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Current advances in understanding of immunopathology of atherosclerosis

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Abstract

The importance of the involvement of the immune system in the development and progression of atherosclerosis was first suggested after the discovery of T cells in atherosclerotic lesions in 1990s. In order to be activated, T cell needs to be presented with an antigen but how this occurs in atherosclerosis has been unclear until recently. Current research has recognised dendritic cells as key initiators and regulators of immune processes in atherosclerosis. Accumulating evidence has revealed novel functions of several subsets of regulatory T cells, which have been shown to maintain immunological tolerance to self-antigens and to inhibit atherosclerosis development by suppressing the inflammatory response of effector T cells. Recent studies have also revealed the importance of natural killer T cells and their interaction with dendritic cells in atherogenesis. This review briefly summarises recent advances in the understanding of immune mechanisms in atherosclerosis and highlights the perspective of immunisation as an approach against this disease.

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References

  1. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK (1986) Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6:131–138

    CAS  PubMed  Google Scholar 

  2. Hansson GK, Holm J, Jonasson L (1989) Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 135:169–175

    CAS  PubMed  Google Scholar 

  3. Hansson GK, Jonasson L (2009) The discovery of cellular immunity in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol 29:1714–1717

    Article  CAS  PubMed  Google Scholar 

  4. Hansson GK (2009) Atherosclerosis—an immune disease: the Anitschkov Lecture 2007. Atherosclerosis 202:2–10

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Ait-Oufella H, Salomon BL, Potteaux S, Robertson AK, Gourdy P, Zoll J, Merval R, Esposito B, Cohen JL, Fisson S, Flavell RA, Hansson GK, Klatzmann D, Tedgui A, Mallat Z (2006) Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 12:178–180

    Article  CAS  PubMed  Google Scholar 

  7. Mallat Z, Gojova A, Brun V, Esposito B, Fournier N, Cottrez F, Tedgui A, Groux H (2003) Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation 108:1232–1237

    Article  CAS  PubMed  Google Scholar 

  8. Mor A, Planer D, Luboshits G, Afek A, Metzger S, Chajek-Shaul T, Keren G, George J (2007) 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 

  9. Whitham S, Ramsamy T (2006) articipatory role of natural killer and natural killer T cells in atherosclerosis: lessons learned from in vivo mouse studies. Canad J Physiol Pharmacol 84:67–75

    Article  Google Scholar 

  10. Bobryshev YV, Lord RS (1995) Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of vascular dendritic cells in athero-resistant and athero-prone areas of the normal aorta. Arch Histol Cytol 58:307–322

    Article  CAS  PubMed  Google Scholar 

  11. Bobryshev YV, Lord RS (1998) Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions. Cardiovasc Res 37:799–810

    Article  CAS  PubMed  Google Scholar 

  12. Bobryshev YV (2010) Dendritic cells and their role in atherogenesis. Lab Invest 90:970–984

    Article  PubMed  Google Scholar 

  13. Stoll G, Bendszus M (2006) Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37:1923–1932

    Article  CAS  PubMed  Google Scholar 

  14. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809

    Article  CAS  PubMed  Google Scholar 

  15. Lord RS, Bobryshev YV (2002) Hallmarks of atherosclerotic lesion development with special reference to immune inflammatory mechanisms. Cardiovasc Surg 10:405–414

    Article  CAS  PubMed  Google Scholar 

  16. Millonig G, Schwentner C, Mueller P, Mayerl C, Wick G (2001) The vascular-associated lymphoid tissue: a new site of local immunity. Curr Opin Lipidol 12:547–553

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Bobryshev YV (2006) Monocyte recruitment and foam cell formation in atherosclerosis. Micron 37:208–222

    Article  CAS  PubMed  Google Scholar 

  19. Niessner A, Goronzy JJ, Weyand CM (2007) Immune-mediated mechanisms in atherosclerosis: prevention and treatment of clinical manifestations. Curr Pharm Des 13:3701–3710

    Article  CAS  PubMed  Google Scholar 

  20. Steinman R, Adams J, Cohn Z (1973) Identification of a novel cell type in peripheral lymphoid organs of mice, morphology, quantitation, tissue distribution. J Exp Med 137:1142–1162

