Medical Hypot hews I u-w w91) ~LoqarnQrcwuKwl991
I 36.~26
Atherosclerosis as an Immune Disease? G. CLEW Servicede Cardbkgie 8, Centre Hospitalier Regional de Meg 57038 Metz Cedex 1, France
Abstract - Immunology has many effects on atherogenesis. In addition to their usual action risk factors for atherosclerosis have an immunomodulating effect and immunomodulation may be a new treatment of atherosclerosis.
Introduction The vascular surface of 1000 sq m represents an interface between man and his environment. This surface is permanently exposed to aggressive attacks which are inherent to the existence of life, with an endless process of destruction and repair and interference with various immunologically active agents (1). Aggressions are manifold and different including mechanical, toxic, infectious and immunological insults, leading to anatomical or functional injury of the endothelial cells (2). The attacked cells respond by releasing various cytokines, prostaglandins, leukotrienes and other mediators since they are in close contact with blood elements and hemostatic agents in order to maintain their standard state of life. This process is usually accurately regulated and leads to complete anatomical and functional recovery. Quite often, however, on a genetically fragile background the intensive and repeated aggressions may induce atherosclerotic lesions sometimes leading to serious final complications such as circulatory failure and thrombosis. Histo-immunologcial studies (3) by using monoclonal antibodies have suggested that atheroscleDate received27 April 1990 Date acccpd 21 June 1990
rotic injury belongs to immune disorders involving macrophages (4), T-lymphocytes (5), immunoglobulins (6), complement (7) and vascular smooth muscle cells expressing histccompatibility antigens (8). More recently, the macrophage has been considered as a key cell in atherogenesis (9, 10); first of all, it is a major contributor in the immune system (11). Macrophages arc able to secrete a great number of mediators with manifold effects (12); they am also cleaning cells being capable of removing cell debris and cholesterol from the vessel wall and carrying them to the site of catabolism (13). Their multiple functions ate governed by antigens and numerous cytokines involving regulatory loops among various immunologically active cells (14); these loops are under the control of the neuroendocrine system (15). When one of the mechanisms becomes ineffective, macrophages become foam cells by accumulating cholesterol. The secreted mediators (16) amplify the injury and participate in the cell recruitment. Smooth muscle cells start to leave the media and reach the intima under the influence of growth factors whose receptors are modulated by certain cytokines (17). These cells also become secretory and immunocompetent (18.19). accumulate cholesterol as
24
25
ATHEROK!LER0SIs As IN IMMUNE DLWASE?
macrophages do and participate in the formation of References the lipid plaque, as the final consequenceof the fatty 1. Haust MD.
degenerationof the cells.
Atherogenesis seems to be correlated with immune dysregulation of multiple origins, one of them being dyslipidemia (20) representing more than a risk factor (21), but a true cause of atherosclerosis (22). This process can be understood when one is aware of the role of lipids in the structure and the function of cell membranes (23), as well as in the importance of various mediators in the function of the immune system (24). Yet the consequences of dietetic manipulations are not all beneficial (25, 2.6) and dyslipidemias are neither necessarily nor sufficiently enough to induce atherosclerosis. The immunological state of an individual does not rely only on his eating habits, it is also controlled by the infectious and parasitic environment which can modulate the activity of immunocompetent cells and the rate of cytokine release. The epidemiological differences among developed and developing countries with respect to the incidence of cardiovascular diseases may be explained in this way. Hygiene and antibiotic therapy are certainly involved in the frequency of these diseases in developed countries (27). Finally, all factors which are likely to modulate immune processes are able to interface with atherogenesis. Disorders of the neumendocrine regulation of the immune system can account for the role of stress in atherogenesis, whereas the increase in the occurrence of cardiovascular diseases in relation to the lifespan may be connected lo immune dysregulations inherent to ageing and the length of exposure to risk factors.
