前言：細胞凋亡是在自體免疫疾病患者中，重要的致病機轉之一，有些相關的研究發表文章，它往往是在細胞受偒後接著發生。而白血球細胞發生凋亡，一般相信在全身急性發炎反應的緩解，以及避免受傷組織發生繼發性的傷害中扮演重要的角色。根據過去的報告中，其發生率在全身性紅斑狼瘡(SLE)患者的免疫細胞，包括B 細胞、T 細胞、巨噬細胞、各式免疫相關細胞都有被報告過，但是其詳細的機轉卻很少人提到。自體免疫疾病患者中，疾病反覆復發的情形並不少見。在過去的報告中，其發生率約佔一至兩成的全身性紅斑狼瘡患者會在兩年內反覆復發。反覆復發所影響的器官包括腎臟、骨頭關節、神經系統或是其他內臟器官等等。
　　方法：我們假設發炎的分子堆積、細胞的凋亡增加和減少內皮細胞再生能力都會在SLE 患者疾病活化時同時發生，而病毒的活化和細胞內病毒受器的改變可能和疾病活性有關，同時，我們相信，使用藥物治療可以改善發炎和減少氧化壓力和改善內皮細胞再生能力。同時，將進一步探討細胞凋亡的分子機轉，並研究凋亡和抗病毒免疫的相關性。而內皮幹細胞(EPC)在主要幫助血管內皮的修復，同時相關的內皮和細胞間黏著分子(ICAM-1)也細胞和內皮活化也和疾病活性有相關，將探討它們在SLE 患體內的角色。
　　結果：研究結果顯示，SLE 患者細胞凋亡比其它疾病對照組要來的高，其中，B 細胞凋亡分子APO2.7 和疾病活性成正相關。而SLE 合併神經病變的患者，它的發生和自體免疫抗體anti-Ro 有關，同時我們發現有神經病變的患者的疾病活性比沒有的患者來得高。而氧化壓力在我們目前的研究，和疾病本身的活性沒有相關性。而EPC,ICAM-1 和疾病活性成正相關，但是L-selectin 和疾病活性成負相關。在病毒感染方面，如果SLE 患者本身的抗病毒能力差的患者，疾病活性就可能會比較高。同時，我們發現caspase-9 和疾病活性成負相關。這個研究指出，粒腺體在疾病活性高的SLE 患者週邊白血球細胞內有活化的跡象。這些都還需要更大型的研究來證實。

　　Introduction: Apoptosis is one important pathogenesis associated with disease activity in systemic lupus erythematosus (SLE). The inflammation reactions secondary to the underlying autoimmune disease is believed to play an important role in aberrant apoptosis in lupus, and activates inflammatory cell to propagate the immune reaction, and finally, involved the organ damage, and so is the disease activity. Apoptosis is a complex process and may take several hours to develop. Clinical evidence of SLE patients suffers from both defective regeneration and mobilization of circulating endothelial progenitor cells.
　　Method: We hypothesize that significantly increased these inflammatory biomarkers, increase leukocyte apoptosis and circulating autoantibodies in SLE patients with disease flare up, and the aberrant viral activation with consumption of intracellular viral receptor is associated elevated lupus disease activity, and we also speculate that immunosuppressant adjuvant treatments can suppress the either inflammation or oxidative stress reaction, decrease leukocyte apoptosis and improve disease activity gradually. Endothelial progenitor cells (EPC) are helping vessel regeneration, but the adhesion molecules are directing inflammatory cells against vessels. Their roles in lupus will be explored in this current study, and the link between it and the disease activity will also be studied.
　　Results: Study result showed apoptosis is significantly higher in SLE than disease and normal control, and B cell APO2.7 is positively associated with disease activity. The anti-Ro autoantibody is associated with neuropsychiatric SLE, and neuropsychiatric SLE patients have higher disease activity than non-neuropsychiatric SLE patients. The adhesion molecule ICAM-1 and EPC number are positively associated with disease activity. Another adhesion molecule L-selectin is negatively associated with disease activity. Besides, we noticed that poor immunity to virus is associated with higher disease activity in SLE patients. The caspase-9 level is also negatively associated with disease activity. This study indicates mitochondrial activation is prevalent in active SLE patients. All of these need further investigation.

