Tolerance to the Nuclear Antigen La

描述（由申请人提供）：正常机制的基本知识 免疫耐受和自身反应性T细胞识别的决定因素 在导致自身免疫的免疫事件之前， 被理解关于对膜的免疫耐受性已经了解了很多， 分泌抗原，主要是通过使用转基因技术，但 对蛋白质耐受的正常机制的认识存在空白 细胞核的抗原。然而，大多数自身抗原，如La/SS-B， 针对系统性自身免疫性疾病干燥综合征？s综合征和全身 红斑狼疮由蛋白质组成，定位于细胞核。在 为了理解对核抗原的耐受性和自身免疫性， 因此，必须将核抗原作为一个特殊类别进行研究， 抗原。这项研究将确定T细胞耐受的机制， 使用自身抗原La作为范例的系统性抗核自身免疫， 细胞核的蛋白质自身抗原。 使用K02独立调查员奖机制，候选人寻求 获得受保护的研究时间，以扩大现有的资助工作，了解 对临床重要核抗原的耐受性和自身免疫性， 决定人类La（hLa）neo-self中枢耐受性的机制 hLa转基因（Tg+）小鼠中的抗原。此外，申请人？之权益 细胞凋亡碎片可能具有免疫原性或耐受性的假设 核抗原将与受资助的ROl工作合并（主要在 本申请）以确定胸腺中的细胞凋亡是否 影响对hLa新自身抗原的中枢耐受性。这些新 计划将利用同事和合作者的专业知识 琳达汤普森，一个受人尊敬的T细胞发育生物学家，谁将扮演一个 在促进候选人的职业发展方面发挥重要作用， 个人和专业的互动。候选人将从 机构的行政职责，过多的授权书撰写职责， 以及过多的教学任务，以便职业发展计划采取 地方 在剩下的工作中，外周耐受La核的机制， 抗原将通过追踪hLa特异性供体T细胞的命运来确定 在携带或缺乏hLa转基因的受体小鼠的外周中。 hLa Tg+（耐受性）和hLa Tg-（非耐受性）T细胞的共转移将被实施。 进行，以确定抑制是否是对La的耐受模式 核抗原最后，T细胞识别 免疫显性和亚显性决定因素在启动耐受性或 对La核抗原的自身免疫将通过确定是否 它们可以引发能够为抗La自身抗体的产生提供帮助的T细胞。

DESCRIPTION (provided by applicant): A primary knowledge of normal mechanisms of immune tolerance and the kind of determinants recognized by autoreactive T cells are required before the immunological events leading to autoimmunity may be understood. Much has been learned about immune tolerance to membrane and secreted antigens, largely through the use of transgenic technology, but there is a gap in knowledge regarding normal mechanisms of tolerance to protein antigens of the nucleus. Yet, the majority of autoantigens, like La/SS-B, targeted in the systemic autoimmune diseases Sjogren?s syndrome and systemic lupus erythematosus are composed of protein and localize to the nucleus. In order for tolerance and autoimmunity to nuclear antigens to be comprehended, it is therefore imperative that nuclear antigens be studied as a special class of antigen. This study will determine mechanisms of T cell tolerance in systemic anti-nuclear autoimmunity using the autoantigen La as a paradigm for protein autoantigens of the nucleus. Using the K02 Independent Investigator Award mechanism, the candidate seeks to obtain protected research time to expand existing funded work on understanding tolerance and autoimmunity to a clinically important nuclear antigen by determining mechanisms of central tolerance to the human La (hLa) neo-self antigen in hLa transgenic (Tg+) mice. Furthermore, the applicant?s interest in the hypothesis that apoptotic debris may be immunogenic or tolerogenic for nuclear antigens will be merged with the funded ROl work (largely presented in the present application) to determine whether apoptosis in the thymus influences central tolerance to the hLa neo-self antigen. These new initiatives will take advantage of the expertise of colleague and collaborator Linda Thompson, a respected T cell developmental biologist, who will play a significant role in facilitating the candidate's career development through personal and professional interactions. The candidate will be freed from institutional administrative duties, excessive grant writing responsibilities, and excessive teaching duties in order for the career development plan to take place. In the remaining work, mechanisms of peripheral tolerance to the La nuclear antigen will be determined by tracking the fate of hLa specific donor T cells in the periphery of recipient mice that either bear or lack the hLa transgene. Co-transfer of hLa Tg+ (tolerant) and hLa Tg- (non-tolerant) T cells will be conducted to determine whether suppression is a mode of tolerance to the La nuclear antigen. Finally, the relative roles of T cells recognizing immunodominant and subdominant determinants in initiating tolerance or autoimmunity to the La nuclear antigen will be resolved by determining whether they can prime T cells capable of providing help for the production of anti-La autoantibodies.