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The immune system in atherosclerosis

Abstract

Cardiovascular disease, a leading cause of mortality worldwide, is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Lesions of atherosclerosis contain macrophages, T cells and other cells of the immune response, together with cholesterol that infiltrates from the blood. Targeted deletion of genes encoding costimulatory factors and proinflammatory cytokines results in less disease in mouse models, whereas interference with regulatory immunity accelerates it. Innate as well as adaptive immune responses have been identified in atherosclerosis, with components of cholesterol-carrying low-density lipoprotein triggering inflammation, T cell activation and antibody production during the course of disease. Studies are now under way to develop new therapies based on these concepts of the involvement of the immune system in atherosclerosis.

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Figure 1: Immune components of the atherosclerotic plaque.

Katie Vicari

Figure 2: T cell activation in the vessel wall.

Katie Vicari

Figure 3: Activation of innate immune responses in the atheroma.

Katie Vicari

Figure 4: Inverse relationship between the uptake of antigen-presenting cells and T cell recognition of oxLDL.

Katie Vicari

Figure 5: Mechanisms of LDL tolerance and autoreactivity: a hypothesis.

Katie Vicari

References

  1. Dahlof, B. Cardiovascular disease risk factors: epidemiology and risk assessment. Am. J. Cardiol. 105, 3A–9A (2010).

    Article  PubMed  Google Scholar 

  2. Lloyd-Jones, D.M. Cardiovascular risk prediction: basic concepts, current status, and future directions. Circulation 121, 1768–1777 (2010).

    Article  PubMed  Google Scholar 

  3. Hansson, G.K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Hansson, G.K., Robertson, A.K.L. & Söderberg-Nauclér, C. Inflammation and atherosclerosis. Annu. Rev. Pathol. 1, 297–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Tabas, I., Williams, K.J. & Boren, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116, 1832–1844 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Skålen, K. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Bochkov, V.N. et al. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT. Blood 99, 199–206 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Gharavi, N.M. et al. Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. J. Biol. Chem. 282, 31460–31468 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Gargalovic, P.S. et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26, 2490–2496 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Binder, C.J. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat. Med. 9, 736–743 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Caligiuri, G. et al. Phosphorylcholine-targeting immunization reduces atherosclerosis. J. Am. Coll. Cardiol. 50, 540–546 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Schiopu, A. et al. Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis. Circulation 110, 2047–2052 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Zernecke, A., Shagdarsuren, E. & Weber, C. Chemokines in atherosclerosis: an update. Arterioscler. Thromb. Vasc. Biol. 28, 1897–1908 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Smith, J.D. et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc. Natl. Acad. Sci. USA 92, 8264–8268 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Niessner, A. et al. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation 114, 2482–2489 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Niessner, A. & Weyand, C.M. Dendritic cells in atherosclerotic disease. Clin. Immunol. 134, 25–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Tedgui, A. & Mallat, Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol. Rev. 86, 515–581 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Kovanen, P.T. Mast cells: multipotent local effector cells in atherothrombosis. Immunol. Rev. 217, 105–122 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Grabner, R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J. Exp. Med. 206, 233–248 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Lundberg, A.M. & Hansson, G.K. Innate immune signals in atherosclerosis. Clin. Immunol. 134, 5–24 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Greaves, D.R. & Gordon, S. The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. J. Lipid Res. 50 Suppl, S282–S286 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Tall, A.R. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J. Intern. Med. 263, 256–273 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Yvan-Charvet, L. et al. ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. Circ. Res. 106, 1861–1869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Edfeldt, K., Swedenborg, J., Hansson, G.K. & Yan, Z.Q. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105, 1158–1161 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Curtiss, L.K. & Tobias, P.S. Emerging role of toll-like receptors in atherosclerosis. J. Lipid Res. 50, 5340–5345 (2009).