Recent concepts at the pathogaresir d athemclerusk. CMAJ 140. 929, 1989. 2. Munro JM. htran RS. ‘Ihe pthogenerir of ahrmsclm-
sia: athcrogenesisand inflammation.Lab Invest 58,249-X1, 1988. 3. Gown AM. TaukadatT, RoarR. II. Immunocytochanial analysis of the cellular composition d human atherosclerotic lesions. Am J Pathol 126. 191-207.1986. 4. Mitchinsan MJ. Ball RY. Macrqhges and athemgmesis. Lancet 2, l&148.1987. 5. Emewn EE, Robettson AL T-Lymphcyter in aonic and
6.
7.
8.
9.
10.
11. 12. 13.
14. 15.
Conclusion
16.
Atherogenesis can therefore be summarized as an aggressive process as the repairing of the vascular wall is modulated by the immune system. Any individual has his own immunological story and has in his vessels the fingerprints of various incidents, before often dying of thrombosis induced by misregulated messengers of immunity. If these conditions are concerned, the treatment of atherosclerosis cannot be assumed as a simple dietetic correction of dyslipidemias since these interventions are neither the only nor the best ways to regulate the immune processes. Gamma interferon is an endogeneous inhibitor of growth factors (28,29,30) and the hepatic metabolism of cholesterol is also dependent on cytokines (31). The therapeutic induction of adaptation and the use of immuno-modulator treatment (32) would possibly facilitate a reduction in frequency of atherosclerosis.
17.
18.
19.
20. 21. 22.
23. 24.
mary intimas. Their potentiil role in atherogenesis. Am J Path01130.369-376. 1988. Hansson GK; Bondjers G, Bylocka A, Hjalmarsson L Ultrastmctural studies on the localixation of IgG in the aortic atdothelium intima of atherosclerotic and nar atherosclerotic rabbits. Exp Mal pathd 33.302315. 1980. Niculescu F, Rus GH, Vlaiuu R. Activation of human temrinal complement pathway in atherosclerosis. Clin Immunol Immunopa~&ol. 45,- 147-155, 1987. Jcnassm L. Holm J. Hansson GK. Smocah muscle celb express Ia antigens during arterial response to injury. Lab Invest 58.310-315, 1988. Gerrity RG. The role of the moncqtc in athcrogcnesis I. Transit&r of bIood-home monocytes into foam celb in fatty lesions. Am J Pathol 103, 181-190. 1981. Joris I, Zand T. Nunnari JJ. Krolikowski FJ. Majno G. Studies on the pathogenesis of atherosclerosis. I. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats. Am J Path 113,341358.1983. Geppert TD, Lipsky PE. Immunoregulatory activities of macrophages. Transpl Pmc 20. 1154-l 155, 1988. Nathan CF. Secretory products of macrophages. J Clin Invest 3 19-326.1987. Gerrity RG. The role of the monocytc in atherogmesis II. Migratim of foam cells from atherosclerotic lesions. Am J Path. 103.191-200, 1981. Van Furth R. Mononuclear phagocytes. Characteristics, physiology and function. Martinus Nyhoff, 1985. Ricci M. Immunoregulation in clinical diseases: an overview. Clin Immunol Immunopath S3S12. 1989. Ross R. Platelet derived growth factor. Lancct 1. 1179-1182, 1989. Rubin K. Hansson GK et al. Induction of B-type receptors for platelet-derived growth factor in vascular inflammatiar: possible implications for development of vascular proliferative lesions. Lancet 1, 1353-1356, 1988. Warner SJC. Auger KR. Libby l? Human interleukm I induces interleukin 1 g& expmssim~in human vascular smooth muscle cells. J Exu Med 165.1316-1331.1987. Libby P, Wamer SJC, Salomon RN, Birinyi LK. Production of platelet-derived growth factor-like mitogar by smooth muscle cells from human atheroma. New Engl J Med. 318, 1493-1498. 1988. Klurfeld DM. Interactions of immune function with lipids and atherosclerosis. Crit Rev Tox. 11.333-365, 1983. Shekelle RB. Stamler J. Dietary cholesterol and iscbaemic heart disease. Lancct 1, 1177-1178, 1989. Steinberg D et al. Beyond chdesterol. Modifications of lowdensity lipoprotein that incmasc its atherogenicity. New Engl J Med 320.915-924, 1989. Yeagle PL. Lipid regulatim of cell membrane structum and function. Faseb J 3, 1833-1841. 1989. PaImblad J. Gyllmhammar H. Effect of dietary lipids on im-
