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，都表现出与主要组织相容性复合体(MHC)的特定等位基因密切相关。这种联系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形成了理论，直到今天在很大程度上仍然没有得到证实。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格格不入。这里提出的建议将检验一个新的假说，该假说是基于现有证据提出的。这里提出的基本假设是，第二类MHC编码的蛋白质编码信号转导配体，与其他细胞上的细胞表面受体相互作用，并触发信号事件。在某些情况下，这种相互作用可能引发异常的细胞事件，这可能有助于疾病的发展，或导致此类疾病的严重程度。将在这里研究的模型系统涉及最近发现的由某些HLA-DRB1等位基因编码的配体，并在与被鉴定为钙网蛋白(CRT)的细胞表面受体接触时触发细胞内的氧化应激。为了验证这一基本假设，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。对于体外实验，内皮细胞培养将与配体或其对照试剂处理，并将研究表型和功能导致动脉粥样硬化的后果。体内实验将包括在表达MHC编码配体的转基因小鼠中确定加速AS的特征。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。这项拟议的研究可能会带来范式的转变，从而提高我们的知识，进而有助于为许多疾病设计更好的治疗方法。与公共卫生相关：这里提出的研究将检验一种新的假说，该假说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，显示由被称为“主要组织相容性复合体”的基因编码的某些蛋白质，激活了排列在血管内侧的细胞的氧化应激。这些发现可以解释许多疾病的机制，包括动脉粥样硬化，这是美国导致残疾和死亡的主要原因。

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.