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涉及旨在理解免疫显性表位生成所涉及步骤的机制研究。免疫优势是一种早已被认识到但至今仍不清楚的现象。众所周知，免疫系统集中于并响应于来自侵入性致病性损伤的非常少的代表性表位（称为免疫显性表位），所述侵入性致病性损伤的范围为例如感染剂和自身免疫性疾病、过敏症和癌症中的抗原靶标。在所有这些情况下，免疫系统对MHC分子背景下的抗原肽要么积极响应，要么不响应。我们对抗原呈递途径的理解的最新进展表明，抗原加工和选择的步骤严重影响呈递给T细胞的肽库。最近，我们已经取得了相当大的进展，在开发一个还原抗原处理系统的MHC II类分子，利用五个纯化的蛋白质组分的II类抗原呈递途径。值得注意的是，该系统产生了限制于HLA-DR 1的生理学相关的免疫显性表位。在这个提议中，我们将扩展这个MHC II系统到另一个MHC II类分子HLA-DR 4，并将探索表位捕获和抗原加工所涉及的步骤。总的来说，我们建议解剖T细胞免疫优势的潜在因素。目的1将探讨抗原捕获和加工之间的时间关系。在目标2中，我们将研究表位层次和DM的作用，在目标3中，我们将分析HLA-DO对表位捕获和编辑的贡献。因此，了解免疫显性表位的特性，以及清楚地了解它们在细胞内是如何产生的，可以指导有效的免疫治疗药物的设计。 公共卫生相关性：开发有效的疫苗和合理设计用于干预自身免疫性疾病或癌症的治疗剂依赖于对病原体上的关键区域或来自癌细胞或自身的蛋白质的良好了解，这些蛋白质可以被免疫系统靶向并且通常被称为抗原表位。免疫系统识别这些表位，并通过其细胞组分T细胞和B细胞产生特异性反应。特定的细胞被激活并对抗感染，然后可以保留病原体的记忆以备将来的攻击（记忆细胞）。我们的研究概述了这一建议解决的途径，生理相关的抗原表位的免疫系统选择的理解。我们在本申请中的假设是基于我们实验室开发的强大的新技术产生的强有力的初步数据。由于其独特的极简主义性质，它可以有效地剖析涉及抗原加工及其呈递给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的步骤，研究人员可以设计基于智能的生物制剂，因此可以非常有效，同时避免非特异性副作用。

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.