The problem of accelerated atherosclerosis in systemic lupus erythematosus: Insights into a complex co-morbidity

Summary

Rheumatic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), are associated with antibodies to “self” antigens. Persons with autoimmune diseases, most notably SLE, are at increased risk for developing accelerated cardiovascular disease. The link between immune and inflammatory responses in the pathogenesis of cardiovascular disease has been firmly established; yet, despite our increasing knowledge, accelerated atherosclerosis continues to be a significant co-morbidity and cause of mortality in SLE. Recent animal models have been generated in order to identify mechanism(s) behind SLE-accelerated atherosclerosis. In addition, clinical studies have been designed to examine potential treatments options. This review will highlight data from recent studies of immunity in SLE and atherosclerosis and discuss the potential implications of these investigations.

Keywords

Systemic lupus erythematosus - atherosclerosis - autoimmunity - cardiovascular disease

• References

• 1 Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003; 56: 481-490.
• 2 Vanholder R, De Keyser F, Kips J. et al. The pathophysiology of lupus erythematosus. Eur J Dermatol 1998; 8: 4-7.
• 3 Munoz LE, van Bavel C, Franz S. et al. Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus 2008; 17: 371-375.
• 4 Liu Z, Bethunaickan R, Huang W. et al. Interferon-alpha accelerates murine systemic lupus erythematosus in a T cell-dependent manner. Arthritis Rheum 2011; 63: 219-229.
• 5 Mathian A, Weinberg A, Gallegos M. et al. IFN-alpha induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB/c mice. J Immunol 2005; 174: 2499-2506.
• 6 Bengtsson AA, Sturfelt G, Truedsson L. et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 2000; 9: 664-671.
• 7 Ronnblom L, Alm GV, Eloranta ML. The type I interferon system in the development of lupus. Semin Immunol 2011; 23: 113-121.
• 8 Urowitz MB, Bookman AA, Koehler BE. et al. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976; 60: 221-225.
• 9 Trager J, Ward MM. Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol 2001; 13: 345-351.
• 10 Esdaile JM, Abrahamowicz M, Grodzicky T. et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001; 44: 2331-2337.
• 11 Manzi S, Selzer F, Sutton-Tyrrell K. et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999; 42: 51-60.
• 12 Manzi S, Meilahn EN, Rairie JE. et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145: 408-415.
• 13 Tyrrell PN, Beyene J, Feldman BM. et al. Rheumatic disease and carotid intima-media thickness: a systematic review and meta-analysis. Arterioscl Thromb Vasc Biol 2010; 30: 1014-1026.
• 14 Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol 2006; 2: 99-106.
• 15 Kaplan MJ. Cardiovascular disease in rheumatoid arthritis. Curr Opin Rheumatol 2006; 18: 289-297.
• 16 Gerli R, Schillaci G, Giordano A. et al. CD4+CD28- T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation 2004; 109: 2744-2748.
• 17 Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 1999; 100: 2124-2126.
• 18 George J, Harats D, Gilburd B. et al. Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. Circulation 1999; 99: 2227-2230.
• 19 Lopes-Virella MF, Binzafar N, Rackley S. et al. The uptake of LDL-IC by human macrophages: predominant involvement of the Fc gamma RI receptor. Atherosclerosis 1997; 135: 161-170.
• 20 Hasunuma Y, Matsuura E, Makita Z. et al. Involvement of beta 2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol 1997; 107: 569-573.
• 21 Haque S, Gordon C, Isenberg D. et al. Risk factors for clinical coronary heart disease in systemic lupus erythematosus: the lupus and atherosclerosis evaluation of risk (LASER) study. J Rheumatol 2010; 37: 322-329.
• 22 McMahon M, Grossman J, FitzGerald J. et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006; 54: 2541-2549.
• 23 Srivastava R, Yu S, Parks BW. et al. Autoimmune-mediated reduction of high-density lipoprotein-cholesterol and paraoxonase 1 activity in systemic lupus erythematosus-prone gld mice. Arthritis Rheum 2011; 63: 201-211.
• 24 McMahon M, Grossman J, Skaggs B. et al. Dysfunctional Pro-Inflammatory High Density Lipoproteins Confer Increased Risk for Atherosclerosis in Women with Systemic Lupus Erythematosus. Arthritis Rheum 2009; 60: 2428-2437.
• 25 Lahita RG, Rivkin E, Cavanagh I. et al. Low levels of total cholesterol, high-density lipoprotein, and apolipoprotein A1 in association with anticardiolipin antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 1993; 36: 1566-1574.
