DYSREGULATION OF THE IMMUNE SYSTEM IN AUTOIMMUNITY

本课程的目标是了解监管和监管失衡 自身免疫中的免疫系统。该计划涉及协作 三个部门成员之间的互动，并被组织为 三个核心设施支持的四个项目。该领域的专业知识 免疫学、分子生物学和生物化学的研究重点将放在喷口 启动和维持自身免疫反应，以及调节 流程。其中含有自身免疫力。我们将解决以下问题 问题。启动自身免疫反应的要求是什么？是 自体免疫反应是由什么机制调控的，如果是这样的话？免疫吗？ 在正常情况下，调节是否包含自身免疫反应？ 最后，持续的自身免疫反应是否仍然是慢性的，因为它们 从单一发起响应到对其他响应的多样性 来自同一组织的自身抗原？这些问题将通过以下方式解决 这些机构的首席调查人员之间的协作互动 项目，具体如下： (1)使用R.A.Flavell表达T细胞受体的转基因小鼠 针对髓鞘碱性蛋白和L基因靶向的小鼠- 选择素或E-和P-选择素，选择素在血管紧张素转换酶的形成中的作用 EAE将被确定。发展对选择素的要求 以及作为这一要求的基础的机制将 确定，重点关注必须表达L-选择素的细胞类型， 选择素在白细胞进入中枢神经系统中的作用 选择素在中枢神经系统中的潜在作用。 (2)C.A.Janeway Jr.-这个项目将调查以下四个方面 实验性变态反应性脑脊髓炎(EAE)的调节：为什么小鼠 缺乏B细胞不能完全解决他们的疾病；为什么 不能与其他受体形成细胞会导致自发性疾病 在小鼠中转基因识别髓鞘的TCR；为什么小鼠的细胞 与其他受体一起导致小鼠自发性疾病 识别髓鞘的TCR；为什么拥有相同受体的小鼠 杂合子对GLD得自发性疾病；而L的作用是什么？ 在EAE中选择，与项目1合作。 (3)M.J.Shlomchik转基因小鼠模型将用于研究 B细胞表达疾病相关自身抗体的调节， 类风湿因子(RF)，在正常和自身免疫小鼠中。与一些人形成对比的是 其他自身抗体模型，来自这些转基因的RF B细胞是有能力的 以启动免疫反应。因此，研究将集中在RF B细胞如何 在正常小鼠的Ag刺激后进行调节并在 自身免疫小鼠，以及是什么阻止了RF转基因的慢性自身免疫 老鼠。 (4)M.J.Mamula，Pi--这个项目将研究自体多肽的作用 在T细胞自身免疫的启动和持续过程中 系统性红斑狼疮(SLE)和多发性硬化(EAE)模型。 B细胞作为自身抗原在系统性红斑狼疮模型中的作用 红斑狼疮(SLE)和多发性硬化症(EAE)。B细胞在人类免疫系统中的作用 自身抗原提呈细胞将与机制相关地进行检查 导致自身免疫中的表位扩散。最后，这项工作将 研究一种新的翻译后多肽修饰 天然存在于细胞中，并对自身多肽具有免疫力。 这四个项目将得到一个行政核心的支持，以 作为一个整体协调项目，一个转基因小鼠核心 提供基因靶向和转基因啮齿动物对其中大多数必不可少 研究，和FACS核心，使我们能够分离细胞进行分析和 来分析所有这些项目中的细胞。该计划由以下人员协调 项目教职员工的频繁会议将这些不同的 解决共同目标的方法。

The goal of this program is to understand the regulation and dysregulation of the immune system in autoimmunity. The program involves collaborative interaction 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 vents 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 diversity 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- Using transgenic mice expressing a T cell receptor specific for myelin basic protein (MPB) and gene targeted mice lacing L- selectin or E- and P-selectin, the role of selectins in the development of EAE will be determined. The requirement of selectins for the development of disease, as well as the mechanisms which underlie this requirement will be determined, focusing on the cell types which must express L-selectin, the role of selectins in the entry of leukocytes into the CNS and the potential role of selectins within the CNS. (2) C.A. Janeway Jr.- This project will investigate four aspects of the regulation of experimental allergic encephalomyelitis (EAE): Why are mice lacking B cells unable to fully resolve their disease; why does the inability to form cells with other receptors lead to spontaneous disease in mice transgenic for a TCR that recognizes myelin; why do mice cells with other receptors lead to spontaneous disease in mice transgenic for a TCR that recognizes myelin; why do mice with the same receptor who are heterozygous for gld get spontaneous disease; and what is the role of L- selectin in EAE, in collaboration with project 1. (3) M.J. Shlomchik- 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 these transgenics are competent to initiate an immune response. Thus, studies will focus on how RF B cells are regulated after Ag stimulation in normal mice and propagated in autoimmune mice, 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 Band T cell autoimmunity in models of systemic lupus erythematosus (SLE) and multiple sclerosis (EAE). The role of B cells as autoantigen in models of systemic lupus erythematosus (SLE) and multiple sclerosis (EAE). The role of B cells as autoantigen presenting cells will be examined with relevance to mechanisms that lead to epitope spreading in autoimmunity. Finally, this work will study a novel post-translational peptide modification that arises naturally in cells and confers immunity to self peptides. These four projects will be supported by an administrative core to coordinate the project as a whole, 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 faculty bringing together these diverse approaches to address a common goal.