Immunopathogenic features in calcific aortic stenosis

描述（由申请人提供）：本研究钙化主动脉狭窄（CAS）免疫致病特征的建议是基于初步数据，显示CAS瓣膜小叶的ct（3T）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T细胞克隆在瓣膜内明显增殖。瓣膜中扩增克隆的子集与血液中的克隆具有相同的3链序列，这意味着血液中的扩增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都是CDS谱系，这表明识别I类MHC背景下呈现的肽的T细胞在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，也与单纯的非抗原特异性炎症趋化因子吸引不相容。他们提出了基于这一提议的假设：CAS中瓣膜损伤的一个主要组成部分是由适应性免疫反应驱动的瓣膜内T细胞克隆扩增介导的。我们设想，T细胞激活要么是由血流动力学应变对瓣膜组织中新诱导的蛋白质的原发性自身免疫反应引起的，要么是初始的动脉粥样硬化反应触发了对动脉粥样硬化病变中元素的叠加特异性适应性T细胞反应。在这两种情况下，核心因素是特定的I类MHC分子将阀肽呈现给bbb3t细胞受体的能力。我们的总体目标是进一步了解在主动脉瓣狭窄组织中浸润大量扩增的T细胞克隆在CAS发病机制中的意义，具体目标是：1。确定瓣膜浸润扩展的bbbb3t细胞克隆在瓣膜不同区域的克隆组成，确定它们与血液中克隆祖细胞的关系和意义，并描述它们的克隆T细胞受体是否表现出表明它们驱动这一过程的结构特征。2. 确定是否存在HLA I类等位基因，HLA- a， B和C，这可能会通过扩展浸润性CDS T细胞识别的特定肽的呈现来解释发生CAS的易感性。3. 定义狭窄瓣膜炎症和损伤部位的转录表型，以更好地了解活化的T细胞如何通过钙化、新生血管和纤维化导致瓣膜损伤。这项工作将推动CAS作为一种不可逆的退行性过程的观点的转变，为识别驱动抗原奠定基础，并为设计特异性免疫调节疗法来阻止这种严重疾病的无情进展带来希望。

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.