 |
| 2.2.1.2 Histological features | 第50-55页 |
| 2.2.2- Cellular and molecular characteristics of BLEL | 第55-71页 |
| 2.2.2.1- Biological processes and pathways involved in BLEL pathogenesis | 第55-59页 |
| 2.2.2.2- Inflammatory cytokines profiling in BLEL | 第59-62页 |
| 2.2.2.3- MIF and its receptors expression and distribution in BLEL tissues | 第62-66页 |
| 2.2.2.4- Resistance to apoptosis in BLEL | 第66-68页 |
| 2.2.2.5- Increased cell proliferation in BLEL | 第68-69页 |
| 2.2.2.6- MAPKs and PI3K/Akt signaling pathways are involved in BLEL pathogenesis | 第69-70页 |
| 2.2.2.7- TLRs signalization pathways are activated in BLEL | 第70-71页 |
| 2.2.3- Molecular basis and prediction tools of the malignant transformation in BLEL | 第71-83页 |
| 2.2.3.1- Genes and pathways associated with the occurrence of malignancy in benign lymphoepithelial lesions | 第71-82页 |
| 2.2.3.2- Prediction tools for the occurrence of malignancy in BLEL | 第82-83页 |
| 2.3- Discussion | 第83-86页 |
| 2.3.1 Cellular and molecular features of BLEL pathogenesis | 第83-84页 |
| 2.3.2 Molecular features of malignant lymphoma occurrence in BLEL | 第84-86页 |
| 2.4- Conclusion | 第86-88页 |
| Chapter 3: Implications of MIF in the pathogenesis of BLEL | 第88-110页 |
| 3.1- Materials and methods | 第89-92页 |
| 3.1.1- Biological materials | 第89页 |
| 3.1.2- Proliferation and apoptosis assays | 第89-90页 |
| 3.1.3- Western blotting | 第90页 |
| 3.1.4- Immunofluorescence assays | 第90-91页 |
| 3.1.5- Statistical analysis | 第91-92页 |
| 3.2- Results | 第92-106页 |
| 3.2.1- Characteristic of the BLEL primary cell used | 第92-93页 |
| 3.2.2- MIF induced resistance to apoptosis in BLEL primary cells | 第93-98页 |
| 3.2.3- MIF induced proliferation of BLEL primary cells | 第98-101页 |
| 3.2.4- MIF differentially regulated MAPKs and PI3K/AKT cascades in BLEL cells | 第101-103页 |
| 3.2.5- MIF induced and regulated fibrosis in BLEL | 第103-106页 |
| 3.3- Discussion | 第106-108页 |
| 3.4- Conclusion | 第108-110页 |
| Chapter 4: TLR7 and TLR8 activation differently regulate MIF expression in cells and organs | 第110-136页 |
| 4.1- Materials and methods | 第111-115页 |
| 4.1.1- Mice | 第111页 |
| 4.1.2- Primary cells and Cell lines | 第111页 |
| 4.1.3- Cell culture | 第111-112页 |
| 4.1.4- Stimulation with TLR7/8 activator R848 | 第112页 |
| 4.1.5- RT-qPCR | 第112-113页 |
| 4.1.6- ELISA | 第113页 |
| 4.1.7- Western blot | 第113-114页 |
| 4.1.8- Immunohistochemistry | 第114页 |
| 4.1.9- Cells immunofluorescence assays | 第114页 |
| 4.1.10- Statistical analysis | 第114-115页 |
| 4.2- Results | 第115-132页 |
| 4.2.1- TLR7/8 differently regulates MIF expression in BLEL primary cells | 第115-117页 |
| 4.2.2- TLR7/8 differently regulate MIF expression in other cell and organ types | 第117-132页 |
| 4.2.2.1-TLR7/8 expression in cells and mice tissues before and post activation with R | 第117-120页 |
| 4.2.2.2- TLR7/8 activation regulate differently MIF and its receptors expression in cells | 第120-125页 |
| 4.2.2.3- TLR7/8 induced an organ-dependent expression and redistribution of MIF and its receptors in vivo | 第125-132页 |
| 4.3- Discussion | 第132-134页 |
| 4.4- Conclusion | 第134-136页 |
| Conclusions and recommendations | 第136-140页 |
| References | 第140-156页 |
| Appendix | 第156-224页 |
| Appendix 1- Dose-response, Cells proliferation assays and Kinetic of MIF release following exposition to TLR7/8 activator R848 | 第156-157页 |
| Appendix 2- List of antibodies | 第157-159页 |
| Appendix 3- Complete GO biological process associated to the up-regulated DEGs in BLEL | 第159-180页 |
| Appendix 4- Complete GO biological process associated with the down-regulated DEGs in BLEL | 第180-211页 |
| Appendix 5- MLEL specimen information | 第211-217页 |
| Appendix 6: BLEL specimen information | 第217-224页 |
| Achievements | 第224-226页 |
| Acknowledgements | 第226页 |