    Article  CAS  PubMed  Google Scholar 

  21. Lotze M, Thomson A (2001) Dendritic cells: biology and clinical applications, Ed 2nd edn. Academic, San Diego, California, USA

    Google Scholar 

  22. Bobryshev YV (2005) Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur Heart J 26:1700–1704

    Article  PubMed  Google Scholar 

  23. Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI (2006) Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med 203:2073–2083

    Article  CAS  PubMed  Google Scholar 

  24. Choi JH, Do Y, Cheong C, Koh H, Boscardin SB, Oh YS, Bozzacco L, Trumpfheller C, Park CG, Steinman RM (2009) Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med 206:479–505

    Article  Google Scholar 

  25. Randolph GJ, Potteaux S (2010) Vascular dendritic cells as gatekeepers of lipid accumulation within nascent atherosclerotic plaques. Circ Res 106:227–229

    Article  CAS  PubMed  Google Scholar 

  26. Lipscomb M, Masten B (2002) Dendritic cells: immune regulators in health and disease. Physiol Rev 82:97–130

    CAS  PubMed  Google Scholar 

  27. Steinman R, Hawiger D, Nussenzweig M (2003) Tolerogenic dendritic cells. Ann Rev Immunol 21:685–711

    Article  CAS  Google Scholar 

  28. Heath W, Belz G, Behrens G (2004) Cross-presentation, dendritic cell subsets and the generation of immunity to cellular agents. Immunol Rev 199:9–26

    Article  CAS  PubMed  Google Scholar 

  29. de Jong E, Smits H, Kapsenberg M (2005) Dendritic cell-mediated T cell polarization. Springer Semin Immunopathol 26:289–307

    Article  PubMed  Google Scholar 

  30. Gelin C, Sloma I, Charron D, Mooney N (2006) Regulation of MHC II and CD1 antigen presentation: from ubiquity to security. J Leukoc Biol 85:215–224, 2009

    Article  Google Scholar 

  31. Niessner A, Weyland C (2009) Dendritic cells in atherosclerotic disease. Clin Immunol 134:25–32

    Article  PubMed  Google Scholar 

  32. Bobryshev YV, Taksir T, Lord RS, Freeman MW (2001) Evidence that dendritic cells infiltrate atherosclerotic lesions in apolipoprotein E-deficient mice. Histol Histopathol 16:801–808

    CAS  PubMed  Google Scholar 

  33. Ozmen J, Bobryshev YV, Lord RS, Ashwell KW (2002) Identification of dendritic cells in aortic atherosclerotic lesions in rats with diet-induced hypercholesterolaemia. Histol Histopathol 17:223–237

    CAS  PubMed  Google Scholar 

  34. Steinman RM, Hawiger D, Liu K, Bonifaz L, Bonnyay D, Mahnke K, Iyoda T, Ravetch J, Dhodapkar M, Inaba K, Nussenzweig M (2003) Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann NY Acad Sci 987:15–25

    Article  CAS  PubMed  Google Scholar 

  35. Naik SH, Metcalf D, van Nieuwenhuijze A, Wicks I, Wu L, O'Keeffe M, Shortman K (2006) Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat Immunol 7:663–671

    Article  CAS  PubMed  Google Scholar 

  36. Shortman K, Naik S (2007) Steady-state and inflammatory dendritic cell development. Nat Rev Immunol 7:19

    Article  CAS  PubMed  Google Scholar 

  37. Ueno H, Klechevsky E, Morita R, Aspord C, Cao T, Matsui T, Di Pucchio T, Connolly J, Fay JW, Pascual V, Palucka AK, Banchereau J (2007) Dendritic cell subsets in health and disease. Immunol Rev 219:118–142

    Article  CAS  PubMed  Google Scholar 

  38. Wilson NS, El-Sukkari D, Belz GT, Smith CM, Steptoe RJ, Heath WR, Shortman K, Villadangos JA (2003) Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102:2187–2194

    Article  CAS  PubMed  Google Scholar 

  39. Auffray C, Sieweke M, Geissmann F (2003) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Ann Rev Immunol 27:669–692