MEDICAL HYpoTHEsEs
26 munity and inflammation. APMJS %. 571-583.1988. 25. Leaf A. Management of hypercholwterolemia Are prevmtive interventiats advisable? New Engl J 321.680684, 1989. 26. Isles CG. Hole DJ, Gillis CR, Hawthorne VM, Lever AE Plasma ChoJesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey. Brit Mcd J 298.920-924.1989. 27. CJerc G. Clerc M. Ecology and arteriosclerosis. Medical Hypotheses 21,97-103.1986. 28. Balkwill FR. Pkotide renulatow factors. Interferons. Lancet 1. 1060-1063.198-9. 29. Warner SJC, Friedman GB, Libby l? Immune interferon inhibitors proliferation and induces 2’-5’-Gligoadenylate syn-
geneexpresaicn in human vascualr smooth muscle cells. J Clm Invest 83.11761182, 1989. 30. Hansson GK. Jonassat L. Hdm J, Clowes MM, Qowes AW. a interferon mgulates vascular smoah muscle proliieration and Ia antigen expmssion in vivo and in vitro. Cir Res 62, 712-719. 1988. 3 1. Nimer SD. Champlin RE. Golde DW. Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor. JAMA 260.32973300,1988. 32. Duff GW. Peptide regulatory factors in nut-malignant disease. Lancet 1.143~1434,1989. thetaae
I 36.~26
Atherosclerosis as an Immune Disease? G. CLEW Servicede Cardbkgie 8, Centre Hospitalier Regional de Meg 57038 Metz Cedex 1, France
Abstract - Immunology has many effects on atherogenesis. In addition to their usual action risk factors for atherosclerosis have an immunomodulating effect and immunomodulation may be a new treatment of atherosclerosis.
Introduction The vascular surface of 1000 sq m represents an interface between man and his environment. This surface is permanently exposed to aggressive attacks which are inherent to the existence of life, with an endless process of destruction and repair and interference with various immunologically active agents (1). Aggressions are manifold and different including mechanical, toxic, infectious and immunological insults, leading to anatomical or functional injury of the endothelial cells (2). The attacked cells respond by releasing various cytokines, prostaglandins, leukotrienes and other mediators since they are in close contact with blood elements and hemostatic agents in order to maintain their standard state of life. This process is usually accurately regulated and leads to complete anatomical and functional recovery. Quite often, however, on a genetically fragile background the intensive and repeated aggressions may induce atherosclerotic lesions sometimes leading to serious final complications such as circulatory failure and thrombosis. Histo-immunologcial studies (3) by using monoclonal antibodies have suggested that atheroscleDate received27 April 1990 Date acccpd 21 June 1990
rotic injury belongs to immune disorders involving macrophages (4), T-lymphocytes (5), immunoglobulins (6), complement (7) and vascular smooth muscle cells expressing histccompatibility antigens (8). More recently, the macrophage has been considered as a key cell in atherogenesis (9, 10); first of all, it is a major contributor in the immune system (11). Macrophages arc able to secrete a great number of mediators with manifold effects (12); they am also cleaning cells being capable of removing cell debris and cholesterol from the vessel wall and carrying them to the site of catabolism (13). Their multiple functions ate governed by antigens and numerous cytokines involving regulatory loops among various immunologically active cells (14); these loops are under the control of the neuroendocrine system (15). When one of the mechanisms becomes ineffective, macrophages become foam cells by accumulating cholesterol. The secreted mediators (16) amplify the injury and participate in the cell recruitment. Smooth muscle cells start to leave the media and reach the intima under the influence of growth factors whose receptors are modulated by certain cytokines (17). These cells also become secretory and immunocompetent (18.19). accumulate cholesterol as
24
25
ATHEROK!LER0SIs As IN IMMUNE DLWASE?
