DYSREGULATION OF THE IMMUNE SYSTEM IN AUTOIMMUNITY

这个项目的目标是了解调节和失调 自身免疫中的免疫系统。该计划涉及协作 三个部门的成员之间的互动，并组织成 四个项目由三个核心设施支持。领域的专门知识 免疫学、分子生物学和生物化学的专家将集中研究 启动和维持自身免疫反应， 流程.含有自身免疫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 自身免疫反应的调节，如果是这样，通过什么机制？是否免疫 正常情况下是否存在自身免疫反应？ 最后，持续的自身免疫反应是否仍然是慢性的， 从单一的启动反应到对其他反应的多样性 来自同一组织的自身抗原这些问题将通过以下方式解决： 这些主要研究者之间的合作互动 这些项目如下： （1）R.A. Flavell-使用表达T细胞受体的转基因小鼠 特异性髓鞘碱性蛋白（MPB）和基因靶向小鼠lacing L- 选择素或E-和P-选择素，选择素在发展中的作用， 将确定EAE。发展对选材要求 疾病，以及作为这一要求基础的机制将 确定，重点是必须表达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CNS中的潜在作用。 (2)C.A.小珍妮薇本项目将从四个方面进行研究， 调节实验性过敏性脑脊髓炎（EAE）：为什么小鼠 缺乏B细胞无法完全解决他们的疾病;为什么 不能与其他受体形成细胞导致自发性疾病 在识别髓鞘的TCR转基因小鼠中;为什么小鼠细胞 与其他受体导致自发性疾病的转基因小鼠， 识别髓鞘的TCR;为什么具有相同受体的小鼠 gld杂合子得到自发性疾病;和什么是L-的作用 选择素在EAE中，与项目1合作。 (3)M. J. Shlomchik-转基因小鼠模型将用于研究 调节表达疾病相关自身抗体的B细胞， 类风湿因子（RF），在正常和自身免疫小鼠。不同于某些 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 启动免疫反应因此，研究将集中在RF B细胞如何 在正常小鼠中Ag刺激后受到调节，并在 自身免疫性小鼠，以及如何预防RF转基因小鼠的慢性自身免疫性 小鼠 (4)M. J. Mamula，PI-该项目将研究自我肽的作用 在带状T细胞自身免疫的启动和持续中， 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狼疮模型中的作用 红斑狼疮（SLE）和多发性硬化症（EAE）。B细胞作为 自身抗原提呈细胞将与机制的相关性进行检查 导致自身免疫中表位扩散。最后，这项工作将 研究一种新的翻译后肽修饰， 天然存在于细胞中并赋予自身肽免疫力。 这四个项目将得到一个行政核心的支持， 协调整个项目，一个转基因小鼠核心， 提供基因靶向和转基因啮齿动物所必需的大多数这些 研究，和一个流式细胞仪核心，使我们能够分离细胞进行分析， 来分析所有这些项目中的细胞。该计划由以下机构协调： 该计划的教师经常会议汇集这些不同的 为实现共同目标而努力。

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.