Résumés
Résumé
La formation et le développement des plaques d’athérome résultent d’une interaction dynamique entre la paroi des vaisseaux et le sang circulant. L’étape cruciale de la constitution des plaques semble être la présence de lipoprotéines oxydées dans l’espace sous-endothélial, qui entraîne l’expression locale de facteurs responsables de l’infiltration de la paroi par des monocytes et des lymphocytes T. L’athérosclérose est ainsi une maladie immuno-inflammatoire, différents composants du système immunitaire assumant un rôle protecteur ou délétère dans le devenir de la maladie. D’où l’idée de développer, à partir de la modulation de la réponse immunitaire, de nouvelles thérapeutiques préventives et curatives pour lutter contre les maladies cardiovasculaires, première cause de décès dans les pays industrialisés.
Summary
Cardiovascular diseases represent one of the most important causes of death in the world. The underlying pathogenetic process is atherosclerosis which leads to the progressive reduction of the arterial lumen and therefore to the ischemia of the perfused organs. Atherogenesis results from the interaction between the biology of the arterial wall and the various stress stimuli present in the circulating blood. The first steps of atherogenesis occur very early, already during the fetal life. Those arterial segments that are subjected to the initiating causes (including hemodynamic stress) show altered endothelial permeability and allow the infiltration of macromolecules, like lipoproteins, in the subintimal space. At the same time, the smooth muscle cells that are subjected to the same local factors produce proteoglycans able to bind lipoproteins and to promote their oxidation. Oxidized lipoproteins induce the expression of chemokines and adhesion molecules on the luminal surface of the endothelium, which then allow the local recruitment of monocytes-macrophages and T lymphocytes. This is a local inflammatory process that, in theory, should contribute to reestablish the homeostasis of the vascular wall by promoting the elimination of injured tissue and its repair. Unfortunately, for unknown reasons, the immuno-inflammatory reaction persists and autoamplifies, the various components of the immune response finally contributing to the pathogenesis of atherosclerosis as well as of atherosclerotic complications.
Parties annexes
Références
- 1. Braunwald E. Cardiovascular medicine at the turn of the millenium: triumphs, concerns, and opportunities. N Eng J Med 1997; 337: 1360-9.
- 2. Napoli C, D’Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 1997; 100: 2680-90.
- 3. Lee RT, Yamamoto C, Feng Y, et al. Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells. J Biol Chem 2001; 276: 13847-51.
- 4. Li H, Cybulsky MI, Gimbrone MA Jr, Libby, P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb 1993; 13: 197-204.
- 5. Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 1876-90.
- 6. Virchow R. Phlogose und thrombose in Gefäss-system: Gesammelte Abhandlungen zur Wissenschaftlichen Medicin. Frankfurt-am-Main: Meidinger Sohn, 1856.
- 7. Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Suenram CA, Rozek MM. Atherosclerosis as an inflammatory process. The roles of the monocyte- macrophage. Ann NY Acad Sci 1985; 454: 115-20.
- 8. Kohchi K, Takebayashi S, Hiroki T, Nobuyoshi M. Significance of adventitial inflammation of the coronary artery in patients with unstable angina: results at autopsy Circulation 1985; 71: 709-16
- 9. Khan BV, Parthasarathy SS, Alexander RW, Medford RM. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J Clin Invest 1995; 95: 1262-70.
- 10. Cushing SD, Berliner JA, Valente AJ, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA 1990; 87: 5134-8.
- 11. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA 1995; 92: 3893-7.
- 12. Nicoletti A, Caligiuri G, Tornberg I, Kodama T, Stemme S, Hansson GK. The macrophage scavenger receptor type A directs modified proteins to antigen presentation. Eur J Immunol 1999; 29: 512-21.
- 13. Caligiuri G, Nicoletti A, Zhou X, Tornberg I, Hansson GK. Effects of sex and age on atherosclerosis and autoimmunity in apoE- deficient mice. Atherosclerosis 1999; 145: 301-8.
- 14. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996; 93: 1354-63.
- 15. Davies MJ, Thomas AC. Plaque fissuring - the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 1985; 53: 363-73.
- 16. Friedman GD, Klatsky AL, Siegelaub AB. The leukocyte count as a predictor of myocardial infarction. N Engl J Med 1974; 290: 1275-8.
- 17. De Beer FC, Hind CR, Fox KM, Allan RM, Maseri A, Pepys MB. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 1982; 47: 239-43.
- 18. Van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 36-44.
- 19. Neri Serneri GG, Abbate R, Gori AM, et al. Transient intermittent lymphocyte activation is responsible for the instability of angina. Circulation 1992; 86: 790-7.
- 20. Caligiuri G, Liuzzo G, Biasucci LM, Maseri A. Immune system activation follows inflammation in unstable angina: pathogenetic implications. J Am Coll Cardiol 1998; 32: 1295-304.
- 21. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994; 331: 417-24.
- 22. Caligiuri G, Paulsson G, Nicoletti A, Maseri A, Hansson GK. Evidence for antigen-driven T-cell response in unstable angina. Circulation 2000; 102: 1114-9.
- 23. Itabe H, Takeshima E, Iwasaki H, et al. A monoclonal antibody against oxidized lipoprotein recognizes foam cells in atherosclerotic lesions. Complex formation of oxidized phosphatidylcholines and polypeptides. J Biol Chem 1994; 269: 15274-9.
- 24. Salonen JT, Yla-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883-7.
- 25. Uyemura K, Demer LL, Castle SC, et al. Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest 1996; 97: 2130-8.
- 26. Naruko T, Ueda M, Haze K, et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 2002; 106: 2894-900.
- 27. Biasucci LM, D’Onofrio G, Liuzzo G, et al. Intracellular neutrophil myeloperoxidase is reduced in unstable angina and acute myocardial infarction, but its reduction is not related to ischemia. J Am Coll Cardiol 1996; 27: 611-6.
- 28. Buffon A, Biasucci LM, Liuzzo G, D’Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347: 5-12.
- 29. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today1995; 16: 34-8.
- 30. Austrup F, Vestweber D, Borges E, et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 1997; 385: 81-3.
- 31. Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000; 101: 2883-8.
- 32. Saren P, Welgus HG, Kovanen PT. TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 1996; 157: 4159-65.
- 33. Caligiuri G, Rudling M, Ollivier V, et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med 2003; 9: 10-7.
- 34. Laurat E, Poirier B, Tupin E, et al. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 2001; 104: 197-202.
- 35. Caligiuri G, Stahl D, Kaveri S, et al. Autoreactive antibody repertoire is perturbed in atherosclerotic patients. Lab Invest 2003; 83: 839-47.
- 36. Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 2002; 109: 745-53.
- 37. Freigang S, Horkko S, Miller E, Witztum JL, Palinski W. Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol 1998; 18: 1972-82.
- 38. Zhou X, Caligiuri G, Hamsten A, Lefvert AK, Hansson GK. LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 108-14.
- 39. Saoudi A, Simmonds S, Huitinga I, Mason D. Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of the autoantigen-specific T cells. J Exp Med 1995; 182: 335-44.
- 40. Taylor-Robinson AW, Phillips RS. B cells are required for the switch from Th1- to Th2-regulated immune responses to Plasmodium chabaudi chabaudi infection. Infect Immun 1994; 62: 2490-8.