ATVB In Focus
Immunity and Atherosclerosis
In the last two years, the concept that atherosclerosis is an inflammatory disease has moved from the scientific journals to the lay press and TV programs. Family physicians are as interested as vascular biologists in inflammatory mechanisms of the vessel wall. CRP is used to screen for and monitor coronary heart disease patients, and antiinflammatory strategies are being developed as targets for cardiovascular therapy.
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Inflammation is an effector mechanism of the immune system. It is elicited after activation of immunity through the adaptive and/or innate pathways. While the former depends on antigen recognition by T and B cells, the latter pathway is activated when pathogen-associated molecular patterns ligate pattern recognition receptors on several cell types, including macrophages and endothelial cells. Innate immunity does not depend on clonal expansion and therefore mounts rapid responses to invading microorganisms. As a drawback, it relies on recognition of molecular patterns that are shared by microbial molecules (eg, endotoxins and heat shock proteins) but which may also appear on endogenous ones. In contrast, adaptive immunity is highly specific, with millions of T and B cell receptors generated through somatic rearrangements of T cell receptors and Ig genes. This makes for a remarkable degree of fine specificity in the adaptive immune response. The price for this high degree of specificity is loss of speed. Each unique receptor is present on only one or a few cells; specific cells therefore have to multiply repeatedly before effector responses of sufficient magnitudes can be mounted. These features make adaptive immunity less important in the immediate response to a microbial challenge but of paramount importance for protection against repeated assaults by the same pathogen. In the form of vaccination, protective adaptive immunity is one of the great successes of medicine. However, adaptive as well as innate immune receptors may inadvertently recognize autologous molecules and precipitate autoimmune reactions.
Our knowledge of immune mechanisms involved in atherosclerosis has expanded dramatically. Twenty years ago, the first reports were published showing the presence of activated immune cells in human atherosclerotic lesions,1 demonstrating that vascular cells can present antigen to T cells,2 and identifying a capacity of vascular cells to produce as well as respond to immune cytokines.3 Several disease-associated antigens were identified, including oxidized low-density lipoprotein4 and heat shock protein-60,5 and hypotheses were put forward regarding the role of immune/inflammatory mechanisms in atherosclerosis.
In recent years, the use of gene-targeted mouse models has provided new insights into the immunopathogenesis of atherosclerosis and made it possible to test hypotheses regarding the role of specific immune molecules in the disease process. Interrogation of the transcriptome and proteome of cells involved in human disease has increased our knowledge of immune/inflammatory gene regulation in atherosclerotic lesions and revealed unexpected molecular participants in the process. Finally, analysis of immune/inflammatory markers in well-defined clinical and epidemiological materials has provided important information about disease development and also encouraging news suggesting a predictive value for some of the markers.
Arteriosclerosis, Thrombosis, and Vascular Biology will devote a series of Brief Reviews to Immunity and Atherosclerosis. We start by painting an exciting scenario for the future: vaccination against atherosclerosis. In this first Brief Review of the series, Jan Nilsson, P.K. Shah, and I provide an overview of the experimental studies that have identified antigen-specific protective mechanisms and outline key issues for future development in the area. Subsequent contributions to the series will deal with Cellular Immunity, Humoral Immunity, Innate Immunity, and Regulatory Cells and Cytokines. We hope that you will find it exciting reading in an important area of atherosclerosis research.
Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986; 6: 131–138.
Warner S, Auger KR, Libby P. Interleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cells. J Immunol. 1987; 139: 1911–1917.
Palinski W, Rosenfeld ME, Yla-Herttuala S, Gurtner GC, Socher SS, Butler SW, Parthasarathy S, Carew TE, Steinberg D, Witztum JL. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989; 86: 1372–1376.
Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G. Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb. 1992; 12: 789–799.