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Atherosclerosis and autoimmunity section V, Anti-endothelial cell antibodies and athrrosclerosis PDF

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PREFACE Atherosclerosis is a prolonged process that starts in to injury hypothesis of atherosclerosis" [6-9], it the second decade of life, progresses slowly and the became accepted that this process is an outcome clinical manifestations appear in the 4-5* decade of a chronic inflammatory reaction in the artery. onwards. The early lesions, i.e., fatty streaks, may be This book deals with knowledge accrued in the past seen already during fetal development and regress decade concerning the role of inmiunity in the ini soon after birth [1], but reappear in early adoles tiation and perpetuation of atherosclerosis [10-13]. cence and may progress into more complex lesions, The participation of monocyte derived macrophages that take many years to regress [2]. Evidence based and lymphocytes, the latter mostly activated T-cells on large studies provided proof that hypercholes [14] pointed to the involvement of the immune terolemia is a leading risk factor for atherogenesis system in this inflammatory reaction. There is con [3]. In addition, other risk factors, such as hyperten vincing evidence that LDL, once modified by mac sion, smoking, diabetes, low HDL, homocysteine- rophages within the arterial wall, can be responsible mia were identified. for T-cell activation [15]. Circulating antibodies to Within the last two decades it was recognized oxidized LDL have been demonstrated in animals that risk factors interact to promote development of and humans [15]. Inmiune activation was invoked coronary artery disease (CAD) [3]. Thus, smoking also for other antigens, such as heat shock proteins as a single risk factor, manifests clinically as a res [16, 17]. The above mentioned antigens were found piratory disease, but in conjunction with high LDL to be present in atherosclerotic lesions [15, 18]. In cholesterol levels enhances CAD very markedly [4]. IL-4 knockout mice fewer atherosclerotic lesions The same is true for hypertension and diabetes, that after heat shock protein injection were seen, indi in presence of hypercholesterolemia will increase cating an important role of this cytokine in the the risk for CAD several-fold. It has been generally response to heat shock protein [19]. Involvement of accepted that the known risk factors account for CD40 and CD40 ligand in atherogenesis (mediators only 50% of patients with CAD [5]. One plausible of immune responses) is supported by their expres explanation for underestimation of the contribution sion in most cellular elements of the atheroma [20]. of known risk factors to mortality and morbidity In LDL receptor deficient mice, injection of anti- of CAD could be that the definition of "normality" CD40L antibodies reduced atherosclerosis mark requires more rigorous re-evaluation. Three decades edly [20]. In addition, various infections of micro ago, 300 mg/dL of plasma cholesterol, 180 mg/dL of bial (chlamydia pneumoniae) or viral (adenoviruses LDL cholesterol, blood pressure of 160/95 mm Hg, and herpesviridae) origin [21, 22] have been pro were considered to be within upper normal limits. posed as candidates for vascular injury which may Information from large-scale intervention studies culminate in atherogenesis. Among them herpesvi for secondary prevention of CAD permitted to rede ruses were shown to activate the coagulation system fine these limits. Thus the upper normal limit for and accelerate progression of atherosclerosis [23]. LDL cholesterol has been continuously decreasing The immune approach to atherosclerosis led to <100 mg/dL, and recently even <80 mg/dL is also to the use of immunization against oxidized considered as a therapeutic goal. The latter values LDL. Thus injection of homologous malonyl dialde- start to approach those found in free living non- hyde modified LDL (MDA-LDL) to WHHL rabbits human primates, who also develop atherosclerosis resulted in reduction of atherosclerosis [24]. Simi when exposed to "western type" diets. lar results were obtained also in apoE deficient mice Since the formulation by R.Ross of the "response hyperimmunized with homologous MDA-LDL [25]. vn On the other hand, immunization to heat shock pro 5. Oliver MF. Prevention of coronary heart disease - prop teins of mice fed an atherogenic diet resulted in aganda, promises, problems, and prospects. Circulation enhancement of fatty streak formation [26]. In anal 1986;73:1-9. ogy, when LDL receptor deficient [27] and apoE 6. Ross R, Glomset JA. The pathogenesis of atherosclero deficient mice were immunized to P-2-glycoprotein sis. N Engl J Med 1976;295:369-377; 420-425. 