Project 3: Epitope Selection in Type 1 Diabetes

项目摘要/摘要-项目3 1型糖尿病(T1D)是一种严重的自身免疫性疾病，其发病率一直在稳步上升 近几年来不断增加。它是由于患者的T细胞对胰腺的免疫攻击所致 这选择性地消除了驻留在胰岛器官中的产生胰岛素的β细胞 朗格汉斯终于来了。患T1D的风险既与环境因素有关，也与遗传因素有关。 主要的遗传因素与编码第II类分子的基因的多态有关 主要组织相容性基因复合体(MHCII)。 MHCII分子的通常功能通常是捕获来自于 外源蛋白呈递和激活CD4+T细胞，以指导这些细胞击退 感染。由于MHCII分子也可以捕获和呈现来自宿主自己的多肽 蛋白质，免疫系统已经发展出一种精心设计的两阶段机制来预防这些 自体多肽在组织上诱导针对宿主的自身免疫反应。第一阶段 包括在胸腺发育早期对胸腺中的CD4+T细胞进行预检查，以消除其 抗原识别受体(TCR)可以与含有自体肽的MHCII分子结合。这个 第二阶段涉及外周器官中一组调节性T细胞，以处理具有 不知何故逃过了胸腺预检。然而，在适当的条件下，一些CD4+T细胞 特定于来自胰岛蛋白的某些多肽偷偷通过这两个过滤器 导致T1D。项目3的主要目标是确定为什么T细胞特定于某些 胸腺中的胰多肽被删除，而其他的则不是，看看这一信息是否可以 用来增强外周调节性T细胞，以防止逃犯的激活。 在项目3中，我们的主要假设是，胸腺逃逸的人识别出在胸腺中结合较差的肽 将胸腺转移到相关的MHCII危险等位基因，从而突破胸腺的第一滤器。我们 将通过改变胸腺中各种胰多肽的表达来检验这一假说 这对这些特异性的CD4+T细胞的出现有什么影响。我们还将测试 通过改造相关的肽来更好地与MHCII风险等位基因结合，我们可以创建一种 “超级激动剂”，可用于清除致病T细胞或增强外周血细胞的活性 调节T细胞，以防止致病T细胞的激活。

Project Summary/Abstract – Project 3 Type-1 diabetes (T1D) is a serious autoimmune disease, whose incidence has been steadily increasing in recent years. It results from an immune attack on the pancreas by the patients T cells that selectively eliminates the insulin-producing beta cells that reside in the organs Islets of Langerhans eventually. The risk of developing T1D is tied to both environmental and genetic factors. The main genetic factor is tied to the polymorphisms in the genes encoding Class II molecules within the major histocompatibility gene complex (MHCII). The usual function of MHCII molecules is usually to capture antigenic peptides derived from foreign proteins for presentation to and activation of CD4+ T cells in order direct these cells fight off infections. Since MHCII molecules can also capture and present peptides derived the host's own protein, the immune system has developed an elaborate two stage mechanism for preventing these self-peptides from inducing an autoimmune response against the hosts on tissues. The first stage involves a pre-check of CD4+ T cells in the thymus early in their development eliminating T cell whose antigen recognizing receptor (TCR) can engage an MHCII molecule containing a self-peptide. The second stage involves a set of regulatory T cells in the peripheral organs to deal with T cells that have somehow escaped the thymic pre-check. However, under the right conditions some of CD4+ T cells specific for certain peptides derived from pancreatic islet proteins sneak through both of these filters to cause T1D. The main objective of Project 3 is to determine why the T cells specific some pancreatic peptides are deleted in the thymus, while others are not, and to see if this information can be used to beef up the peripheral regulatory T cells to prevent the activation of the escapees. In Project 3 our main hypothesis is that the thymic escapees recognize peptides that bind poorly in the thymus to the relevant MHCII risk alleles and therefore break through the thymic first filter. We will test this hypothesis by altering the expression of various pancreatic peptides in the thymus to see what effect this has on the appearance of CD4+ T cells of those specificities. We will also test the idea that by engineering the relevant peptide to bind better to the MHCII risk alleles we can create a “super agonist” that can be used to delete pathogenic T cells or to boost the activity of the peripheral regulatory T cells to prevent the activation of the pathogenic ones.