2017-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645532摘要：腎病症候群是導致末期腎病變很重要的疾病，免疫功能的異常被認為是原發性腎病症候群的致病原因。人體的免疫系統是由精確的調控系統（特別是調控T細胞，Treg）來回復感染清除後的發炎反應及避免過度活化以至於攻擊自體的組織。在一些自體免疫系統疾病，如紅斑性狼瘡、類風濕及腦炎，研究顯示：調控T細胞的異常是疾病產生的重要原因。除了T細胞外，一些B細胞（如CD19+CD24hiCD38hi B細胞，或PD-L1hi B細胞）也有抑制T細胞、巨噬細胞或中性球的作用，同時也可促進Treg的分化。CD19+CD24hiCD38hi B細胞（Breg）是透過B細胞分泌IL-10，PD-L1hi B細胞是透過與T細胞上的PD-1作用，來影響T細胞。在紅斑性狼瘡及類風濕關節炎， Breg的數目是減少或是缺乏抑制功能；注入 PD-L1hi B細胞可以改善自體免疫實驗性動物腦炎。原發性腎病症候群是自體免疫系統疾病，Breg或PD-L1hi B細胞也有可能減少或功能異常，使得免疫系統過於活躍而傷害到腎臟 。我們因此假設：Breg細胞或PD-L1hi B細胞在原發性腎病症候群的病人數量是減少的，或者功能有所異常。增加BregB或PD-L1hi B細胞可以改善腎絲球發炎及蛋白尿。我們的初步臨床研究顯示：跟正常人比較，Breg的數量在微小病變（minimal change disease）及局部腎絲球硬化（focal segmental sclerosis）的病人是減少的，膜性腎病變（membranousnephropathy）的病人也有傾向是減少的。另外，我們也發現Breg在6個月內達到完全緩解的病人數量也是顯著減少。PD-L1hi B細胞在病人的變化分析則尚未進行。我們將在3年計畫中，將進一步收集更多病人，證實Breg或PD-L1hi B細胞在原發性腎病症候群病人數量是減少的，或者抑制功能有所缺陷。也將進一步分析這些人STAT3訊息傳遞機轉影響IL-10分泌的情形。我們也將分析影響B細胞增生及分化的因子，如各類T細胞（特別是TFH）、血漿中BAFF及Breg及PD-L1hi B細胞上的BAFF receptor表現與這些B細胞數量及功能上的關係。以上這些結果，我們也將在不同腎病症候群病理診斷的病人間或是對免疫抑制治療有不同反應的病人間作比較。也嘗試以microarray探討影響上述Breg數量或功能在不同病人間表現不同的可能因子。我們也將在動物蛋白尿模式證實：給予B10細胞（老鼠的Breg細胞）或PD-L1hi B細胞可以減緩LPS動物模式的蛋白尿或MRLlpr/lpr紅斑性狼瘡的腎絲球發炎。如果能證實Breg細胞或PD-L1hi B細胞在原發性腎病症候群的角色，並且找出不同病人間影響Breg細胞或PD-L1hi B細胞數量及功能的分子，我們將能從調控抑制性B細胞的途徑，發展新的治療原發性腎病症候群方針，提高治療成效並減少副作用，對腎臟研究及生醫產業提供新的方向。<br> Abstract: Nephrotic syndrome is an important cause of end stage renal disease. Immunedysfunction is believed to be the cause of glomerular damage in idiopathic nephroticsyndrome (INS). The immune function is modulated by a regulatory mechanism (such as Tregcells) to avoid over reaction and induce tolerance to self-antigen. In autoimmune disease, suchas systemic lupus erythromatosus or rheumatoid arthritis impairment of Treg cells is the causeof immune dysfunction. Some B cells (CD19+CD24hiCD38hi or PD-L1hi B cells) also haveinhibitory function on T cells, macrophage and neutrophil. They also induce the generation ofTreg cells. The inhibitory function of CD19+CD24hiCD38hi B cells (Breg) is through thesecretion of IL-10 while the PD-L1hi B cells is through the ligation of their PD-L1 with PD-1on other immune cells. In SLE or RA, Breg is decreased or functionally impaired. Infusion ofPD-L1hi B cells improves autoimmune experimental encephalitis. INS is an disease ofautoimmune disease, therefore, it is possible Bregs or PD-L1hi B cells are also decreased orfunctionally impaired leading to immune system over activity and glomerular damage.We hypothesize that: The amount of Bregs or PD-L1hi B cells is decrease or the functionis impaired in INS patients. Increase of Breg or PD-L1hi B cells will attenuate the glomerularinjury in INS patients. Our preliminary results revealed that the amount of Breg cells isdecreased in minimal change disease or focal segmental sclerosis patients and tended todecrease in membranous nephropathy patients. We also found that the Breg cells is lower inpatients who got complete remission 6 months after immunosuppression when compared topatients who did not get complete remission. The PD-L1hi B cells are to be analyzed in ourpatients in the future.In this 3 years project, we will collect more patients to prove that Breg and PD-L1hi Bcells is less or functionally impaired in INS patients. We will also examine IL-10 secretionsignaling pathway STAT3 activity. The factors influencing inhibitory B cells function andnumber, such as T cell subset (especially TFH), serum BAFF and BAFF receptor expressionon Breg or PD-L1hi B cells will be correlated to the status of inhibitory B cells. We willcompare them between different INS pathological diagnosis patients and normal subjects orbetween patients with different response to immunosuppression. The microarray for gene ormiRNA expression will be performed to find out why patients who got complete remissionhad less Breg cells than patients who didn’t get complete remission. In animal study, we willinfuse B10 cells (mice Breg cells) or PD-L1hi B cells into LPS proteinuric and MRLlpr/lpr lupusmice model to see whether infusion of inhibitory B cells could attenuate autoimmuneglomerulonephritis or not.If Bregs or PD-L1hi B cells are indeed less or functionally impaired in INS and we canfind out the factor influencing Breg or PD-L1hi B cells, we will be able to develop a newtreatment strategy through modulation of inhibitory B cells for INS. This will provide betterimmunosuppression with lower side effect in the management of INS.腎病症候群免疫抑制抑制性B細胞蛋白尿nephrotic syndromeimmunosuppressioninhibitory B cellsproteinuria