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. ? ? ?
| Winchester, Robert; Wiesendanger, Margrit; O'Brien, Will et al. (2011) Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. J Immunol 187:1006-14 |
| Wu, Henry D; Maurer, Mathew S; Friedman, Richard A et al. (2007) The lymphocytic infiltration in calcific aortic stenosis predominantly consists of clonally expanded T cells. J Immunol 178:5329-39 |
