2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649230摘要：全身性紅斑狼瘡一直都是全身性自體免疫疾病的代表，主要是會產生自體抗體來對抗體內許多的組織和器官，而造成各種的症狀，如關節炎、溶血性貧血、肋膜炎和心包膜炎等疾病。而在這些自體抗體所認識的抗原主要是核蛋白相關的的各個成份，包括ribonucleoprotein、組織蛋白(histone)、核小體(nucleosome)和DNA 等抗體，都一再被證明是在全身性紅斑狼瘡重要的自體抗原。而在全身性紅斑狼瘡的致病機轉中有一個很重要的就是B 細胞的過度活化，其中有一群B 細胞會表現出CD5 的分子，稱為B-1 細胞，與傳統的B 細胞在功能上有些不同。而這群B-1 細胞第一年：我們計畫要分離出傳統的B 細胞和在狼瘡小鼠會受到活化的B-1 細胞，再進一步分析這些細胞的功能和細胞激素分泌的情形。在此一研究中可以進一步了解是否在傳統B 細胞和B-1 細胞在抗體分泌和功能上是否有相當大的不同，也可以確定這群B-1 細胞是否會分泌高量的IL-10，而表現出IL-10 與目前最常被研究的細胞調節功能是否有任何相關。第二年：我們想進一步研究這些B 細胞，包括傳統B 細胞和B-1 細胞是否會影響到T 細胞的活化和發育。因此，我們計畫將建立試管內細胞培養的方式將分離出的傳統B 細胞或是B-1細胞與分離出的T 細胞一道培養，再進一步分析這些T 細胞的功能，尤其是細胞激素分泌的情形。第三年：我們要進一步將這些分離出的傳統B 和B-1 細胞來作為抗原呈現細胞(APCs)，再與目前已知的自體抗原如核小體、組織蛋白或是凋亡小體一道培養，看是否可以當成一個好的APCs。尤其是B-1 細胞一直都被認為會自動分泌許多自體抗體，包括IgM 抗DNA 抗體等，這些會自動分泌抗體的B-1 細胞是否較能夠有效地處理和呈現自體抗原。目前對全身性紅斑狼瘡的機轉都還不是很清楚，而目前的治療也都主要是依賴一些免疫抑制劑，還是無法完全控制病情，所以進一步研究其真正的機轉，對未來的治療研發將有很大的幫忙。在此一計畫中，我們將針對全身性紅斑狼瘡的B 細胞作更進一步的研究，可以了解其在致病機轉中所扮演的角色，而且也可以了解是否能夠研發出更新的治療方法。<br> Abstract: Systemic lupus erythematosus is the protype of systemic autoimmune disease, characterized by theappearance of anti-DNA antibody and glomerulonephritis. One of the major mechanisms ofautoimmunity is the breakdown of self-tolerance and the appearance of autoreactive T and B cells.Especially, B cell hyperactivity has been thought to be the critical abnormality in the autoimmuneprone NZB/W F1 mice. In this proposal we plan to study the role of these subset of B cells in theprocessing and presentation of self-antigen to T cells. In addition, we also like to investigate if theB-1 cells expressing high level of IL-10 with the regulatory function. During the second year, wewill look into the effect of B cells on the activation and development of T cells. Furthermore, wealso like to analyze the epitopes of self-antigens recognized by the autoreactive T cells with thehelp of B cells. We believe our projects will shed light on further understanding the pathogenicmechanisms and exploring the future therapy for systemic lupus erythematosus.First year: We like to isolate B-1 and conventional B cells for the analysis of the function and alsocytokine profiles. In addition, we plan to study further the antibody production of different subsetsof B cells, especially focus on the B-1 cells and conventional B cells. In addition, we also likestudy if IL-10 producing B-1 cells could exert inhibitory effect of T cells function.Second year: We like to study the role of different subpopulation of B cells in the stimulation of Tcells. Especially, we plan to investigate if these different B cells can affect the T cells developmentin a co-culture system. We will further analyze the function and cytokine profile of T cells afterincubation.Third year: We plan to study the ability of different subsets of B cells for the processing andpresentation of self-antigens such as apoptotic bodies and nucleosome for the stimulation ofself-reactive T cells. Further we like to compare the epitopes identified by B cells and other antigenpresenting cells (APCs) such as dendritic cells.We believe further clarification of function and cytokine profile of B cells including conventional Bcells and B-1 cells might provide the invaluable information on pathogenic mechanisms of these Bcells. In the future, we might target these pathogenic B cells for the further therapeutic designs.