DIS/REGULATION OF THE IMMUNE SYSTEM IN AUTOIMMUNITY

该计划的目标是了解法规， 自身免疫中免疫系统的失调。 该方案涉及 三个部门成员之间的协作互动，是 由三个核心设施支持的四个项目组成。 免疫学、分子生物学和生物化学领域的专业知识 将重点关注引发和维持自身免疫反应的事件， 以及包含自身免疫的调节过程。 我们将解决 以下问题？ 发起的要求是什么 自身免疫反应 自身免疫反应是否受到调节，如果是， 什么机制？ 免疫调节是否包含自身免疫反应 在正常情况下？ 最后，持续的自身免疫反应 因为它们从单一的初始反应多样化， 对来自同一组织的其他自身抗原的反应 这些问题 将通过校长之间的合作互动来解决 这些项目的调查人员如下： (1)R.A. Flavell，PI -使用表达SV 40-T抗原的转基因小鼠 以及T细胞受体转基因小鼠， 识别抗原，在这个系统中导致自身免疫的机制 将被确定，以及调节自身免疫的机制， 反应 SV 40-T免疫应答多样化的作用 将研究其他腺泡抗原的抗原。 (2)C. A.小珍妮薇PI -该项目将测试假设， 调节自身免疫T细胞可以防止单克隆T细胞攻击 但无法遏制多克隆攻击 它还将测试 假设自身免疫性T细胞反应通过以下方式多样化： 自身反应性B细胞募集新的T细胞的作用 响应的特殊性。 最后，它将描述 监管和多样化在发电方面的相互作用 自身免疫 (3)M. J. Shlomchik，PI -转基因小鼠模型将用于研究 表达疾病相关自身抗体的B细胞的调节， 类风湿因子（RF），在正常和自身免疫小鼠。 相比 一些其他的自身抗体模型，来自第一系列的RF B细胞， 转基因生物似乎有能力引发免疫反应。 因此，在本发明中， 研究将集中在为什么RF B细胞逃避耐受性和什么阻止 RF转基因小鼠的慢性自身免疫。 (4)M. J. Mamula，PI -这个项目将研究自我的作用 肽在B和T细胞启动和延续中的作用 系统性红斑狼疮（SLE）模型中的自身免疫。 自身反应性T细胞将被研究其良好的特异性， 自发性和抗原诱导性自身免疫中的SLE自身抗原。 最后，我们将研究自身免疫如何从单一的 启动自身抗原上其他位点的决定簇;一种机制， 可能会加剧狼疮自身免疫。 这四个项目将由一种转基因小鼠支持 核心是提供基因靶向和转基因啮齿动物所必需的大多数 和一个流式细胞仪核心，让我们能够分离细胞， 分析和分析所有这些项目中的细胞。 该计划是 通过频繁的项目设施会议进行协调， 将这些不同的方法结合起来，以实现一个共同的目标。

The goal of this program is to understand the regulation and disregulation of the immune system in autoimmunity. The program involves collaborative interactions between members of three Departments, and is organized into four projects supported by three Core facilities. Expertise in the field of immunology, molecular biology, and biochemistry will focus on the events that initiate and sustain autoimmune responses, and the regulatory processes which contain autoimmunity. We will address the following questions? What are the requirements to initiate autoimmune responses? Are autoimmune responses regulated, and if so, by what mechanisms? Does immune regulation contain autoimmune responses under normal circumstances? Finally, do sustained autoimmune responses remain chronic because they diversify from a single initiating response to responses to other autoantigens from the same tissue? These questions will be addressed by collaborative interactions between the Principal Investigators of these projects, which are as follows: (1) R.A. Flavell, PI - Using transgenic mice expressing SV40-T antigen in the acinar pancreas, and T cell receptor transgenic mice which recognize antigen, mechanisms that lead to autoimmunity in this system will be determined, as well as mechanisms which regulate that autoimmune response. The role of diversification of the immune response from SV40-T antigen to other acinar antigens will be investigated. (2) C. A. Janeway, Jr. PI - This project will test the hypothesis that regulation of autoimmune T cells can prevent a monoclonal T cell attack on tissues, but cannot contain a polyclonal attack. It will also test the hypothesis that the autoimmune T cells response diversifies through the action of autoreactive B cells that recruit T cells of novel specificities to the response. Finally, it will characterize the interplay between regulation and diversification in generating autoimmunity. (3) M. J. Shlomchik, PI - Transgenic mouse models will be used to study the regulation of B cells expressing a disease-related autoantibody, rheumatoid factor (RF), in normal and autoimmune mice. In contrast to some other autoantibody models, RF B cells from the first series of transgenics appear competent to initiate an immune response. Thus, studies will focus on why RF B cell escape tolerance and what prevents chronic autoimmunity in RF transgenic mice. (4) M. J. Mamula, PI - This project will examine the role of self peptides in the initiation and perpetuation of both B and T cell autoimmunity in models of systemic lupus erythematosus (SLE). Autoreactive T cells will be investigated for their fine specificity to SLE autoantigens in spontaneous and antigen-induced autoimmunity. Finally, we will study how autoimmunity may diversify from a single initiating determinant to other sites on autoantigens; a mechanism that may exacerbate lupus autoimmunity. These four projects will be supported by a genetically modified mouse core to provide gene targeted and transgenic rodents essential to most of these studies, and a FACS core, to allow us to separate cells for analysis and to analyze cells in all of these projects. The program is coordinated by frequent meetings of the program facility bringing together these diverse approaches to address a common goal.