    Article  CAS  Google Scholar 

  26. Michelsen, K.S. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl. Acad. Sci. USA 101, 10679–10684 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat. Med. 10, 416–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Kirii, H. et al. Lack of interleukin-1b decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 656–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Elhage, R. et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc. Res. 59, 234–240 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Seimon, T.A. et al. Atherogenic lipids and lipoproteins trigger CD36–TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 12, 467–482 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. West, X.Z. et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467, 972–976 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Miller, Y.I. et al. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J. Biol. Chem. 278, 1561–1568 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Mullick, A.E., Tobias, P.S. & Curtiss, L.K. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. 115, 3149–3156 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rajamaki, K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE 5, e11765 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Edfeldt, K. et al. Involvement of the antimicrobial peptide LL-37 in human atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 26, 1551–1557 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Samuelsson, B., Morgenstern, R. & Jakobsson, P.J. Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol. Rev. 59, 207–224 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Hui, Y. et al. Targeted deletions of cyclooxygenase-2 and atherogenesis in mice. Circulation 121, 2654–2660 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bäck, M. et al. Leukotriene B4 signaling through NF-kB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia. Proc. Natl. Acad. Sci. USA 102, 17501–17506 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Heller, E.A. et al. Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation 112, 578–586 (2005).

    Article  PubMed  Google Scholar 

  42. Mehrabian, M. et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ. Res. 91, 120–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Spanbroek, R. et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc. Natl. Acad. Sci. USA 100, 1238–1243 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qiu, H. et al. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc. Natl. Acad. Sci. USA 103, 8161–8166 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Helgadottir, A. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36, 233–239 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Andersson, J., Libby, P. & Hansson, G.K. Adaptive immunity and atherosclerosis. Clin. Immunol. 134, 33–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Reardon, C.A. et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 1011–1016 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Zhou, X., Nicoletti, A., Elhage, R. & Hansson, G.K. Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102, 2919–2922 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Caligiuri, G., Nicoletti, A., Poirier, B. & Hansson, G.K. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J. Clin. Invest. 109, 745–753 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Major, A.S., Fazio, S. & Linton, M.F. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 22, 1892–1898 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Binder, C.J. et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J. Clin. Invest. 114, 427–437 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ait-Oufella, H. et al. B cell depletion reduces the development of atherosclerosis in mice. J. Exp. Med. 207, 1579–1587 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kyaw, T. et al. Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J. Immunol. 185, 4410–4419 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Palinski, W., Miller, E. & Witztum, J.L. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc. Natl. Acad. Sci. USA 92, 821–825 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ameli, S. et al. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler. Thromb. Vasc. Biol. 16, 1074–1079 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Nilsson, J., Hansson, G.K. & Shah, P.K. Immunomodulation of atherosclerosis: implications for vaccine development. Arterioscler. Thromb. Vasc. Biol. 25, 18–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Hulthe, J. et al. Antibody titers against oxidized LDL are not elevated in patients with familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 18, 1203–1211 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Tornvall, P., Waeg, G., Nilsson, J., Hamsten, A. & Regnstrom, J. Autoantibodies against modified low-density lipoproteins in coronary artery disease. Atherosclerosis 167, 347–353 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Fredrikson, G.N. et al. Association between IgM against an aldehyde-modified peptide in apolipoprotein B-100 and progression of carotid disease. Stroke 38, 1495–1500 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Sjogren, P. et al. High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction. Eur. Heart J. 29, 2218–2226 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Tsimikas, S. et al. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J. Lipid Res. 48, 425–433 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Paulsson, G., Zhou, X., Tornquist, E. & Hansson, G.K. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 20, 10–17 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Liuzzo, G. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Mach, F., Schönbeck, U., Sukhova, G.K., Atkinson, E. & Libby, P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394, 200–203 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Olofsson, P.S. et al. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117, 1292–1301 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Ludewig, B. et al. Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. Proc. Natl. Acad. Sci. USA 97, 12752–12757 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gotsman, I. et al. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J. Clin. Invest. 117, 2974–2982 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gupta, S. et al. IFN-g potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Whitman, S.C., Ravisankar, P., Elam, H. & Daugherty, A. Exogenous interferon-g enhances atherosclerosis in apolipoprotein E-/- mice. Am. J. Pathol. 