• 26 O'Neill SG, Giles I, Lambrianides A. et al. Antibodies to apolipoprotein A-I, high-density lipoprotein, and C-reactive protein are associated with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2010; 62: 845-854.
• 27 Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 2000; 13: 277-285.
• 28 Furukawa F, Tanaka H, Sekita K. et al. Dermatopathological studies on skin lesions of MRL mice. Arch Dermatol Res 1984; 276: 186-194.
• 29 Furukawa F, Yoshimasu T. Animal models of spontaneous and drug-induced cutaneous lupus erythematosus. Autoimmun Rev 2005; 4: 345-350.
• 30 Morel L. Mouse models of human autoimmune diseases: essential tools that require the proper controls. PLoS Biol 2004; 2: E241
• 31 Aprahamian T, Rifkin I, Bonegio R. et al. Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med 2004; 199: 1121-1131.
• 32 Feng X, Li H, Rumbin AA. et al. ApoE-/-Fas-/-C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis and osteopenia. J Lipid Res 2007; 48: 794-805.
• 33 Ma Z, Choudhury A, Kang SA. et al. Accelerated Atherosclerosis in ApoE-Deficient Lupus Mouse Models1. Clin Immunol 2008; 127: 168-175.
• 34 Morel L, Rudofsky UH, Longmate JA. et al. Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1994; 1: 219-229.
• 35 Morel L, Yu Y, Blenman KR. et al. Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain. Mamm Genome 1996; 7: 335-339.
• 36 Morel L, Mohan C, Yu Y. et al. Functional dissection of systemic lupus erythematosus using congenic mouse strains. J Immunol 1997; 158: 6019-6028.
• 37 Stanic AK, Stein CM, Morgan AC. et al. Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Proc Natl Acad Sci USA 2006; 103: 7018-7023.
• 38 Braun N, Wade N, Wakeland E. et al. Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr-/- mice. Lupus 2008; 17: 1070-1078.
• 39 Wade NS, Stevenson BG, Dunlap DS. et al. The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice. Lupus 2010; 19: 34-42.
• 40 Ait-Oufella H, Herbin O, Bouaziz JD. et al. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med 2010; 207: 1579-1587.
• 41 Kyaw T, Tay C, Khan A. et al. Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J Immunol 2010; 185: 4410-4419.
• 42 Asanuma Y, Chung CP, Oeser A. et al. Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors. J Rheumatol 2006; 33: 539-545.
• 43 Svenungsson E, Fei GZ, Jensen-Urstad K. et al. TNF-alpha: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease. Lupus 2003; 12: 454-461.
• 44 Lopez-Pedrera C, Aguirre MA, Barbarroja N. et al. Accelerated atherosclerosis in systemic lupus erythematosus: role of proinflammatory cytokines and thera-peutic approaches. J Biomed Biotechnol 2010; epub ahead of print..
• 45 Huber SA, Sakkinen P, Conze D. et al. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999; 19: 2364-2367.
• 46 Schieffer B, Selle T, Hilfiker A. et al Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation. United States. 2004; 3493-3500.
• 47 Mallat Z, Gojova A, Marchiol-Fournigault C. et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001; 89: 930-934.
• 48 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: 10-17.
• 49 Von Der Thusen JH, Kuiper J, Fekkes ML. et al. Attenuation of atherogenesis by systemic and local adenovirus-mediated gene transfer of interleukin-10 in LDLr-/- mice. Faseb J 2001; 15: 2730-2732.
• 50 Houssiau FA, Lefebvre C, Vanden Berghe M. et al. Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus 1995; 4: 393-395.
• 51 Mageed RA, Prud'homme GJ. Immunopathology and the gene therapy of lupus. Gene Ther 2003; 10: 861-874.
• 52 Robertson AK, Rudling M, Zhou X. et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 2003; 112: 1342-1350.
• 53 Gojova A, Brun V, Esposito B. et al. Specific abrogation of transforming growth factor-beta signaling in T cells alters atherosclerotic lesion size and composition in mice. Blood 2003; 102: 4052-4058.
• 54 Kohut E, Hajdu M, Gergely P. et al. Expression of TGFbeta1 and its signaling components by peripheral lymphocytes in systemic lupus erythematosus. Pathol Oncol Res 2009; 15: 251-256.
• 55 Elbeldi-Ferchiou A, Ben Ahmed M, Smiti-Khanfir M. et al. Resistance to Exogenous TGF-beta Effects in Patients with Systemic Lupus Erythematosus. J Clin Immunol 2011; 31: 574-583.
• 56 Jackson M, Ahmad Y, Bruce IN. et al. Activation of transforming growth factor-beta1 and early atherosclerosis in systemic lupus erythematosus. Arthritis Res Ther 2006; 8: R81
• 57 Wofsy D, Seaman WE. Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. J Immunol 1987; 138: 3247-3253.
• 58 Jevnikar AM, Grusby MJ, Glimcher LH. Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. J Exp Med 1994; 179: 1137-1143.
• 59 Koh DR, Ho A, Rahemtulla A. et al. Murine lupus in MRL/lpr mice lacking CD4 or CD8 T cells. Eur J Immunol 1995; 25: 2558-2562.
