Molecular Mechanisms of HLA-DO in Antigen Processing

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MHC II类辅助蛋白HLA-DO的作用机制及其在免疫显性表位产生中的作用。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，包括另一个MHC II类分子HLA-DO，并将探索其对表位捕获和加工的贡献。目的1将探索HLA-DO如何与MHC II和HLA-DM相互作用的机制方面，从而导致肽结合的调节，并且在目的2中，我们将研究HLA-DO对来自全长蛋白质抗原的表位捕获和编辑以及免疫显性的贡献。对HLA-DO功能及其在抗原加工和免疫显性表位选择中的作用的清楚理解可以指导有效的免疫治疗剂的设计。 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）。本申请中概述的我们的研究解决了对调节抗原表位向免疫系统呈递的基本过程的理解。通过了解参与抗原加工的不同蛋白质如何参与这一系列复杂的反应，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。公共卫生

DESCRIPTION (provided by applicant): The project described in this application addresses a mechanistic study aimed at understanding the mechanism of action of MHC class II accessory protein, HLA-DO and its role 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 include another MHC class II molecules HLA-DO and would explore its contribution to epitope capture and processing. Aim 1 would explore mechanistic aspects of how HLA-DO interacts with MHC II and HLA-DM, leading to regulation of peptide binding, and in Aim 2 we would investigate contributions of HLA-DO to epitope capture and editing from full length protein antigens and immunodominance. A clear understanding of HLA-DO function and its role in antigen processing and the selection of immunodominant epitopes, 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 application addresses understanding of the fundamental processes that regulate presentation of antigenic epitopes to the immune system. By knowing how different proteins involved in antigen processing can participate in this complex series of reactions, investigators can design biologics that are intelligently based and therefore can be highly effective while avoiding nonspecific side effects. Public Health