157, 1819–1824 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Whitman, S.C., Ravisankar, P. & Daugherty, A. IFN-g deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/- mice. J. Interferon Cytokine Res. 22, 661–670 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Buono, C. et al. Influence of interferon-g on the extent and phenotype of diet-induced atherosclerosis in the LDLR-deficient mouse. Arterioscler. Thromb. Vasc. Biol. 23, 454–460 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Lee, T.S., Yen, H.C., Pan, C.C. & Chau, L.Y. The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 19, 734–742 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Davenport, P. & Tipping, P.G. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am. J. Pathol. 163, 1117–1125 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hauer, A.D. et al. Blockade of interleukin-12 function by protein vaccination attenuates atherosclerosis. Circulation 112, 1054–1062 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Whitman, S.C., Ravisankar, P. & Daugherty, A. Interleukin-18 enhances atherosclerosis in apolipoprotein E−/− mice through release of interferon-gamma. Circ. Res. 90, E34–E38 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Buono, C. et al. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc. Natl. Acad. Sci. USA 102, 1596–1601 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Frostegard, J. et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145, 33–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. King, V.L., Szilvassy, S.J. & Daugherty, A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor-/- mice. Arterioscler. Thromb. Vasc. Biol. 22, 456–461 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Huber, S.A., Sakkinen, P., David, C., Newell, M.K. & Tracy, R.P. T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 103, 2610–2616 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. King, V.L., Cassis, L.A. & Daugherty, A. Interleukin-4 does not influence development of hypercholesterolemia or angiotensin II-induced atherosclerotic lesions in mice. Am. J. Pathol. 171, 2040–2047 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Miller, A.M. et al. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 205, 339–346 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. de Boer, O.J. et al. Differential expression of interleukin-17 family cytokines in intact and complicated human atherosclerotic plaques. J. Pathol. 220, 499–508 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Eid, R.E. et al. Interleukin-17 and interferon-g are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 119, 1424–1432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Erbel, C. et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J. Immunol. 183, 8167–8175 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. van Es, T. et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem. Biophys. Res. Commun. 388, 261–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Smith, E. et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 121, 1746–1755 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Taleb, S. et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J. Exp. Med. 206, 2067–2077 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Veillard, N.R., Steffens, S., Burger, F., Pelli, G. & Mach, F. Differential expression patterns of proinflammatory and antiinflammatory mediators during atherogenesis in mice. Arterioscler. Thromb. Vasc. Biol. 24, 2339–2344 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. de Boer, O.J., van der Meer, J.J., Teeling, P., van der Loos, C.M. & van der Wal, A.C. Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions. PLoS ONE 2, e779 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ait-Oufella, H. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 12, 178–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Mor, A. et al. Role of naturally occurring CD4+CD25+ regulatory T cells in experimental atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 27, 893–900 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Klingenberg, R. et al. Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30, 946–952 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Sasaki, N. et al. Oral anti-CD3 antibody treatment induces regulatory T cells and inhibits the development of atherosclerosis in mice. Circulation 120, 1996–2005 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Vliegen, I., Herngreen, S.B., Grauls, G.E., Bruggeman, C.A. & Stassen, F.R. Mouse cytomegalovirus antigenic immune stimulation is sufficient to aggravate atherosclerosis in hypercholesterolemic mice. Atherosclerosis 181, 39–44 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Hansson, G.K. & Libby, P. The immune response in atherosclerosis: a double-edged sword. Nat. Rev. Immunol. 6, 508–519 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Wick, G., Knoflach, M. & Xu, Q. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu. Rev. Immunol. 22, 361–403 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Afek, A. et al. Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis. J. Autoimmun. 14, 115–121 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Harats, D., Yacov, N., Gilburd, B., Shoenfeld, Y. & George, J. Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. J. Am. Coll. Cardiol. 40, 1333–1338 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Maron, R. et al. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 106, 1708–1715 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Tsan, M.F. & Gao, B. Heat shock proteins and immune system. J. Leukoc. Biol. 85, 905–910 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Steinberg, D. The LDL modification hypothesis of atherogenesis: an update. J. Lipid Res. 50 Suppl, S376–S381 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Stemme, S. et al. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA 92, 3893–3897 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhou, X., Robertson, A.K., Hjerpe, C. & Hansson, G.K. Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 26, 864–870 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Fredrikson, G.N. et al. Identification of immune responses against aldehyde-modified peptide sequences in apoB associated with cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 23, 872–878 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Nicoletti, A. et al. The macrophage scavenger receptor type A directs modified proteins to antigen presentation. Eur. J. Immunol. 29, 512–521 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Hjerpe, C., Johansson, D., Hermansson, A., Hansson, G.K. & Zhou, X. Dendritic cells pulsed with malondialdehyde modified low density lipoprotein aggravate atherosclerosis in Apoe−/− mice. Atherosclerosis 209, 436–441 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Hermansson, A. et al. Immunotherapy with tolerogenic apolipoprotein B-100 loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation (in the press).