macrophages do and participate in the formation of References the lipid plaque, as the final consequenceof the fatty 1. Haust MD.
degenerationof the cells.
Atherogenesis seems to be correlated with immune dysregulation of multiple origins, one of them being dyslipidemia (20) representing more than a risk factor (21), but a true cause of atherosclerosis (22). This process can be understood when one is aware of the role of lipids in the structure and the function of cell membranes (23), as well as in the importance of various mediators in the function of the immune system (24). Yet the consequences of dietetic manipulations are not all beneficial (25, 2.6) and dyslipidemias are neither necessarily nor sufficiently enough to induce atherosclerosis. The immunological state of an individual does not rely only on his eating habits, it is also controlled by the infectious and parasitic environment which can modulate the activity of immunocompetent cells and the rate of cytokine release. The epidemiological differences among developed and developing countries with respect to the incidence of cardiovascular diseases may be explained in this way. Hygiene and antibiotic therapy are certainly involved in the frequency of these diseases in developed countries (27). Finally, all factors which are likely to modulate immune processes are able to interface with atherogenesis. Disorders of the neumendocrine regulation of the immune system can account for the role of stress in atherogenesis, whereas the increase in the occurrence of cardiovascular diseases in relation to the lifespan may be connected lo immune dysregulations inherent to ageing and the length of exposure to risk factors.
Recent concepts at the pathogaresir d athemclerusk. CMAJ 140. 929, 1989. 2. Munro JM. htran RS. ‘Ihe pthogenerir of ahrmsclm-
sia: athcrogenesisand inflammation.Lab Invest 58,249-X1, 1988. 3. Gown AM. TaukadatT, RoarR. II. Immunocytochanial analysis of the cellular composition d human atherosclerotic lesions. Am J Pathol 126. 191-207.1986. 4. Mitchinsan MJ. Ball RY. Macrqhges and athemgmesis. Lancet 2, l&148.1987. 5. Emewn EE, Robettson AL T-Lymphcyter in aonic and
6.
7.
8.
9.
10.
11. 12. 13.
14. 15.
Conclusion
16.
Atherogenesis can therefore be summarized as an aggressive process as the repairing of the vascular wall is modulated by the immune system. Any individual has his own immunological story and has in his vessels the fingerprints of various incidents, before often dying of thrombosis induced by misregulated messengers of immunity. If these conditions are concerned, the treatment of atherosclerosis cannot be assumed as a simple dietetic correction of dyslipidemias since these interventions are neither the only nor the best ways to regulate the immune processes. Gamma interferon is an endogeneous inhibitor of growth factors (28,29,30) and the hepatic metabolism of cholesterol is also dependent on cytokines (31). The therapeutic induction of adaptation and the use of immuno-modulator treatment (32) would possibly facilitate a reduction in frequency of atherosclerosis.
17.
18.
19.
20. 21. 22.
