Class II MHC Allele-Specific Signaling: A New Paradigm in Disease Pathogenesis

描述（由申请人提供）：许多疾病，无论是免疫介导的还是非免疫的，都与主要组织相容性复合体（MHC）的特定等位基因密切相关。这种关联背后的机制目前尚不清楚。现有的范式在三十多年前就已经被理论化了，但至今仍未得到证实。因此，我们对关系到数百万人健康的基本生物机制的理解与现代科学概念脱节。这里提出的建议将检验一个基于现有证据制定的新假设。本文提出的基本假设是II类mhc编码蛋白编码信号转导配体，这些配体与其他细胞上的细胞表面受体相互作用并触发信号传导事件。在某些情况下，这种相互作用可能引发异常的细胞事件，可能导致疾病的发展，或导致此类疾病的严重程度。这里将研究的模型系统涉及最近发现的配体，该配体由某些HLA-DRB1等位基因编码，并在与细胞表面受体（已被确定为钙网蛋白（CRT））接触时触发细胞中的氧化应激。为了验证潜在的假设，将在体外和体内研究这种配体-受体相互作用对动脉粥样硬化（AS）严重程度的潜在贡献。在体外实验中，内皮细胞培养物将用配体或其控制试剂处理，并将研究表型和功能性动脉粥样硬化后果。体内实验将包括确定表达mhc编码配体的转基因小鼠的加速AS特征。CRT的作用将通过有条件地删除其编码基因或敲入突变基因来研究。拟议的研究可以引入一种范式转变，从而提高我们的知识，这反过来又可以帮助设计更好的治疗许多疾病的方法。公共卫生相关性：这里提出的研究将检验一个新的假设，可以为许多疾病的机制提供新的见解。它是基于最近的发现，表明某些蛋白质，被称为“主要组织相容性复合体”的基因编码，激活血管内侧细胞的氧化应激。这一发现可以解释许多疾病的发病机制，包括动脉粥样硬化，这是美国致残和死亡的主要原因。

DESCRIPTION (provided by applicant): Many diseases, both immune-mediated and non-immune, demonstrate strong association with particular alleles of the major histocompatibility complex (MHC). The mechanism underlying such associations is presently unknown. The existing paradigm, which had been theorized more than three decades ago, remains largely unverified to this day. As a result, our understanding of a fundamental biologic mechanism, which pertains to the health of millions, is out of step with modern scientific concepts. The proposal presented here will examine a new hypothesis, formulated based on current evidence. The underlying hypothesis proposed here is that class II MHC-encoded proteins encode signal transduction ligands that interact with cell surface receptors on other cells and trigger signaling events. Under certain circumstances, such interactions could provoke aberrant cellular events that may contribute to disease development, or to the severity of such diseases. The model system that will be studied here involves a recently discovered ligand encoded by certain HLA-DRB1 alleles and triggers oxidative stress in cells upon contact with a cell surface receptor that had been identified as calreticulin (CRT). In order to verify the underlying hypothesis, the potential contribution of this ligand-receptor interaction to the severity of atherosclerosis (AS) will be studied both in vitro and in vivo. For in vitro experiments, endothelial cell cultures will be treated with the ligand or its control reagents and the phenotypic and functional atherogenic consequences will be studied. The in vivo experiments will involve determination of accelerated AS features in transgenic mice expressing the MHC-encoded ligand. The role of CRT will be studied by conditional deletion of its encoding gene, or by knocking-in a mutated gene. The proposed research could introduce a paradigm shift thereby improve our knowledge, which in turn could help to design better therapies for many diseases. PUBLIC HEALTH RELEVANCE: The research proposed here will examine a novel hypothesis that could provide new insight into the mechanism of many diseases. It is based on recent findings, showing that certain proteins, coded by genes called the "major histocompatibility complex", activate oxidative stress in cells that line the inner side of blood vessels. The findings could explain the mechanism of many diseases, including atherosclerosis, a major cause of disability and death in the US.