  108. Hermansson, A. et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J. Exp. Med. 207, 1081–1093 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Huang, W. & Glass, C.K. Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance. Arterioscler. Thromb. Vasc. Biol. 30, 1542–1549 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Glass, C.K. & Saijo, K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat. Rev. Immunol. 10, 365–376 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Liao, J.K. & Laufs, U. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol. 45, 89–118 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jury, E.C., Isenberg, D.A., Mauri, C. & Ehrenstein, M.R. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J. Immunol. 177, 7416–7422 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Hansson, G.K. & Bjorkholm, M. Tackling two diseases with HDL. Science 328, 1641–1642 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Klareskog, L. & Hamsten, A. Statins in rheumatoid arthritis–two birds with one stone? Lancet 363, 2011–2012 (2004).

    Article  PubMed  Google Scholar 

  116. Wang, X. et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat. Genet. 37, 365–372 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat. Genet. 37, 486–494 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Dwyer, J.H. et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N. Engl. J. Med. 350, 29–37 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gabriel, S.E. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am. J. Med. 121, S9–S14 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Holmqvist, M.E. et al. No increased occurrence of ischemic heart disease prior to the onset of rheumatoid arthritis: results from two Swedish population-based rheumatoid arthritis cohorts. Arthritis Rheum. 60, 2861–2869 (2009).

    Article  PubMed  Google Scholar 

  122. Dixon, W.G. et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 56, 2905–2912 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Muller-Ehmsen, J. & Schwinger, R.H. TNF and congestive heart failure: therapeutic possibilities. Expert Opin. Ther. Targets 8, 203–209 (2004).

    Article  PubMed  Google Scholar 

  124. Zink, A. et al. European biologicals registers: methodology, selected results and perspectives. Ann. Rheum. Dis. 68, 1240–1246 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Ridker, P.M., Hennekens, C.H., Buring, J.E. & Rifai, N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 342, 836–843 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Andersson and A.-K. Robertson for critical reading of the manuscript. Supported by the Swedish Research Council, Foundation for Strategic Research, VINNOVA, the Swedish Heart-Lung Foundation, the Leducq Foundation and the European Union (AtheroRemo project).

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Correspondence to Göran K Hansson.

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TG.K.H. and A.H. have submitted patent applications in the area reviewed.

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Hansson, G., Hermansson, A. The immune system in atherosclerosis. Nat Immunol 12, 204–212 (2011). https://doi.org/10.1038/ni.2001

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