系統識別號 U0026-0308201503050200
論文名稱(中文) PPARγ缺失所導致免疫失調
論文名稱(英文) Immune disturbance caused by PPARγ deficiency
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 劉雅惠
研究生(英文) Ya-Hui Liu
學號 S58971219
學位類別 博士
語文別 英文
論文頁數 82頁
口試委員 指導教授-蔡佩珍
中文關鍵字 過氧化物酶增生因子活化受體γ  脾臟肥大  Th17  B細胞活化  自體免疫 
英文關鍵字 PPARγ  splenomegaly  Th17  B cell activation  autoimmunity 
中文摘要 代謝以及自體免疫疾病的發生在工業國家有大幅增加的情況,這當中似乎有個共通因子能同時調節代謝以及自體免疫的平衡。過氧化物酶增生因子活化受體γ (PPARγ) 是能被配位體所激活的核內轉錄因子並且調控了許多的代謝路徑,包含脂質的生合成、醣類的代謝以及發炎反應。然而在生物體內,PPARγ 參與在免疫平衡的角色上仍然未被完全了解。表達25% PPARγ 的模式小鼠 (PpargC/-小鼠)在14 個月大的年齡具有高量的抗dsDNA 抗體、抗核抗體以及免疫沉積物堆積在腎絲球體中,發展出類紅斑性狼瘡的自體免疫疾病。而在這些症狀之前,年紀輕的時候就有脾臟腫大的現象,為脾臟細胞聚集數量增加以及B 淋巴細胞活化所致,而非造血作用轉移到脾臟所造成。此外PpargC/-小鼠的脾臟細胞其sphingosine-1-phosphate receptor 1 (S1P1)的表達量下降,妨礙了淋巴細胞外出可能是聚集在脾臟的機制之一。而在機制上,發現Th17 的極性以及IL-17 的訊息傳遞在PpargC/- CD4+ T 淋巴細胞都有增加的情形,說明了在生物體內的微環境下PPARγ 低表達量的CD4+ T 淋巴細胞在脾臟能調節B 淋巴細胞的過度活化。最後,利用給予piolitazone 的方式活化僅剩的PPARγ 能夠增加S1P1 的表現量、降低Th17 在脾臟的量以及減緩脾臟肥大的情形。總言,我們的研究證實在 T 淋巴細胞內Pparg 表量的下降是個重要的因子造成自發性類紅斑性狼瘡自體免疫疾病的發生,並且發現PPARγ 的新角色在淋巴細胞的移行以及參與在Th17 和B淋巴細胞的對話。
英文摘要 Metabolism and autoimmune disease have experienced a dramatic increase in industrialized countries. A common factor regulating both metabolic and autoimmune balance is suggested. PPARγ is a nuclear transcription factor that modulates diverse functions, including lipid biosynthesis, glucose metabolism and inflammation. However, its specific role in the balance of immunity in vivo has not been fully explored. PpargC/- mice expressing PPARγ at 25% normal level exhibited higher levels of autoantibodies and developed lupus nephritis, resembling the development of a lupus-like autoimmune syndrome by 14 months of age. These symptoms are preceded by splenomegaly in the early age, which is associated with increases of splenocyte accumulation and B-cell activation, but not relocation of hematopoiesis to the spleen. Reduced expression of sphingosine-1-phosphate receptor 1 (S1P1) and diminished migration toward S1P in the PpargC/- splenocytes supports the hindrance of lymphocyte egression as a mechanism for their accumulation. Mechanistically, increased Th17 polarization and IL-17 signaling in the PpargC/- CD4+ T-cells contributed to the B-cell hyper-activation in the spleen. Finally, activation of the remaining PPARγ in PpargC/- mice by pioglitazone increased S1P1 level, decreased Th17 population in the spleen, and ameliorated splenomegaly. Together, our data demonstrate that reduction of Pparg expression in T-helper cells is a critical factor for spontaneous lupus-like autoimmune diseases and define a novel role of PPARγ in lymphocyte trafficking and crosstalk between Th17 and B-cells.
論文目次 Abstract I
Chinese abstract II
Acknowledgement III
Contents IV
Figure list VII
Abbreviations X
Chapter 1. Introduction 1
1.1 Systemic lupus erythematosus (SLE) 1
1.2 Lupus nephritis 1
1.3 Epidemiologic association between SLE and obesity 2
1.4 Peroxisome proliferator-activated receptor gamma (PPARγ) 3
1.5 PPARγ ligands 4
1.6 PPARγ in immunoregulation 5
1.7 PPARγ hypomorphic mice 7
1.8 Sphingosine-1-phosphate receptor 1 8
Chapter 2. Objective and Specific Aims 9
2.1 Objective 9
2.2 Specific aims 9
Chapter 3. Materials and Methods 11
3.1 Mice 11
3.2 Micro-computed tomography (micro-CT) 11
3.3 Flow cytometry 12
3.4 Migration assay 12
3.5 TUNEL assay 13
3.6 Anti-dsDNA ELISA 13
3.7 Detection of anti-nuclear antibodies and immune complex deposition 14
3.8 Scoring of mesangial matrix expansion 14
3.9 BrdU labeling 14
3.10 CFSE labeling 15
3.11 In vitro lymphocyte proliferation and apoptosis assay 15
3.12 In vitro co-culture assay 15
3.13 In vitro CD4+ T-cell differentiation 16
3.14 Western blot analysis 16
3.15 Tissue collection and RNA analysis 17
3.16 Statistical analysis 17
Chapter 4. Results 18
4.1 Spleen enlargement in PPARγ hypomorphic mice 18
4.2 No signs of extramedullary hematopoiesis in the young PpargC/- mice 18
4.3 Reduced S1P1 and migration in the splenocytes of PPARγ hypomorphic mice 19
4.4 Increased proliferation of B-cells and apoptotic cells in vivo in the spleen of PPARγ hypomorphic mice 20
4.5 Increased autoantibody production and development of a lupus-like syndrome in aged PPARγ hypomorphic mice 21
4.6 PPARγ deficiency in effector T-helper cells causes increased B-cell activation 22
4.7 Increased Th17 polarization in PPARγ hypomorphic mice 23
4.8 Enhanced Th17 function promotes B-cell activation through IL-17 signaling in PPARγ hypomorphic mice 24
4.9 Pioglitazone ameliorates splenomegaly in PPARγ hypomorphic mice 24
Chapter 5. Discussion 26
5.1 Phenotype of mice with PPARγ hypomorph 26
5.2 PPARγ regulates lymphocyte trafficking through S1P1 27
5.3 Role of PPARγ in CD4+ T-cells-mediated B-cell activation 28
5.4 Compared the PPARγ hypomorphic mice used in this study with others in autoimmunity 28
5.5 PPARγ regulation in Th17 polarization 29
5.6 Discussion of some discrepancies between our results and previously reported studies 30
5.7 Gene-dosage variation of PPARγ 31
5.8 Clinical studies of PPARγ SNP in autoimmunity 31
Chapter 6. Conclusion 34
References 36
Figures 46
Tables 79
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