Immunopathogenic features in calcific aortic stenosis

描述（由申请人提供）：本研究钙化性主动脉瓣狭窄（CAS）免疫病理学特征的建议基于初步数据，初步数据显示CAS中瓣膜瓣叶的ct β T细胞淋巴细胞浸润主要由少数高度扩增的T细胞克隆组成，这些克隆似乎在瓣膜中显著增殖。瓣膜中扩增的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，表明在CAS中识别I类MHC背景下呈递的肽的T细胞的重要作用。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，并且与简单的非抗原特异性炎性趋化因子吸引不相容。他们提出了这一提议的假设：CAS中瓣膜损伤的主要组成部分是由适应性免疫应答驱动的瓣膜内T细胞克隆扩增介导的。我们设想，T细胞活化的结果，无论是从一个主要的自身免疫反应的蛋白质新诱导的瓣膜组织的血流动力学应变，或初始动脉粥样硬化反应触发叠加的特定适应性T细胞反应的一个元素在动脉粥样硬化病变。在这两种情况下，中心因素是特定I类MHC分子将瓣膜肽呈递给受体的能力。|3 T细胞受体。总体目标是促进对在CAS发病机制中发现的浸润狭窄主动脉瓣组织的显著扩增的T细胞克隆的意义的理解，具体目标是：1。确定瓣膜浸润性扩张的克隆组成，|3 T细胞克隆在不同区域的参与瓣膜，确定它们的关系和血液中的克隆祖细胞的意义，并描绘其克隆T细胞受体是否表现出结构特征，表明他们驱动的过程。2.确定是否存在HLA I类等位基因（HLA-A、B和C），这些等位基因可能通过呈递扩增的浸润CDS T细胞识别的特定肽而导致发生CAS的易感性。3.定义狭窄瓣膜中炎症和损伤部位的转录表型，以更好地了解激活的T细胞如何通过钙化、新生血管形成和纤维化导致瓣膜损伤。这项工作应该增加动力的CAS作为一个不可逆的退行性过程的不断变化的观点，为识别驱动抗原的阶段，并希望设计特定的免疫调节治疗的可能性，以阻止这种严重的疾病的无情的进展。

DESCRIPTION (provided by applicant): This proposal to investigate immunopathogenic features in calcific aortic stenosis (CAS) is based on preliminary data showing that the ct(3T cell lymphocytic infiltration of 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 underlying this 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 advancing understanding of the significance of the substantially expanded T cell clones found infiltrating the 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.