Role of DM in Generation of Immunodominant Epitope(s)

描述(由申请人提供)：本申请中描述的项目解决了一项旨在了解免疫优势表位产生过程中涉及的步骤的机制研究。免疫优势是一种早已被认识到的现象，但到目前为止仍不清楚。众所周知，免疫系统关注的是极少数具有代表性的表位(称为免疫优势表位)，这些表位来自侵袭性致病物质，包括自身免疫性疾病、过敏和癌症中的抗原靶标。在所有这些情况下，免疫系统要么对MHC分子背景下的抗原肽做出积极反应，要么没有反应。最近我们对抗原呈递途径的了解进展表明，抗原处理和选择的步骤对呈递给T细胞的多肽库有重要影响。最近，我们在开发一种针对MHC II类分子的还原抗原处理系统方面取得了相当大的进展，该系统利用了II类抗原提呈途径的五个纯化蛋白成分。值得注意的是，这个系统产生了生理上相关的免疫优势表位，仅限于人类白细胞抗原-DR1。在这项提案中，我们将把这个MHC II系统扩展到另一个MHC II类分子人类白细胞抗原-DR4，并探索涉及表位捕获和抗原处理的步骤。总体而言，我们建议剖析T细胞免疫优势的潜在因素。目的1探索抗原捕获和加工之间的时间关系。在目标2中，我们将研究表位层级及其在DM中的作用，在目标3中，我们将分析HLA-DO在表位捕获和编辑中的贡献。因此，了解免疫优势表位的特性，以及清楚地了解它们是如何在细胞内产生的，可以指导有效的免疫疗法的设计。 公共卫生相关性：开发有效的疫苗和合理设计干预自身免疫性疾病或癌症的治疗方法，依赖于对病原体关键区域的良好了解，或来自癌细胞或自身的可被免疫系统靶向的蛋白质，通常被称为抗原表位。免疫系统识别这些表位，并通过其细胞成分T细胞和B细胞产生特定的反应。特定的细胞被激活并与感染作斗争，然后可以保留病原体的记忆以备将来的攻击(记忆细胞)。我们在这项提案中概述的研究旨在了解免疫系统选择生理上相关的抗原表位的途径。我们在这一应用中的假设是基于我们实验室开发的一项强大的新技术产生的强大的初步数据。由于其独特的极简主义性质，它可以有效地剖析处理抗原及其呈递给T细胞的步骤。我们相信，我们的发现将改变我们目前对抗原表位选择的看法。通过了解免疫表位捕获及其处理所涉及的步骤，研究人员可以设计基于智能的生物制剂，因此可以在避免非特异性副作用的同时高效。

DESCRIPTION (provided by applicant): The project described in this application addresses a mechanistic study aimed at understanding the steps involved in generation of immunodominant epitopes. Immunodominance is a phenomenon that has long been recognized but yet remains unclear to date. It is well known that the immune system focuses on and responds to very few representative epitopes (referred to as immunodominant epitopes) from invading pathogenic insults ranging from such as infectious agents and, antigenic targets in autoimmune diseases, allergy, and cancer. In each all these cases, the immune system either responds positively or fails to respond to antigenic peptides in the context of MHC molecules. Recent advances in our understanding of the antigen presentation pathway have shown that the steps of antigen processing and selection critically influence the peptide repertoire presented to T-cells. Recently, we have made considerable progress in developing a reductionist antigen processing system for MHC class II molecules that utilizes five purified protein components of the class II antigen presentation pathway. Notably, this system yielded physiologically relevant immunodominant epitopes restricted to HLA-DR1. In this proposal, we will extend this MHC II system to another MHC class II molecules HLA-DR4 and would explore steps involved in epitope capture and antigen processing. Overall, we propose to dissect underlying factors of T-cell immunodominance. Aim 1 would explore the temporal relationship between antigen capture and processing. In Aim 2, we would investigate epitope hierarchy and the role for DM, and in Aim 3, we would analyze contributions of HLA-DO to epitope capture and editing. Hence, knowledge of the identity of immunodominant epitopes, and a clear understanding of how they are generated inside cells, can guide the design of effective immunotherapeutics. PUBLIC HEALTH RELEVANCE: Development of effective vaccines and rational design of therapeutics for intervention in autoimmune diseases or cancer rely on good knowledge of key regions on a pathogen, or proteins from cancer cells or self that can be targeted by the immune system and are generally called antigenic epitopes. The immune system recognizes these epitopes and mounts specific responses through its cellular components, T cells and B cells. The specific cells become activated and fight the infection and then can retain the memory of the pathogen for future attacks (memory cells). Our study outlined in this proposal addresses understanding of the pathways that physiologically relevant antigenic epitopes are selected by the immune system. Our hypothesis in this application is based on strong preliminary data generated by a robust novel technology developed by our laboratory. Because of its unique minimalist nature, it can efficiently dissect steps involved in processing of antigens and their presentation to the T cells. We believe that our findings would change our current view on selection of antigenic epitopes. By knowing steps involved in immune epitope capture and its processing, investigators can design biologics that are intelligently based and therefore can be highly effective while avoiding nonspecific side effects.