2026-11-092026-11-09https://scholars.csmu.edu.tw/handle/123456789/38035（The pathogenesis of autoimmune diseases-the role of protein modification on autoantigens） Arthritis, one of the most important features of autoimmune diseases is the leading cause of disability in the world and leads to physical and psychosocial challenges for these patients. The impact of arthritis on health care costs is enormous. Arthritis has been ranked first as the cause of chronic health problems, long-term disability, and health care consultations, especially in people over 65 years old. Early diagnosis and treatment of arthritis result in less morbidity, maintenance of function, and sometimes prolongation of life. The cost of arthritis was 150 billion in 1992 in US. This amount translates to 2.5% of the Gross National Product. The National Arthritis Data Work Group predicts that over 60 million people will develop a form of arthritis by 2020 (42 million in 1992). The years 2000-2010 were declared as the Bone and Joint decade by UN/WHO. Despite enormous progress in understanding how the immune system works, the pathogensis of systemic autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjogren’s syndrome (SS), and polymyositis/ dermatomyosis (PM/DM) still remains obscure. As a consequence, better treatment of these diseases remains elusive. A conceptual breakthrough in etiology and pathogensis is urgently needed. The autoimmune response is driven by self antigen, and is T cell-dependent. The source of self-antigen that drives the autoimmue response remain unclear. Many recent studies have implicated an important role for cell death processes in mediating the bypass of tolerance to these autoantigens. Apoptosis and its role in the development of autoimmunity have been an active area of research. Apoptosis is characterized by typical morphologic changes in the dying cell that result from biochemical modifications of nuclear and cytoplasmic structural proteins. In response to an apoptotic stimulus, a cascade of cysteine proteases is activated. At least 39 different proteins are known to be cleaved during apoptosis and a subset of known lupus autoantigens are cleaved during apoptosis. It has been proposed that proteolysis may produce novel epitopes required for the production of autoantibodies. Some of post-translation modifications can create new self antigens. Post-translations include phosphorylation, methylation, glycosylation, acylation, deamination/citrullation, isoaspartyl and deimination. This study will concentrate the potential role played by death-specific modifications of autoantigens in bypassing tolerance to highly conserve autoantigens. These proposals include proteomic analyses of methylarginine modification in autoimmune diseases, the effect of transglutaminase 2 on apoptosis in SLE, the role of tissue transglutaminase in the clearance of apoptotic cells, the pathogenesis of RAthe roles of peptidylarginine deiminase (PADI) enzymes in regulation of apoptosis and generation of new autoantigens, and the role of endoplasmic reticulum stress-mediated apoptosis in autoimmune diseases. The important goals of this proposal are to understand the pathogenesis of autoimmune diseases, especially in the relationship of cell death, autoantigen motifications, and tolerance.（探討自體免疫疾病之致病機轉-蛋白質轉譯後之修飾在自體抗原之角色） 關節炎是導致殘障之最主要原因（1），而肌肉關節疾病1992 在美國一年之花費 是美金1500 億左右（2），佔GNP2.5%。美國估計有15%的人口有關節炎（即四千 萬人）；並預測到2020 年將有6 千萬人口得到關節炎（3），WHO 宣佈2000-2010 為骨及關節年，肌肉關節疾病中又以自體免疫疾病造成關節炎最重要及明顯，類 風濕性關節炎經診斷5 年後，有一半的病人無法工作。這些疾病雖非十大死因之 一，但會造成個人，家庭及社會巨大之傷害及損失。 自體免疫疾病包括：類風濕關節炎、紅班性狼瘡、硬皮症等，至今其原因不 明，但最大特徵是病人會產生自體抗體對抗細胞內之蛋白質或酵素（4）而目前 認為自體免疫疾病之產生是自體抗原驅動造成，且是T 細胞Dependent 造成 （Antigen-driving and T cell dependent），故研究自體抗原之產生對自體免 疫疾病之產生具重要之意義。 最近apoptosis 在產生自體抗體及打破tolerence 佔重要之角色（5-8），本 計劃將從二方面來探討：1. apoptosis 及免疫細胞無法清除apoptosis 細胞對 自體抗原之影響；2. 蛋白質轉譯形成新抗原之機轉。而抗原之產生或隱性免疫 抗原決定點（immunocryptic epitope）之顯露是決定自體免疫反應之重要步 驟，這些自體抗原決定點（epitope）是受蛋白質構造，分子切割而改變；如在 apotosis 時引起抗原之改變，及conformation 改變而影響其免疫反應。蛋白質 修飾包括： phosphorylation, methylation, glycosylation, Acylation, Deamidation/citrullation, isoaspartyl 及Deimination（如附件1、2）。 本總計劃之目的就是要探討自體免疫疾病發生之機轉。將著重探討各種不同 的蛋白質修飾後產生之新抗原，及apoptosis 異常或清除障礙，而打破免疫系統 之tolerance 而產生自體抗體及自體免疫疾病之問題。 我們將整合中山免疫所所有老師及生命科學系李主任共同來探討自體免疫疾病 之致病機轉，尤其著重在蛋白質，轉譯後之修飾而產生新抗原，對自體免疫疾病 產生之影響，首先我們將建立自體免疫疾病中心，中心建立後提供各種子計劃所 需之材料及資源，本中心將包括1.收集病人檢體：含血清抗體，genomic DNA， 病人skin，synovium 及kidney 切片標本。2. MRL-lpr/lpr 及NZB/W mice 之繁 殖。3. 建立Keratirocyte-UV 照射導致apoptosis 之模式。子計劃包括：蔡嘉 哲教授將負責紅斑性狼瘡病人其transglutaminase II 蛋白質對apoptosis 之 影響，黃建寧助理教授及李宜儒助理教授Role of tissue transglutaminase in the clearance of apoptotic cells；劉光耀助理教授The pathogenesis of rheumatoid arthritis-the roles of peptidylarginine deiminase (PADI) enzymes in regulation of apoptosis and generation of new autoantigens； 陳孟琦助理教授The role of endoplasmic reticulum stress-mediated apoptosis in autoimmune diseases ； 李娟教授Proteomic analyses of methylarginine modification in autoimmune diseases 等，這些計劃完成後 將有助於本中心對自體免疫疾病之致病機轉有突破性的了解，進而對神秘的自體 免疫疾病之診斷及治療有所幫忙。Project