Immunopathogenic features in calcific aortic stenosis

这项研究钙化性主动脉瓣狭窄（CAS）免疫病理学特征的建议是基于 初步数据显示，CAS中瓣叶的ct（3 T）淋巴细胞浸润主要是 由几个高度扩增的T细胞克隆组成，这些克隆似乎在淋巴细胞中大量增殖。 阀.瓣膜中扩增克隆的子集与血液中的克隆共享相同的β-链序列， 这意味着血液中扩增的克隆可能是组织浸润性T细胞的祖细胞。 此外，血液和瓣膜之间共享的克隆仅为CDS谱系，表明 对于识别在I类MHC背景下呈递的肽的T细胞，其在CAS中起重要作用。 这些发现不同于动脉粥样硬化中主要的多克隆淋巴细胞浸润， 与简单的非抗原特异性炎性趋化因子吸引不相容。他们建议 这一假设的基础：在CAS瓣膜损伤的主要组成部分是介导的， 由适应性免疫反应驱动的瓣膜内的T细胞克隆扩增。我们 设想T细胞活化是由对新的蛋白质的初级自身免疫应答引起的， 在瓣膜组织中由血流动力学应变引起，或者初始动脉粥样化反应触发 叠加的特异性适应性T细胞对动脉粥样硬化病变中的成分的反应。无论是 核心要素是特定I类MHC分子呈递瓣膜肽的能力 到|3 T细胞受体。以提高对《公约》重要性的认识为总目标， 发现大量扩增的T细胞克隆浸润在狭窄的主动脉瓣组织中， CAS的发病机制，具体目标是：1。确定克隆组成的剧目， 瓣膜浸润性扩张|3 T细胞克隆在所涉及的瓣膜的不同区域中，鉴定它们的 血液中克隆性祖细胞的关系和意义，并描述其克隆性T细胞 细胞受体表现出结构特征，表明它们驱动该过程。2.确定是否 是HLA I类等位基因，HLA-A、B和C，这将解释发生CAS的易感性 可能是通过呈递被扩增的浸润CD 8 T细胞识别的特定肽。 3.定义狭窄瓣膜中炎症和损伤部位的转录表型， 更好地了解活化的T细胞如何通过钙化、新血管形成导致瓣膜损伤 和纤维化。这项工作应该增加动力，以改变CAS作为一个不可逆转的退化 过程，为识别驱动抗原奠定了基础，并希望有可能 设计特定的免疫调节疗法来阻止这种严重疾病的无情发展。

This proposal to investigate immunopathogenic features in calcific aortic stenosis (CAS) is based on preliminary data showing that the ct(3T cell lymphocytic infiltrationof valve leaflets in CAS mainly consists of a few highly expanded T cell clones that appear to have considerably proliferated in the valve. A subset of expanded clones in the valve share identical (3-chain sequences with clones in blood, implying that expanded clones in blood are likely progenitors of the tissue-infiltrating T cells. Moreover, the clones shared between blood and the valve were exclusively of CDS lineage, suggesting an important role in CAS for T cells that recognize peptides presented in the context of class I MHC. These findings differ from the predominantly polyclonal lymphocytic infiltration in atherosclerosis and are not compatible with simple non antigen-specific inflammatory chemokine attraction. They suggest the hypothesis underlyingthis proposal: a major component of the valvular injury in CAS is mediated by the T cell clonal expansions within the valve that are driven in an adaptive immune response. We envision that the T cell activation results either from a primary autoimmune response to a protein newly induced in valve tissues by hemodynamic strain, or that an initial atheromatous response triggers a superimposed specific adaptive T cell response to an element in the atheromatous lesion. In both scenarios the central element is the ability of particular class I MHC molecules to present valve peptides to a|3 T cell receptors. With the overall goal of advancingunderstanding of the significance of the substantially expanded T cell clones found infiltratingthe tissues of stenotic aortic valves in the pathogenesis of CAS, the specific aims are: 1. Determine the clonal composition of the repertoire of valve-infiltrating expanded a|3T cell clones in different regions of the involved valve, identify their relationship to and the significance of clonal progenitors in blood and delineate whether their clonal T cell receptors exhibit structural features suggesting they drive the process. 2. Determine whether there are HLA class I alleles, HLA-A, B and C, that would account for the susceptibility to develop CAS perhaps through presentation of the particular peptides recognized by expanded infiltrating CDS T cells. 3. Define the transcriptional phenotype of the sites of inflammation and injury in the stenotic valve to better understand how activated T cells lead to valvular injury through calcification, neovascularization and fibrosis. This work should add impetus to the changing view of CAS as a irreversible degenerative process, set the stage for identification of the driving antigens, and give hope to the possibility of designing specific immunomodulatory therapy to stop the relentless progression of this serious disease.