7. Ross R. The pathogenesis of atherosclerosis - an update. I (a target of autoimmune anticardiolipin antibodies) N Engl J Med 1986;314:488-500. they responded with an accelerated development of 8. Ross R. The pathogenesis of atherosclerosis: a perspec atherosclerosis [28], This antigen was found also tive for the 1990s. Nature 1993;362:801-809. in human atherosclerotic lesions co-localizing with 9. Ross R. Atherosclerosis - an inflammatory disease. N CD4-lymphocytes [29]. When primed lymphocytes Engl J Med 1999;340:115-126. from P2GPI immunized mice were injected into 10. Witztum JL, Palinski W. Editorial. Are immunological LDL-receptor deficient mice, atherosclerotic lesions mechanisms relevant for the development of atheroscle were enhanced [30]. rosis? Clin Immunol 1999;90:153-156. Future research that will be designed to test the 11. Wick G, Perschinka H, Xu Q. Autoimmunity and relative importance of the immune hypothesis in atherosclerosis. Am Heart J 1999;138:5444-5449. atherogenesis will determine the approach to be 12. Palinski W, Witztum JL. Immune responses to oxi taken in CAD prevention and treatment. In the dative neoepitopes on LDL and phospholipids mod meantime, introduction of a primary prevention pro ulate the development of atherosclerosis. J Int Med 2000;247:371-380. gram that encompasses all known risk factors for 13. Nicoletti A, CaHgiuri G, Hansson GK. Immunomodu- CAD, throughout the school curriculum, seems to lation of atherosclerosis: myth and reality. J Int Med us a logical approach, and with the escalating costs 2000;247:397-405. of clinical care of CAD becomes an inescapable 14. Hansson GK. Cell-mediated immunity in atherosclero conclusion. sis. Curr Opin Lipidol 1997;8:301-311. 15. Steinberg D, Witztum JL. Lipoproteins, lipoprotein oxi Olga Stein and Yechezkiel Stein dation, and atherogenesis. In "Molecular Basis of Car Jerusalem, 16* July 2000 diovascular Disease" (KR Chien, Ed.), Saunders, Phila delphia, 1999:458^75. 16. Xu W, Dietrich H, Steiner HJ, Gown AM, Mikuz REFERENCES G, Kaufmann SHE, Wick G. Induction of arterioscle rosis in normocholesterolemic rabbits by immuniza tion with heat shock protein 65. Arterioscler Thromb 1. Napoli C, D'Artmiento FP, Mancini FP, Postiglione 1992;12:789-799. A, Witztum JL, Palumbo G, Palinski W. Fatty streak 17. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones formation occurs in human fetal aortas and is greatly EA. Cutting edge: heat shock protein (HSP) 60 acti enhanced by maternal hypercholesterolemia. Intimal vates the innate immune response: CD 14 is an essential accumulation of low density lipoprotein and its oxida receptor for HSP60 activation of mononuclear cells. J tion precede monocyte recruitment into early athero Immunol 2000;1644;13-17. sclerotic lesions. J Clin Invest 1997;100:2680-2690. 18. Berberian PA, Myers W, Tytell M, Challa V, Bond MG. 2. Stein Y, Stein O. Does therapeutic intervention achieve Immuno- histochemical localization of heat shock pro- slowing of progression or bona fide regression of athero tein-70 in normal-appearing and atherosclerotic speci sclerotic lesions? Arterioscler Thromb Vase Biol 2000; mens of human arteries. Am J Pathol 1990;136:71-80. In press . 19. George J, Shoenfeld Y, Gilburd B, Afek A, Shaish A, 3. Prevention of Coronary Heart Disease: Scientific Back Harats D. Requisite role for interleukin-4 in the accel ground and New Clinical Guidelines. Recommenda eration of fatty streaks induced by heat shock protein tions of the European Atherosclerosis Society prepared 65 or Mycobacterium tuberculosis. Circ Res 2000;86: by the International Task Force for Prevention of 1203-1210. Coronary Heart Disease. Nutr Metab Cardiovasc Dis 20. Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby 1992;2:113-156. P. Reduction of atherosclerosis in mice by inhibition of 4. Stein Y, Harats D, Stein O. Why is smoking a major risk CD40 signalHng. Nature 1998;394:200-203. factor for coronary heart disease in hyperlipidemic sub 21. Danesh J, CoUins R, Peto R. Chronic infections jects? Annals NY Acad Sci 1992;686:66-71. and coronary heart disease: is there a link? Lancet Vlll 1997;350:430^36. 27. George J, Afek A, Gilburd B, Blank M, Levy Y, Aron- 22. Nieto FJ. Infections and atherosclerosis: new clues Maor A, Levkovitz H, Shaish A, Goldberg I, Kopolovic from an old hypothesis? Am J Epidemiol J, Shoenfeld Y. Induction of early atherosclerosis in 1998;148:937-948. LDL receptor deficient mice immunized with 32GPI. 23. Nicholson AC, Hajjar DP. Herpesviruses and thrombo Circulation 1998;15:1108-1105. sis: activation of coagulation on the endothelium. Clin 28. Afek A, George J, Shoenfeld Y, Gilburd B, Levy Y, Chim Acta 1999;286:23-29. Shaish A, Keren P, Janackovic Z, Goldberg I, Kopolovic 24. Palinski W, Miller E, Witztum JL. Immunization of LDL J, Harats D. Enhancement of atherosclerosis in beta- receptor-deficient rabbits with homologous malondial- 2-glycoprotein I-immunized apolipoprotein E-deficient dehyde-modified LDL reduced atherogenesis. Proc Natl mice. Pathobiology 1999;67:19-25. Acad Sci USA 1995;92:821-825. 29. George J, Harats D, Gilburd B, Afek A, Levy Y, 25. George J, Afek A, Gilburd B, Levkovitz H, Shaish Schneiderman J, Barshack I, Kopolovic J, Shoenfeld A, Goldberg I, Kopolovic Y, Wick G, Shoenfeld Y, Y. Immunolocalization of p^-glycoprotein I (apoli Harats D. Hyperimmunization of apo-E-deficient mice poprotein H) to human atherosclerotic plaques. Poten with homologous malondialdehyde low-density lipo tial implications for lesion progression. Circulation protein suppresses early atherogenesis. Atherosclerosis 1999;99:2227-2230. 1998;138:147-152. 30. George J, Gilburd B, Afek A, Levy Y, Kopolovic 26. George J, Shoenfeld Y, Afek A, Gilburd B, Keren P, J, Harats D, Shoenfeld Y Adoptive transfer of P2 Shaish A, Kopolovic J, Wick G, Harats D. Enhanced glycoprotein I (p2GPI)-reactive lymphocytes enhances fatty streak formation in C57BL/6J mice by immuniza atherosclerosis in LDL receptor deficient mice. Circula tion with heat shock protein-65. Arterioscler Thromb tion 2000;102:1822-1827. Vase Biol 1999;19:505-510. IX List of Contributors Olga Amengual Miri Blank Lupus Research Institute Department of Medicine B and the The Rayne Institute Research Center of Autoinmiune Diseases St. Thomas' Hospital Sheba Medical Center London Tel Hashomer United Kingdom Israel Tatsuya Atsumi Department of Medicine II Hokkaido University Anne Bodron School of Medicine Laboratory of Immunology Sapporo Institut de Synergic des Sciences Japan et de la Sante Brest University Medical School Paul A. Bacon Brest Department of Rheumatology France University of Birmingham Birmingham United Kingdom Dan Buskila Rheumatic Disease Unit and Epidermiology Depart Khalil Bdeir ment Department of Pathology Soroka Medical Center Laboratory Medicine Faculty of Health Sciences University of Pennsylvania Ben Gurion University of the Negev Philadelphia, PA19104 Beer Sheva USA Israel H. Michael Belmont Hospital for Joint Diseases Richard Cervera NYU Medical Center Systemic Autoimmune Diseases Unit New York Hospital clinic USA Barcelona, Catalonia Spain A. Biasiolo Department of Clinical and Experimental Medicine Thrombosis Center Jacques Chevalier University of Padova INSERM U430 Via Gattamelata 64 Hopital Broussais 1-35128 Padova Paris Italy France XI Douglas B. Cines Stephen E. Epstein Department of Pathology Cardiovascular Research Institute Laboratory Medicine Washington Hospital Center University of Pennsylvania 110 Irving Street Philadelphia, PA 19104 Washington, DC 20010 USA USA T. Del Ros Mario Febbraio Department of Medical and Surgical Sciences Center of Vascular Biology University of Padova Cornell University Medical College Via Gattamelata 64 1300 York Avenue 1-35128 Padova NewYork, NY 10021 Italy USA Mordechai Deutsch Josep Font The Jerome Schottenstein Cellscan Center Systemic Autoimmune Diseases Unit Department of Physics Hospital clinic Bar-Ian University Barcelona, Catalonia Ramat Gan Spain Israel J. Frostegard B. Devulder Department of Medicine and CMM Internal Medicine Department Karolinska Hospital University Hospital of Lille Karolinska Institutet 59035 Lille Cedex 17176 Stockholm