論文審定書　i
誌謝　ii
中文摘要　iii
英文摘要　iv
目錄　v
圖次　x
表次　xi
前言 內容簡介Introduction　1
　　核心推論 Central hypothesis　08
第一章 研究對象和實驗方法Patients, methodology and statistics　09
　　研究對象的基本特色Baseline characteristics of the study patients　10
　　研究實驗方法和實驗材料Methods and Materials　14
第二章 紅斑性狼瘡疾病活性、自體免疫抗體和周邊血液白血球凋亡的比較 The link between systemic lupus erythematosus disease activity, autoantibodies and peripheral blood apoptosis　27
　　2.0- Material and Methods　28
　　2.1-Introduction　29
　　　2.1.1-Leukocyte apoptosis in SLE　29
　　　2.1.2-Leukocyte apoptosis in disease controls　31
　　　2.1.3-Leukocyte apoptosis in normal controls　34
　　2.2-Result　35
　　　2.2.1-Comparison of apoptosis markers　35
　　　2.2.2-Correlation between clinical severity and autoantibody level　37
　　　2.2.3-Correlation between clinical severity and percentage of leukocyte apoptosis　40
　　2.3- Discussion　41
第三章 比較侵犯神經系統和未侵犯神經系統的紅斑性狼瘡患者之間疾病活性、自體免疫抗體、氧化壓力和周邊血液白血球凋亡的異同 Comparison of disease activity, autoantibodies, and leukocyte
apoptosis between neuropsychiatric (NP) and non-neuropsychiatric (non-NP) systemic lupus erythematosus (SLE) groups　42
　　3.0- Material and Methods　43
　　3.1-Introduction of neuropsychiatric SLE　44
　　3.2-Result　46
　　　3.2.1-Comparison SLEDAI between NP and non-NP SLE　46
　　　3.2.2-Oxidative stress between NP and non-NP SLE　49
　　　3.2.3-Apoptosis between NP and non-NP SLE　51
　　　3.2.4-Selected intracellular proteins between NP and non-NP SLE　54
　　3.3- Discussion　55
第四章 探討紅斑性狼瘡腎盂腎炎和周邊神經病變相關性 Peripheral neuropathy among lupus nephritis (LN) patients　57
　　4.0- Material and Methods　58
　　4.1-Introduction　59
　　　4.1.1-Definition of peripheral neuropathy　59
　　　4.1.2-Definition of lupus nephritis　62
　　4.2-Result : Markers of Peripheral neuropathy among LN patients　63
　　4.3- Discussion　65
第五章 探討半胱氨酸蛋白酶-9, -10 活性和周邊血液白血球凋亡之間的相關性Study of correlation between caspase-9, caspse-10 and leukocyte apoptosis markers in systemic lupus erythematosus　66
　　5.0- Material and Methods　67
　　5.1-Introduction　68
　　　5.1.1-Caspase-9 and caspase-10　68
　　　5.1.2-Possible apoptosis pathways in SLE　73
　　　5.1.3-Mitochondrial pathways in systemic lupus erythematosus　77
　　5.2-Result　78
　　5.3- Discussion　79
第六章 血管內皮幹細胞(KDR+ cell)、細胞間黏著分子(ICAM-I,L-selectin)和紅斑性狼瘡患者的疾病活性之間的相關性Endothelial progenitor cell (KDR+ cell), adhesion molecule (ICAM-I) and lymphocyte surface marker (L-selectin) in SLE, disease and normal controls and their correlation with disease activity　81
　　6.0- Material and Methods　82
　　6.1-Introduction　83
　　6.2-Result　84
　　　6.2.1-KDR+ cells among peripheral leukocyte between groups　84
　　　6.2.2-Adhesion molecules (ICAM-I, L-selectin) between groups　86
　　　6.2.3-SLE disease activity correlation with KDR cells percentage and adhesion molecules (ICAM-I and L-selectin)　87
　　6.3-Discussion　88
第七章 抗病毒之免疫力和紅斑性狼瘡患者的疾病活性之間的相關性Link between anti -virus immunity and systemic lupus erythematosus (SLE) disease activity　89
　　7.1-Introduction　90
　　7.2-Sensor and marker of viral infection and anti-virus immunity　93
　　7.3-MDA5 level and disease activity　95
　　7.4-Divide SLE into high-MDA5 and low-MDA5 groups　97
　　7.5-MDA5 and leukocyte apoptosis in SLE　100
　　7.6-Discussion: MDA5, caspase activation and subgroups in SLE　104
第八章 討論 Discussion　112
第九章 此研究之缺點和未來研究方向 Limitation Of Current Study and Future Research　121
　　9.1- Limitation of current study　122
　　9.2- Future research　124
參考文獻 Reference　127
附錄　141
　　附錄1--英文縮寫全文　142
　　附錄2--The association among leukocyte apoptosis, autoantibodies and disease severity in systemic lupus erythematosus　144
　　附錄3--The Association between Autoantibodies and Peripheral Neuropathy in Lupus Nephritis　151
　　附錄4--The Association between Serological Biomarkers and Primary Sjogren’s Syndrome Associated with Peripheral Polyneuropathy　156
　　附錄5-- The Association among Antioxidant Enzymes, Autoantibodies, and Disease Severity Score in Systemic Lupus Erythematosus: Comparison of Neuropsychiatric and Nonneuropsychiatric Groups　162
　　附錄6-- Investigation of the caspase-dependent mitochondrial apoptotic pathway in mononuclear cells of patients with systemic lupus erythematosus　169

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