2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649317摘要：過敏性紫斑症（Henoch-Schönlein purpura）是一種好發於兒童的全身性小血管炎。目前並無專一實驗室檢查可用於確切診斷過敏性紫斑症，而且真正致病原因目前仍不清楚。先前我們的研究發現過敏性紫斑症急性期血中的IgA會與2醣蛋白I（2 glycoprotein I, 2GPI），特別是其中某些片段的胜肽緊密結合，且這些IgA抗2GPI抗體會與血管內皮細胞交互反應結合，並透過MEK/ERK訊息傳遞路徑促進血管內皮細胞大量分泌IL-8。另外，我們亦發現TH3及TH17細胞在紫斑症急性期也扮演重要的角色。從以上的研究成果我們逐步釐清「專一性免疫」（adaptive immunity）在此血管炎致病過程中的角色扮演。不過，過敏性紫斑症典型的病理切片上發現除了IgA外，補體C3亦會沉積於血管壁上。此外，我們初步發現過敏性紫斑症病童急性期血漿中的C3a及C5a明顯高於緩解期及對照組。因此，我們認為除了「專一性免疫」外，「非專一性免疫」（innate immunity）特別是補體系統在紫斑症致病機轉中也扮演重要角色；而且補體系統的活化應與專一性免疫系統中IgA抗2GPI抗體有著相互之作用。為了驗證上述的假說，我們提出一為期三年的計畫將分別探究（一）兒童過敏性紫斑症是經由何種路徑活化補體。（二）補體活化所產生的具生物活性產物C3a及C5a對血管發炎的影響。（三）C3a及C5a是否影響IgA尤其是IgA抗β2GPI抗體的生成。接下來為了研究過敏性紫斑症中IgA抗β2GPI抗體與補體的作用，同時考量從病童血清或血漿中直接分離取得的polyclonal IgA抗β2GPI抗體其功能變異度高及量之不足，（四）我們將從病童身上分離並製造出IgA抗β2GPI「單株」抗體。利用此單株抗體可進一步確定（五）病童IgA抗β2GPI自體抗體是否具活化補體並傷害血管內皮細胞之作用，以及（六）此自體抗體促進血管內皮細胞產生各種補體蛋白及C3a及C5a受體（C3aR/CD88）之作用。最後，（七）針對補體活化（C3a及C5a血中濃度）與臨床症狀、疾病嚴重度以及病程的相關性進行分析。完成此計畫，將更清楚過敏性紫斑的致病機轉；未來對疾病的診斷、治療、及追蹤將有實質的助益。 <br> Abstract: Henoch-Schönlein purpura (HSP) is a systemic form of small vessel vasculitis that primarily affects children. Nowadays, there is no specific test for the diagnosis of HSP, and the etiology and pathogenesis of this disease are still unknown. Previously, we have found that HSP-derived IgA bound well to 2 glycoprotein I (2GPI) and several fragmental peptides of 2GPI. These 2GPI-reactive IgA then crossly reacted with endothelial cells (EC) to induce IL-8 production by EC through the MEK/ERK signaling pathway. In addition, type 3 T helper (TH3) cells and TH17 cells were also found to be involved in the pathogenesis of HSP. Accordingly, the role of adaptive immunity in HSP is now clarified step by step. However, in addition to IgA, the deposits of complement 3 (C3) are often shown on skin and renal biopsies. Besides, our preliminary findings revealed that plasma levels of C3a and C5a in children with acute HSP were significantly higher than those in patients at convalescent stage and in healthy control. Combined, in addition to adaptive immunity, innate immunity is likely to be involved in the development of HSP. We hypothesized the complement activation and its interaction with IgA anti-β2GPI antibodies may play some roles in the pathogenesis of HSP. To test our hypothesis, we propose a 3-year project to (1) determine the activation pathway of complement system in HSP; (2) to evaluate the contribution of bioactive C3a and C5a in the development of vasculitis; (3) to evaluate the effects of C3a and C5a on the generation of IgA and IgA anti-β2GPI antibodies. Next, to further study the effect of IgA anti-β2GPI antibodies on complement activation and generation, and considering the heterogeneity and low levels of HSP-derived polyclonal β2GPI-reactive IgA, we will (4) generate IgA anti-β2GPI monoclonal antibody from HSP patients. Using such monoclonal antibody, we will (5) determine if IgA anti-β2GPI antibodies could induce complement-dependent EC damage; and (6) evaluate the effect of IgA anti-β2GPI antibodies on the presentation of complement proteins and the receptors of C3a and C5a (C3aR and CD88) by EC. Finally, we will (7) analyze the association between plasma levels of C3a and C5a and clinical symptoms, disease severity, and disease course. The results of this project will provide some clues for a better understanding of HSP and may be helpful to the diagnosis, treatment, and disease follow-up of HSP.過敏性紫斑症補體系統2醣蛋白IIgA單株抗體Henoch-Schönlein purpuracomplement2 glycoprotein IIgA monoclonal antibody