France Sweden Mary vonne Dueymes J-C. Fruchart Laboratory of Inmiunology Research Laboratory on Lipids and Atherosclerosis Institut de Synergic des Sciences INSERM U325 et de la Sante Pasteur Institute of Lille Brest University Medical School Lille Brest France France J. Bruce German Jean-Paul Duong Van Huyen Department of Food Science & Technology Laboratoire d'Anatomic Pathologique University of California at Davis Hopital Europeen Georges Pompidou Davis, CA 95616 France USA P. Duriez Jacob George Research Laboratory on Lipids and Atherosclerosis Department of Medicine B and the INSERM U325 Research Center of Autoimmune Diseases Pasteur Institute of Lille Sheba Medical Center Lille Tel Hashomer France Israel xn M.E. Gershwin Goran K. Hansson Department of Rheumatology/Allergy and Center for Molecular Medicine L8:03 Clinical Immunology Karolinska Hospital University of California at Davis S-17176 Stockholm Davis, CA 95616 Sweden USA Dror Harats Tzipora Goldkorn Institute of Lipid and Atherosclerosis Research Signal Transduction Sheba Medical Center UC Davis School of Medicine Tel Hashomer, Sackler faculty of Medicine TB149, Davis Campus Tel-Aviv University Davis, CA 95616 Tel-Aviv USA Israel Antonio M. Gotto, Jr Abd Al-Roof Higazi Center of Vascular Biology Department of Clinical Biochemistry Cornell University Medical College Hebrew University - Hadassah Medical Center 1300 York Avenue Jerusalem NewYork, NY 10021 IL-91120 Israel USA Graham R.V. Hughes Sandeep Gupta Lupus Research Institute Department of Cardiology The Rayne Institute Whipps Cross Hospital St. Thomas' Hospital Leytonstone London London Ell 1 NR United Kingdom United Kingdom Norman T. Ilowite E. HachuUa Schneider Children's Hospital Internal Medicine Department Long Island Jewish Medical Center University Hospital of Lille Albert Einstein College of Medicine 59035 Lille Cedex New Hyde Park, NY 11040 France New York USA David P. Hajjar Weill Medical College of Cornell University Miguel Ingelmo Department of Pathology, A-626 Systemic Autoimmune Diseases Unit 1300 York Avenue Hospital clinic NewYork, NY 10021 Barcelona, Catalonia USA Spain Jihong Han Luigi luliano Center of Vascular Biology Institute of Clinical Medcine I Cornell University Medical College University La Sapienza 1300 York Avenue Via del Policlinico 155 NewYork, NY 10021 00185 Rome USA Italy xni Sonia Jimenez G.D. Kitas Systemic Autoimmune Diseases Unit Department of Rheumatology Hospital clinic University of Birmingham Barcelona, Catalonia Birmingham Spain United Kingdom Katsunori Jinnouchi Kazuko Kobayashi Second Department of Pathology Department of Cell Chemistry Kumamoto University Institute of Cellular and Molecular Biology School of Medicine Okayama University Medical School Kumamoto 860-0811 Okayama Japan Japan Keiko Kaihara Takao Koike Department of Cell Chemistry Department of Medicine II Institute of Cellular and Molecular Biology Hokkaido University School of Medicine Okayama University Medical School Sapporo Okayama Japan Japan Nitza Lahat Junko Kasahara Lady Davis Carmel Medical Center Department of Cell Chemistry Bruce Rappaport Faculty of Medicine Institute of Cellular and Molecular Biology 7 Michal Street Okayama University Medical School Haifa, 34632 Okayama Israel Japan Marc Lambert Internal Medicine Department Srinivas V. Kaveri University Hospital of Lille INSERM U430 59035 Lille Cedex Hopital Broussais France Paris France Pnina Langevitz The Heller Institute of Medical Research Michel D. Kazatchkine Sheba Medical Center INSERM U430 Tel Hashomer and Sackler Faculty of Medicine Hopital Broussais Tel Aviv University Paris Tel Aviv France Israel Munther A. Khamashta Eduardo C. Lau Lupus Research Institute Specialty Laboratories, Inc. The Rayne Institute Research Laboratory St. Thomas' Hospital 2211 Michigan Avenue London Santa Monica, CA 90404 United Kingdom USA XIV S.N. Lavrentiadou Pier Luigi Meroni Signal Transduction Allergy & Clinical Immunology Unit UC Davis School of Medicine Department of Internal Medicine TB149, Davis Campus University of Milan Davis, CA 95616 IRCCS Istituto Auxologico Italiano USA Milan Italy Yair Levi Department of Medicine B and the Research Center of Autoimmune Diseases Fausta Micheletta Sheba Medical Center Institute of Clinical Medcine I Tel Hashomer University La Sapienza Israel