臺灣博碩士論文加值系統

全身性紅斑性狼瘡(systemic lupus erythematosus, SLE)為一種由自體抗體所引起的全身性自體免疫疾病。病人體內免疫細胞上所表現的先天性免疫受體會受到pathogen-associated molecular patterns (PAMPs)或danger-associated molecular patterns (DAMPs)活化，後續引起過度的免疫反應。Triggering receptor expressed on myeloid cells (TREM)為新發現的一群先天性免疫受體，研究指出其可調控類鐸受體(Toll-like receptor, TLR)所引起之發炎反應。TREMs已被報導會參與多種發炎性疾病的發展，然而其於不同疾病中所扮演的角色可能有所不同。於本論文中，我們建立了帶有TREM缺失的B6.lpr狼瘡小鼠，希望可藉此了解TREMs於紅斑性狼瘡中所扮演的角色。我們發現sTREM-1表現量於狼瘡病人及狼瘡小鼠血清中皆有顯著增高的情形，並且與疾病嚴重程度有正相關性。相較於控制組小鼠，40週大之Trem-1-/-.lpr小鼠有較高的死亡率及較嚴重之狼瘡病徵，包括尿蛋白增加、血清中抗雙股DNA自體抗體濃度上升、較嚴重的腎臟病變以及大量免疫細胞增生。此外，我們發現活化於樹突細胞(dendritic cell, DC)表面所表現的TREM-1後可抑制TLR-9所引起的B細胞活化因子(B cell-activating factor, BAFF)表現，因此Trem-1-/-.lpr小鼠淋巴結樹突細胞及血清中的BAFF表現量皆明顯高於B6.lpr小鼠。相較於Trem-1-/-.lpr小鼠，64週大之Trem-2-/-.lpr小鼠與B6.lpr狼瘡小鼠病情則無顯著差異。然而在腹腔注射脂多糖(lipopolysaccharide, LPS)以模擬病原菌感染後，Trem-2-/-.lpr小鼠則有明顯高於B6.lpr小鼠的存活率。以上結果顯示TREM-1於紅斑性狼瘡的疾病進程中扮演著抑制的角色;相較之下，TREM-2在自然情況下雖不影響狼瘡的發展，但在狼瘡小鼠受病原菌感染時則可使疾病惡化。
在第二部分的研究中我們希望可藉由Trem-1-/-.lpr小鼠來研究可行之治療方式。先前研究指出細胞自噬作用(autophagy)在細胞恆定與存活中扮演重要角色，而我們發現在狼瘡小鼠體內的細胞自噬作用有高於正常小鼠的現象，特別是於Trem-1-/-.lpr小鼠。並且也發現細胞自噬作用與尿蛋白的表現量有顯著正相關性。已上結果顯示細胞自噬作用可能與疾病的發展有關。因此我們將慢病毒(lentivirus)介導之shRNA腹腔注射於Trem-1-/-.lpr小鼠以抑制細胞自噬作用相關基因Atg5的表現，希望藉此探討抑制細胞自噬作用是否可改善小鼠狼瘡病徵。結果顯示注射病毒後小鼠體內細胞自噬作用確實有效受到抑制。而抑制Atg5表現後可減緩Trem-1-/-.lpr小鼠的狼瘡病徵，包含尿蛋白含量下降、血清中抗雙股DNA抗體減少及較輕微的淋巴結腫大。更重要的是，我們發現於Trem-1-/-.lpr小鼠淋巴結中漿細胞及CD4-CD8- T細胞的數量在細胞自噬作用受抑制後明顯降低。以上結果說明抑制細胞自噬作用或許可作為有效的紅斑性狼瘡治療方式。

Activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) plays an important role in the progression of systemic lupus erythematosus (SLE). Triggering receptor expressed on myeloid cells (TREM) is a novel innate immune receptor family which can regulate Toll-like receptor (TLR)-induced inflammatory responses. Roles of TREMs in diseases are still controversial and their roles in lupus still need to be determined. In current study, we aimed to establish TREM knockout B6.lpr mice for studying the role of TREMs in lupus. We found that sTREM-1 expression was increased and correlated with disease activity in both lupus patients and lupus-prone mice. Trem-1-/-.lpr but not Trem-2-/-.lpr mice had lower survival rate than control animals and exhibited more severe lupus symptoms including, proteinuria, anti-dsDNA antibody, nephritis, and immune cell expansions at 40 weeks of age. Moreover, TREM-1 could downregulate TLR-9-induced B cell-activating factor (BAFF) production in dendritic cells (DCs) and, therefore, serum and lymph node DCs of Trem-1-/-.lpr mice had higher BAFF level than those from B6.lpr mice. In contrast, the symptom severities of Trem-2-/-.lpr mice were similar to that found in B6.lpr mice during the 64-week follow-up period. However, Trem-2-/-.lpr mice had higher survival rate than B6.lpr mice after in vivo LPS stimulation. Above results suggested that TREM-1 can act as a suppressor in lupus progression and TREM-2 can exacerbate disease during bacterial infection.
In the second part, we want to find the therapeutic strategy by using Trem-1-/-.lpr mice model. We found that autophagy, which is important for cell homeostasis and survival, was elevated in lupus-prone B6.lpr and especially in Trem-1-/-.lpr mice. Most important, levels of autophagy were positively correlated with the proteinuria levels in Trem-1-/-.lpr mice. These results implied a role of autophagy in the pathogenesis of lupus. Therefore, lentiviral-shRNA targeting Atg5, an autophagy-essential protein, was i.p. injected into Trem-1-/-.lpr mice to determine whether suppressing autophagy can modulate the lupus-like disease. The results showed that shAtg5 could efficiently suppress the autophagy in vivo. Moreover, suppression of Atg5 ameliorated the symptoms of lupus in Trem-1-/-.lpr mice, including proteinuria, anti-dsDNA antibody, and lymphadenopathy. The numbers of plasma cells and CD4-CD8- T cells, which are the major expanded cells in Trem-1-/-.lpr mice, were significantly reduced after lentiviral-shAtg5 administration. These results implied that targeting autophagy may be a feasible therapeutic strategy in lupus.

中文摘要 i
ABSTRACT iii
CONTENTS v
INTRODUCTION 1
1. Systemic lupus erythematosus (SLE) 1
2. Triggering receptor expressed on myeloid cells (TREMs) 8
3. Autophagy 14
PURPOSE 23
MATERIALS 25
1. Human subjects 25
2. Animal models 25
3. PCR primers for genotyping 26
4. PCR primers for RT-qPCR 26
5. ELISA kits and cytometric beads array (CBA) 27
6. Antibodies for FACS and immunofluorescence staining 27
7. Reagents for cell culture and cell stimulation 28
8. Chemicals and other reagents 29
9. Buffers 30
METHODS 33
1. Genotyping 33
2. RT-qPCR 34
3. Flow cytometry 35
4. ELISA and cytometric beads array (CBA) 36
5. Measurement of proteinuria 37
6. Renal pathology 38
7. Culture of BMDCs, bone marrow-derived pDCs (BMpDC), and bone marrow-derived macrophages (BMM) 38
8. In vivo LPS treatment 39
9. Measurement of autophagy 40
10. In vivo knockdown of Atg5 by lentivirus-delivered shRNA 40
11. Statistical analysis 41
RESULTS 42
DISCUSSION 56
REFERENCES 61
FIGURES 80
TABLES 105
APPENDICES 106

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