AUTOREACTIVITY TO AChR IN THE THYMUS OF MG PATIENTS

重症肌无力患者胸腺中 AChR 的自身反应性

基本信息

批准号：
6796790
负责人：
SONIA BERRIH-AKNIN
金额：
$ 12.5万
依托单位：
HOPITAL MARIE LANNELONGUE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-24 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6796790
关键词：
B lymphocyte T lymphocyte acetylcholine antireceptor antibody autoantibody cellular pathology clinical research human subject hyperplasia myasthenia gravis neurotransmitter receptor receptor expression thymus

项目摘要

DESCRIPTION:(provided by applicant): Autoreactivity to AChR in the thymus of MG patientsMyasthenia Gravis (MG) is a disease caused by anti-acetylcholine receptor (AChR) autoantibodies. The thymus is clearly involved in the pathogenesis of MG: 50 percent of patients show thymic hyperplasia and 15 to 20 percent a thymoma; thymectomy is an efficient treatment for many patients. Our hypothesis is that the onset of MG disease with thymic hyperplasia is due to a coincidence of several components: the presence of the autoantigen, predisposition genes (namely MHC and cytokine genes) and a triggering event. In this favorable genetic situation, the triggering event could induce over activation of the immune system. Since AChR is present in the thymus and is highly immunogenic, and could be over expressed after the activation of the immune system, it could be efficiently presented. These events would lead to the formation of germinal centers and to production of anti-AChR antibodies inside the thymus. The long-term objectives of this application are to devise new approaches for treating MG disease. We must first understand the mechanisms underlying the induction of the anti-AChR autoimmune response in the thymus of MG patients. The specific aims are to identify molecular and cellular components of the thymus that may be involved in inducing the anti-AChR autoimmune response and to create new models of thymic hyperplasia based on the data obtained. Several questions will be addressed: 1) Is the pattern of AChR expression normal in the thymic tissue of MG patients? Is AChR up regulated by mediators present in the thymus of MG patients? 2) Is the immune system dysregulated? Are the number and distribution of regulatory cells normal? 3) What are the phenotypic and functional characteristics of the autoreactive T cell clones isolated from the MG thymuses? 4) Where are the autoreactive B cells located in the thymus? and what are their frequencies? 5) What is the cascade of events leading to thymic hyperplasia? How to create an experimental model with thymic hyperplasia? The first 2 objectives will help to define the accurate state of the abnormalities in thymic hyperplasia; the objectives 3 and 4 will characterize the T and B cells involved in the pathogenesis and will be very helpful for defining new therapeutics. Finally if the components relevant for thymic hyperplasia are well defined, we should be able to create a new experimental model in which the pathophysiological role of these components will be directly evidenced and where the cascade of events leading to the thymic anti-AChR antibody production could be easily manipulated. Our project is original because we aim to study physiopathological mechanisms directly at the effector site using the relevant material. Patients with MG undergo thymectomy in our hospital. A large collection of pathological human tissue is available and represents an outstanding research material. Several methods will be used: quantitative autoradiography, quantitative RT-PCR, microarrays, transfection, digital image analysis, microdissection, flow cytometry, T cell clones, in situ hybridization, ELISA, alpha-bungarotoxin binding assays, SCID mice.

描述：（由申请人提供）：Mg胸腺中ACHR的自动反应性患者myasthenia gravis（mg）是由抗乙酰胆碱引起的疾病受体（ACHR）自身抗体。百里香显然参与了 MG的发病机理：50％的患者表现出胸腺增生和15至20 百分比胸腺瘤；胸腺切除术是许多患者的有效治疗方法。我们的假设是，胸膜增生的MG疾病的发作应归因于几个组成部分的巧合：自动抗原的存在，倾向基因（即MHC和细胞因子基因）和触发事件。在这种有利的遗传状况，触发事件可能会导致免疫系统的激活。由于athr存在于胸腺中，并且高度免疫原性，可以在激活后表达过度免疫系统，它可以有效地提出。这些事件将导致生发中心的形成和抗ACHR抗体的产生在胸腺内。此应用程序的长期目标是为治疗MG疾病。我们必须首先了解在MG患者百里香中诱导抗ACHR自身免疫反应。具体目的是确定分子和细胞成分可能参与诱导抗ACHR自身免疫反应的胸腺和根据获得的数据创建胸腺增生的新模型。一些问题将被解决： 1）是Mg的胸腺组织中AChR表达正常的模式患者？受到MG百里香中的介体的调节患者？ 2）免疫系统失调吗？是数量和分布调节细胞正常？ 3）自动反应性T的表型和功能特征是什么从MG胸腺分离出的细胞克隆？ 4）自动反应性B细胞位于胸腺中的哪里？他们是什么频率？ 5）导致胸腺增生的一系列级联反应是什么？如何创建具有胸腺增生的实验模型？前两个目标将有助于定义胸腺增生异常；目标3和4将表征与发病机理有关的T和B细胞将非常有帮助定义新的治疗剂。最后，如果组件与胸腺相关增生定义明确，我们应该能够创建一个新的实验性这些成分的病理生理作用将直接是直接的模型证明了导致胸腺抗ACHR的事件的级联抗体产生很容易被操纵。我们的项目是原始的，因为我们旨在研究生理病理学机制直接使用相关材料直接在效应点。毫克患者在我们医院进行胸腺切除术。大量的病理人组织可用，代表了出色的研究材料。一些将使用方法：定量自显影术，定量RT-PCR，微阵列，转染，数字图像分析，微分解，流量细胞仪，T细胞克隆，原位杂交，ELISA，α-bungarotoxin 结合测定，SCID小鼠。