Via del Policlinico 155 00185 Rome Italy Avi Livneh The Heller Institute of Medical Research Sheba Medical Center Tel Hashomer and Sackler Faculty of Medicine U. Michon-Pasturel Tel Aviv University Internal Medicine Department Tel Aviv University Hospital of Lille Israel 59035 Lille Cedex France Jukka Luoma A.I. Virtanen Institute of Molecular Sciences University of Kuopio Gunda Millonig RO. Box 1627 Institute for Biomedical Aging Research 70211 Kuopio Austrian Academy of Sciences Finland Rennweg 10 A-6020 Innsbruck Galina S. Marder Austria Long Island Jewish Medical Center New York USA Diana Milojevic Schneider Children's Hospital Eiji Matsuura Long Island Jewish Medical Center Department of Cell Chemistry Albert Einstein College of Medicine Institute of Cellular and Molecular Biology New Hyde Park, NY 11040 Okayama University Medical School New York Okayama USA Japan Werner-J. Mayet Outi Narvanen First Medical Department A.I. Virtanen Institute of Molecular Sciences University of Mainz University of Kuopio Langenbeckstrasse 1 PO. Box 1627 55101 Mainz 70211 Kuopio Germany Finland XV Lily Neumann Sonja Praprotnik Rheumatic Disease Unit and Epidermiology Department of Rheumatology Department University Medical Center Soroka Medical Center Ljubljana Faculty of Health Sciences Slovenia Ben Gurion University of the Negev Beer Sheva Israel Mordechai Pras The Heller Institute of Medical Research Andrew C. Nicholson Sheba Medical Center Center of Vascular Biology Tel Hashomer and Sackler Faculty of Medicine Cornell University Medical College Tel Aviv University 1300 York Ave Tel Aviv New York, NY Israel USA Antonino Nicoletti Manuel Ramos-Casals INSERM U430 Systemic Autoimmune Diseases Unit Hopital Broussais Hospital clinic Paris Barcelona, Catalonia France Spain Gerlinde Obermoser Elena Raschi Department of Dermatology Allergy & Clinical Immunology Unit University of Innsbruck Department of Internal Medicine Innsbruck University of Milan Austria IRCCS Istituto Auxologico Italiano Milan S. Frieda A. Pearce Italy Center of Vascular Biology Cornell University Medical College Lubica Rauova 1300 York Avenue Research Institute of Rheumatic Diseases NewYork, NY 10021 Piest'any USA Slovak Repubhc Vittorio Pengo T. Ravid Department of Clinical and Experimental Medicine Signal Transduction Thrombosis Center UC Davis School of Medicine University of Padova TB149, Davis Campus Via Gattamelata 64 Davis, CA 95616 1-35128 Padova USA Italy Ronan Revelen Michelle Petri Laboratory of Immunology Johns Hopkins University School of Medicine Institut de Synergic des Sciences Division of Rheumatology et de la Sante 1830E Monument street Brest University Medical School Baltimore, MD 21205 Brest USA France XVI Monica Riboni R. Scognamiglio Allergy & Clinical Immunology Unit Department of Clinical and Experimental Medicine Department of Internal Medicine Thrombosis Center University of Milan University of Padova IRCCS Istituto Auxologico Italiano Via Gattamelata 64 Milan 1-35128 Padova Italy Italy Norbert Sepp Giovanni Ricevuti Department of Dermatology Section of Internal Medicine and Nephrology University of Innsbruck Department of Internal Medicine and Therapeutics Innsbruck University of Pavia Austria Piazzale Golgi 4 1-27100 Pavia Italy Amarjit S. Sethi Department of Experimental Therapeutics The William Harvey Research Institute London Jozef Rovensky United Kingdom Research Institute of Rheumatic Diseases Nabr. I. Krasku 4 92101 Piest'any Yana Shafran Slovak Repubhc The Jerome Schottenstein Cellscan Center Department of Physics Bar-Ian University A. Ruffati Ramat Gan Department of Medical and Surgical Sciences Israel University of Padova Via Gattamelata 64 Aviv Shaish 1-35128 Padova Institute of Lipid and Atherosclerosis Research Italy Sheba Medical Center Tel Hashomer Israel Naomi Sakashita Second Department of Pathology S. Shapiro Kumamoto University Lady Davis Carmel Medical Center School of Medicine Bruce Rappaport Faculty of Medicine Kumamoto 860-0811 7 Michal Street Japan Haifa, 34632 Israel Andreas Schwarting Yaniv Sherer First Medical Department Department of Medicine B and the University of Mainz Research Center of Autoimmune Diseases Langenbeckstrasse 1 Sheba Medical Center 55101 Mainz Tel Hashomer Germany Israel xvn

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