2019-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/707117摘要：全身性紅斑性狼瘡（systemic lupus erythematosus，SLE）為一常見的兒童自體免疫疾病，台灣兒童全身性紅斑性狼瘡（pSLE）的盛行率約為6.3/100,000（16歲以下兒童），進一步的分析顯示女孩的盛行率為11.2/100,000而男孩的盛行率為1.8/100,000，女與男的比率約為6.2：1。全身性紅斑性狼瘡是個多重器官侵犯的疾病，包括血液系統、腎臟、神經系統、心臟血管系統以及肌肉關節系統等。其中，侵犯腎臟造成腎絲球腎炎經常是造成預後不佳的主要原因之一。相較於成人（34-48%），狼瘡性腎炎（lupus nephritis，LN）更好發於pSLE（50-67%），若沒有接受適當的治療往往造成慢性腎衰竭並進展到end stage renal disease（ESRD）。造成狼瘡性腎炎的致病機轉相當複雜，仍有相當多的部分等待進一步釐清。從腎臟切片可發現球蛋白（主要是IgG）及補體（如 C3，C1q）的沉積，因此認為腎臟的發炎應該是透過抗體與腎臟組織細胞的結合與補體的活化而形成。腎絲球結構中血管內皮細胞是一重要組成。最近我們發現：相較於沒有腎臟侵犯的pSLE病童及健康對照組，罹患class III/IV狼瘡性腎炎且有重度蛋白尿的pSLE患者其周邊血液中IgG抗「人類腎絲球血管內皮細胞」（human renal glomerular endothelial cell，HRGEC）抗體濃度明顯高出許多。為了進一步釐清抗「人類腎絲球血管內皮細胞」自體抗體在兒童狼瘡性腎炎中致病機轉角色的扮演，我們將提出為期3年的計畫，首先我們將致力從具有IgG抗HRGEC抗體的狼瘡性腎炎病童身上製造並取得IgG抗HRGEC「單株」抗體。接著，利用來自病童的單株抗體研究該自體抗體如何引起腎臟的發炎及如何造成蛋白的流失。最後，利用這些單株抗體找尋與疾病相關的專一抗原（specific antigen）。完成此研究，將可提供未來狼瘡性腎炎治療的新標的生物分子（novel target biomolecules）。除此之外，找到與疾病相關的專一抗原後，未來將可發展抗體偵測組套（antibody detection kit），應用於狼瘡性腎炎的臨床診斷與疾病的追蹤。<br> Abstract: Systemic lupus erythematosus (SLE) is one of the most common childhood rheumatic diseases. In Taiwan, the prevalence of juvenile onset SLE (pSLE) is around 6.3 per 100,000 children less than 17 y/o (female: 11.2 per 100,000, male: 1.8 per 100,000), and the female to male ratio is 6.2:1. Many organs and systems can be involved in SLE including hematological system, nervous system, cardiovascular system, kidney, muscle, joints, and so on. Of note, renal involvement often leads to significant morbidity and mortality. Compared with adults, lupus nephritis (LN) occurs more commonly in pSLE (adults: 34-48%, children: 50-67%). The pathogenesis of LN is complicated and to be determined. Renal biopsies of LN patients have shown the deposition of immunoglobulin, especially IgG and complement such as C3 and C1q. Accordingly, it is hypothesized that LN may be induced by the interaction of antibodies and some specific renal structure and the activation of complement system. Among the renal structure, glomerular endothelial cells are important component. Previously, we found that the serum level of IgG anti-human renal glomerular endothelial cell (HRGEC) antibodies was significantly higher in children with class III/IV LN than that in pSLE without renal involvement and that in healthy controls. To further clarify the pathogenic roles of IgG anti-HRGEC antibodies in LN, we will propose a 3-year project. First, we will generate IgG anti-HRGEC “monoclonal antibody” from LN children. Then, we will use patient-derived monoclonal antibody to study the antibody-related mechanisms of nephritis and proteinuria. Finally, we will use such monoclonal antibody to identify LN-specific antigen. Once the project could be completed smoothly, we may provide some novel therapeutic target biomolecules. In addition, using newly identified antigen, antibody detection kit may be developed to assist the diagnosis and follow-up of LN.兒童狼瘡性腎炎人類腎絲球血管內皮細胞單株抗體childhood lupus nephritishuman renal glomerular endothelial cellsmonoclonal antibody