• 60 La Cava A. Lupus and T cells. Lupus 2009; 18: 196-201.
• 61 Crispin JC, Kyttaris VC, Terhorst C. et al. T cells as therapeutic targets in SLE. Nature Rev Rheumatol 2010; 6: 317-325.
• 62 Liossis SN, Ding XZ, Dennis GJ. et al. Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain. J Clin Invest 1998; 101: 1448-1457.
• 63 Valencia X, Yarboro C, Illei G. et al. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 2007; 178: 2579-2588.
• 64 Hsu WT, Suen JL, Chiang BL. The role of CD4CD25 T cells in autoantibody production in murine lupus. Clin Exp Immunol 2006; 145: 513-519.
• 65 Liu MF, Wang CR, Fung LL. et al. Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 2004; 59: 198-202.
• 66 Wan S, Xia C, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J Immunol 2007; 178: 271-279.
• 67 de Boer OJ, van der Meer JJ, Teeling P. et al. Low Numbers of FOXP3 Positive Regulatory T Cells Are Present in all Developmental Stages of Human Atherosclerotic Lesions. PLoS One 2007; 2: e779
• 68 Ait-Oufella H, Salomon BL, Potteaux S. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 2006; 12: 178-180.
• 69 Mor A, Planer D, Luboshits G. et al. Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis. Arterioscl Thromb Vasc Biol 2007; 27: 893-900.
• 70 Wong CK, Lit LC, Tam LS. et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 2008; 127: 385-393.
• 71 Crispin JC, Oukka M, Bayliss G. et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol 2008; 181: 8761-8766.
• 72 Hsu HC, Yang P, Wang J. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008; 9: 166-175.
• 73 Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol 2007; 178: 7849-7858.
• 74 Eid RE, Rao DA, Zhou J. et al. Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 2009; 119: 1424-1432.
• 75 Pejnovic N, Vratimos A, Lee SH. et al. Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet. Mol Immunol 2009; 47: 37-45.
• 76 Erbel C, Chen L, Bea F. et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol 2009; 183: 8167-8175.
• 77 Smith E, Prasad KM, Butcher M. et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010; 121: 1746-1755.
• 78 van Es T, van Puijvelde GH, Ramos OH. et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun 2009; 388: 261-265.
• 79 Taleb S, Romain M, Ramkhelawon B. et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 2009; 206: 2067-2077.
• 80 Cheng X, Taleb S, Wang J. et al. Inhibition of IL-17A in atherosclerosis. Atherosclerosis 2011; 215: 471-474.
• 81 Taleb S, Tedgui A, Mallat Z. Interleukin-17: friend or foe in atherosclerosis?. Curr Opin Lipidol 2010; 21: 404-408.
• 82 Jacob N, Stohl W. Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past, present, and future. Autoimmunity 2010; 43: 84-97.
• 83 Chan OT, Madaio MP, Shlomchik MJ. The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 1999; 169: 107-121.
• 84 Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nature reviews Rheumatology 2010; 6: 326-337.
• 85 Stohl W, Scholz JL, Cancro MP. Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside. Curr Opin Rheumatol 2011; 23: 305-310.
• 86 Wiglesworth AK, Ennis KM, Kockler DR. Belimumab: a BLyS-specific inhibitor for systemic lupus erythematosus. Ann Pharmacother 2010; 44: 1955-1961.
• 87 Major AS, Fazio S, Linton MF. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol 2002; 22: 1892-1898.
• 88 Caligiuri G, Nicoletti A, Poirier B. et al. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 2002; 109: 745-753.
• 89 Binder CJ, Hartvigsen K, Chang MK. et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest 2004; 114: 427-437.
• 90 Horkko S, Bird DA, Miller E. et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest 1999; 103: 117-128.
• 91 Bedi U, Singh M, Singh P. et al. Effects of statins on progression of coronary artery disease as measured by intravascular ultrasound. J Clin Hypertens 2011; 13: 492-496.
• 92 van Leuven S I, Mendez-Fernandez YV, Stroes ES. et al. Statin therapy in lupus-mediated atherogenesis: two birds with one stone?. Ann Rheum Dis 2011; 70: 245-248.
• 93 Petri MA, Kiani AN, Post W. et al. Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 2011; 70: 760-765.
• 94 Aprahamian T, Bonegio R, Rizzo J. et al. Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. J Immunol 2006; 177: 3028-3034.
• 95 Woo JM, Lin Z, Navab M. et al. Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis. Arthritis Res Ther 2010; 12: R93
• 96 Zhou X, Paulsson G, Stemme S. et al. Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apoE-knockout mice. J Clin Invest 1998; 101: 1717-1725.
• 97 Robertson AK, Zhou X, Strandvik B. et al. Severe hypercholesterolaemia leads to strong Th2 responses to an exogenous antigen. Scand J Immunol 2004; 59: 285-293.