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一项机制研究，旨在了解免疫显性表位产生的步骤。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，免疫系统关注并响应入侵致病性损伤的极少数具有代表性的表位（称为免疫显性表位），包括感染性病原体和自身免疫性疾病、过敏和癌症中的抗原靶点。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有积极反应，要么没有反应。抗原递呈途径的最新进展表明，抗原加工和选择的步骤对递呈给t细胞的肽库有重要影响。最近，我们在开发MHC II类分子的还原剂抗原处理系统方面取得了相当大的进展，该系统利用了II类抗原递呈途径的五种纯化蛋白组分。值得注意的是，该系统产生了限制于HLA-DR1的生理相关免疫显性表位。在本提案中，我们将把MHC II系统扩展到另一个MHC II类分子HLA-DR4，并将探索涉及表位捕获和抗原加工的步骤。总之，我们建议剖析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Aim 2中，我们将研究表位结构和DM的作用，在Aim 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身份，并清楚地了解它们是如何在细胞内产生的，可以指导设计有效的免疫疗法。

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.