23. 24.
mary intimas. Their potentiil role in atherogenesis. Am J Path01130.369-376. 1988. Hansson GK; Bondjers G, Bylocka A, Hjalmarsson L Ultrastmctural studies on the localixation of IgG in the aortic atdothelium intima of atherosclerotic and nar atherosclerotic rabbits. Exp Mal pathd 33.302315. 1980. Niculescu F, Rus GH, Vlaiuu R. Activation of human temrinal complement pathway in atherosclerosis. Clin Immunol Immunopa~&ol. 45,- 147-155, 1987. Jcnassm L. Holm J. Hansson GK. Smocah muscle celb express Ia antigens during arterial response to injury. Lab Invest 58.310-315, 1988. Gerrity RG. The role of the moncqtc in athcrogcnesis I. Transit&r of bIood-home monocytes into foam celb in fatty lesions. Am J Pathol 103, 181-190. 1981. Joris I, Zand T. Nunnari JJ. Krolikowski FJ. Majno G. Studies on the pathogenesis of atherosclerosis. I. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats. Am J Path 113,341358.1983. Geppert TD, Lipsky PE. Immunoregulatory activities of macrophages. Transpl Pmc 20. 1154-l 155, 1988. Nathan CF. Secretory products of macrophages. J Clin Invest 3 19-326.1987. Gerrity RG. The role of the monocytc in atherogmesis II. Migratim of foam cells from atherosclerotic lesions. Am J Path. 103.191-200, 1981. Van Furth R. Mononuclear phagocytes. Characteristics, physiology and function. Martinus Nyhoff, 1985. Ricci M. Immunoregulation in clinical diseases: an overview. Clin Immunol Immunopath S3S12. 1989. Ross R. Platelet derived growth factor. Lancct 1. 1179-1182, 1989. Rubin K. Hansson GK et al. Induction of B-type receptors for platelet-derived growth factor in vascular inflammatiar: possible implications for development of vascular proliferative lesions. Lancet 1, 1353-1356, 1988. Warner SJC. Auger KR. Libby l? Human interleukm I induces interleukin 1 g& expmssim~in human vascular smooth muscle cells. J Exu Med 165.1316-1331.1987. Libby P, Wamer SJC, Salomon RN, Birinyi LK. Production of platelet-derived growth factor-like mitogar by smooth muscle cells from human atheroma. New Engl J Med. 318, 1493-1498. 1988. Klurfeld DM. Interactions of immune function with lipids and atherosclerosis. Crit Rev Tox. 11.333-365, 1983. Shekelle RB. Stamler J. Dietary cholesterol and iscbaemic heart disease. Lancct 1, 1177-1178, 1989. Steinberg D et al. Beyond chdesterol. Modifications of lowdensity lipoprotein that incmasc its atherogenicity. New Engl J Med 320.915-924, 1989. Yeagle PL. Lipid regulatim of cell membrane structum and function. Faseb J 3, 1833-1841. 1989. PaImblad J. Gyllmhammar H. Effect of dietary lipids on im-
MEDICAL HYpoTHEsEs
26 munity and inflammation. APMJS %. 571-583.1988. 25. Leaf A. Management of hypercholwterolemia Are prevmtive interventiats advisable? New Engl J 321.680684, 1989. 26. Isles CG. Hole DJ, Gillis CR, Hawthorne VM, Lever AE Plasma ChoJesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey. Brit Mcd J 298.920-924.1989. 27. CJerc G. Clerc M. Ecology and arteriosclerosis. Medical Hypotheses 21,97-103.1986. 28. Balkwill FR. Pkotide renulatow factors. Interferons. Lancet 1. 1060-1063.198-9. 29. Warner SJC, Friedman GB, Libby l? Immune interferon inhibitors proliferation and induces 2’-5’-Gligoadenylate syn-
geneexpresaicn in human vascualr smooth muscle cells. J Clm Invest 83.11761182, 1989. 30. Hansson GK. Jonassat L. Hdm J, Clowes MM, Qowes AW. a interferon mgulates vascular smoah muscle proliieration and Ia antigen expmssion in vivo and in vitro. Cir Res 62, 712-719. 1988. 3 1. Nimer SD. Champlin RE. Golde DW. Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor. JAMA 260.32973300,1988. 32. Duff GW. Peptide regulatory factors in nut-malignant disease. Lancet 1.143~1434,1989. thetaae
