第二型轉麩胺脢和自體免疫疾病之研究

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Title:	第二型轉麩胺脢和自體免疫疾病之研究 The Study of Relationship between Transglutaminase 2 (Tg2) and Autoimmune Disease
Authors:	蔡嘉哲;劉光耀
Contributors:	中山醫學大學：微生物免疫研究所
Date:	2010
Issue Date:	2011-07-01T03:31:56Z (UTC)
Abstract:	第二型轉麩胺?（TG2）是一多功能之蛋白，可促進蛋白之修飾（Protein modification），在細胞膜內（transmembrane signaling）有G 蛋白之功能及促進細胞及細胞基質之作用（cell-matrix interaction），TG2 與自體免疫疾病之產生有密切關係，老鼠如把TG2 去除（TG2-/-）會產生脾臟腫大、自體抗體、腎炎等像紅斑性狼瘡之症狀，此外，TG2 有擔任細胞凋亡及清除凋亡細胞之角色。細胞凋亡及清除凋亡細胞不正常會導致死亡細胞在體內之堆積而產生自體免疫疾病，而TG2 本身亦是一種自體抗原與產生Celiac病有關，故本研究將建立TG2 基因轉染(Transfection)並挑選永久轉染的T細胞Jurkat cell 細胞株，研究TG2 大量表現時細胞內之訊息及細胞凋亡之變化，包括粒線體膜電位、Ca2+及G 蛋白之變化，我們也將探討TG2 大量表現時細胞是否會產生新的抗原及細胞激素（cytokines）之改變。另外，也將研究Celiac 病之抗體包括anti-TG2 及endomysial 抗體，並測各種免疫疾病病人之Celiac病相關抗體。最後，我們將探討乾燥症（Sjogren syndrome）有否與TG2 及 muscarine receptor之抗體有關，Sjogren syndrome被發現有anti-muscarine receptor 3 (M3R)抗體而引起乾燥，我們將探討以Sjogren syndrome病人之唾液腺做免疫組織化學染色證明是否有TG2 及M3R 之表現，以具M3R 之細胞株A253 及Caco2 來研究M3R 並以Carbachol（MR 刺激劑）及TG2 之抑制來研究Ca2+之變化，並以anti-centromere抗體（ACA）及anti-SS-A/Ro 及anti-AA-B/La 抗體來研究是否有抗M3R 之作用，此將可證明我們過去觀察Sjogren syndrome 病人含有ACA 抗體卻沒有 anti-SS-A/Ro 及anti-AA-B/La之現象。三年計畫如下第一年：建立永久的TG2 Transfected 之Jurkat cell line及研究其特性第二年：延續第一年之細胞，建立凋亡機轉、活性及G蛋白機能等，並研究TG2-Transfected T cell 之細胞激素及以2-D研究新抗原第三年：研究TG2 及臨床疾病關係，包括Celiac 病、乾燥症之muscarine receptor 3 抗體及 anti-centromere抗體之關係及影響G蛋白及Ca2+之特性. Transglutaminase 2 (TG2) is a multifunctional protein, which catalyzes Ca2+-dependent protein modifications, acts as a G protein in transmembrane signaling and as a cell surface adhesion mediator. It has been implicated that TG2 might play a role in apoptotic cell death, as well as in the in vivo clearance of the apoptotic cells. The striking feather is the development of lupus-like syndrome including splenomegaly, autoantibodies, and immune complex glomerulonephritis in TG2 knock-out mice. The clearance of apoptoctic cells is also defective in these mice. In recent years, evidence has accumulated that the autoimmune response can be initiated as a result of defects in apoptosis and/or removal of apoptotic cells. In addition, TG2 plays a role in celiac disease, which is chearacterized by high levels of anti-TG2 antibodies. The study will establish a permanent TG2-transfected Jurkay cell line for the study over-expression of TG2 in T cells, the role of TG2 in Celiac diseases, the neoantigens with over-expression of TG2, and G-protein function in relating to muscarine receptor 3 antibody in Sjogren’s syndrome. Recently we have observed that some patients with Sjogren’s syndrome have anticentromere antibody, but never have anti-SSA/Ro and/or anti-SS-B/Lo antibodies. Anticentromere antibody may play a role in inducing Sjogren’s Syndrome. The first year Over-expression of TG2 in Jurkat T cells and establish a permanent TG2-transfected T cell line for the study of apoptosis, and G-protein function. The second year Continue to characterize the TG2-transfected cell lines and look for neoantigens and cytokines production with the over-expression of TG2 cell lines The third year 1、The relationship of Celiac Disease and TG2 2、Anti-TG2 autoantibody in patients with autoimmune diseases 3、M3R and TG2 and anticentromere antibody in Sjogren’s syndrome It have been reported that anti-muscarinic receptor 3 autoantibody exist in patients of primary sjogren’s syndrome. The antibody target to muscarinic receptor 3, and block the neurotransmitter stimulation. There have a antagonist effect on cytosolic calcium flux, resulting in reduced secretion of salivary and lacrimal gland. On the other hand, it have been reported that transglutaminase 2 (TG2) has GTPase activity and has been shown to be involved in intracellular signal transduction, so we would like to examine whether TG2 act as G protein involved in cytosolic calcium induction in sjogren’s syndrome. We first observed the expression of TG2 and muscarinic receptor 3 by immunofluorescence or immunohistochemistry. Next, we will examine the cytosolic calcium via muscarinic receptor 3 stimulation after inhibiting the GTPase activity of TG2.
URI:	https://ir.csmu.edu.tw:8080/ir/handle/310902500/3988
Appears in Collections:	[免疫學研究所] 研究計劃

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