Immunopathology of Cardiovascular Diseases

Philippe Krebs

Citation
Philippe Krebs, Immunopathology of Cardiovascular Diseases, Ph.D. Thesis, ETH Zürich, Zürich, Switzerland, 2005.
Descriptions
Abstract:

Cardiovascular diseases such as atherosclerosis, coronary heart disease, and dilated cardiomyopathy, are the principal cause of mortality in industrialized countries. Chronic inflammatory processes are of major importance in the pathogenesis of atherosclerotic disease and myocarditis. Initial injury is likely to be elicited by infectious agents that can sustain chronic immune responses and immunopathology by persisting in the cardiovascular system. Such chronic infections may eventually overcome tolerance and induce reactivity against self-antigens with exacerbation of the disease. Indeed, autoimmune reactions have been hypothesized to be involved in the pathogenesis of myocarditis and atherosclerosis. To shed light on the mechanisms behind chronic cardiovascular diseases, we used a transgenic mouse model in which autoimmunity can be specifically elicited in the heart and the aorta (SM-LacZ mice). The two first studies deal with the role and significance of B cells and their accompanying autoantibody signatures in systemic and heart-specific autoimmunity, respectively. The third and the fourth sections describe how virus elicited CD8+ T cells can either be exhausted and functionally impaired in conditions of high antigen expression in the periphery, or lead to the exacerbation of atherosclerosis and chronic immunopatholgy in a model of antigen persistence in the cardiovascular system. In the first part of this work we present a preliminary investigation on the autoimmune B cell response engendered following infection with cytopathic (vaccinia virus, VV and vesicular stomatitis virus, VSV) or non-cytopathic (lymphocytic choriomeningitis virus, LCMV) viruses. Applying the SEREX method (serological identification of recombinantly expressed antigens), we show that viruses induce antibodies against a broad panel of autoantigens. Furthermore, the different viruses triggered distinct autoantibody responses, thus suggesting that virus infections may leave specific "autoantibody fingerprints" in the infected host. The second chapter is dedicated to the characterization of the anti-self IgG response in organ-specific autoimmunity. Here the SEREX approach was used to molecularly dissect heart-specific autoimmune B cell responses that develop during the course of experimental autoimmune myocarditis (EAM). Upon immunization with a peptide derived from cardiac myosin heavy chain α (myhcα) we found that the vast majority of the autoantibodies generated in BALB/c mice was specific for portions of the myosin protein that did not encompass the immunogenic peptide, hence revealing intramolecular epitope spreading. This strong focusing on myhcα was also a hallmark of the B cell response against heart antigens, that was induced upon myocardial damage following MCMV infection which generally precipitates a broad spectrum of anti-self antibodies. Furthermore, myocarditis severity correlated with both intra- and intermolecular epitope spreading. Therefore, evaluation of the focusing of an antibody response to disease-related self-determinants may help to assess both the susceptibility to and the progression rate of autoimmune cardiac damage. The third study investigates the fate of transgene-specific CD8+ T cells following abortive infection with a recombinant adenovirus. We found that specific CD8+ T cells expanded only in a very narrow dose range and that they were functionally impaired. Infection of SM-LacZ mice led to the deletion of these specific CD8+ T cells and, consequently, transgenic mice did not develop myocarditis. Our results suggest that the outcome of vaccination with recombinant adenoviruses is critically dependent on the antigen load in peripheral tissues. The last chapter is an immunologic analysis of the mechanisms underlying atherosclerosis in an infectious situation. Although hypercholesterolemic APOE(-/-) and APOE(-/-)×SM-LacZ mice mounted comparable T cell responses to a recombinant MCMV-LacZ virus, persistent expression of the βgalactosidase transgene in the vasculature, as it occurs in APOE(-/-)×SM-LacZ mice, dramatically exacerbated atherosclerosis and elicited chronic cellular infiltrations in the aorta. Therefore, our data provide evidence for the role of persistent vascular infections with pathogens and the ensuing specific immunopathology in atherogenic processes.

Annotation:

Diss. ETH No. 16068

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