    Article  Google Scholar 

  40. Gautier EL, Huby T, Saint-Charles F, Ouzilleau B, Pirault J, Deswaerte V, Ginhoux F, Miller ER, Witztum JL, Chapman MJ, Lesnik P (2009) Conventional dendritic cells at the crossroads between immunity and cholesterol homeostasis in atherosclerosis. Circulation 119:2367–2375

    Article  CAS  PubMed  Google Scholar 

  41. Wang L, Li D, Yang K, Hu Y, Zeng Q (2008) Toll-like receptor 4 and mitogen-activated protein kinase signal system are involved in activation of dendritic cells in patients with acute coronary syndrome. Immunology 125:122–130

    Article  CAS  PubMed  Google Scholar 

  42. Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI (2010) Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res 106:383–390

    Article  CAS  PubMed  Google Scholar 

  43. Ludewig B, Freigang S, Jäggi M, Kurrer MO, Pei YC, Vlk L, Odermatt B, Zinkernagel RM, Hengartner H (2000) Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. Proc Natl Acad Sci USA 97:12752–12757

    Article  CAS  PubMed  Google Scholar 

  44. Angeli V, Llodrá J, Rong JX, Satoh K, Ishii S, Shimizu T, Fisher EA, Randolph GJ (2004) Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilisation. Immunity 21:561–574

    Article  CAS  PubMed  Google Scholar 

  45. Packard RR, Maganto-García E, Gotsman I, Tabas I, Libby P, Lichtman AH (2008) CD11c(+) dendritic cells maintain antigen processing presentation capabilities and CD4(+) T-cell priming efficacy under hypercholesterolemia conditions. Circ Res 103:965–973

    Article  CAS  PubMed  Google Scholar 

  46. Habets KL, van Puijvelde GH, van Duivenvoorde LM, van Wanrooij EJ, de Vos P, Tervaert JW, van Berkel TJ, Toes RE, Kuiper J (2010) Vaccination using oxidised low-density lipoproteins-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice. Cardiovasc Res 85:622–630

    Article  CAS  PubMed  Google Scholar 

  47. Hjerpe C, Johansson D, Hermansson A, Hansson GK, Zhou X (2010) Dendritic cells pulsed with melondialdehyde modified low density lipoprotein aggravate atherosclerosis in ApoE (−/−) mice. Atherosclerosis 209:436–441

    Article  CAS  PubMed  Google Scholar 

  48. van Es T, van Puijvelde GH, Foks AC, Habets KL, Bot I, Gilboa E, Van Berkel TJ, Kuiper J (2010) Vaccination against Foxp3(+) regulatory T cells aggravates atherosclerosis. Atherosclerosis 209:74–80

    Article  PubMed  Google Scholar 

  49. Alderman CJ, Bunyard PR, Chain BM, Foreman JC, Leake DS, Katz DR (2002) Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment? Cardiovasc Res 55:806–819

    Article  CAS  PubMed  Google Scholar 

  50. Matzinger P (2007) Friendly and dangerous signals: is the tissue in control? Nat Immunol 8:11–13

    Article  CAS  PubMed  Google Scholar 

  51. Doherty TM, Fisher EA, Arditi M (2006) TLR signaling and trapped vascular dendritic cells in the development of atherosclerosis. Trends Immunol 27:222–227

    Article  CAS  PubMed  Google Scholar 

  52. Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336, 2007

    Article  CAS  PubMed  Google Scholar 

  53. Erbel C, Sato K, Meyer FB, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM (2007) Functional profile of activated dendritic cells in unstable atherosclerotic plaque. Basic Res Cardiol 102:123–132

    Article  CAS  PubMed  Google Scholar 

  54. Yilmaz A, Lochno M, Traeg F, Cicha I, Reiss C, Stumpf C, Raaz D, Anger T, Amann K, Probst T, Ludwig J, Daniel WG, Garlichs CD (2004) Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques. Atherosclerosis 176:85–93

    Article  Google Scholar 

  55. Asselin-Paturel C, Trinchieri G (2005) Production of type I interferons: plasmacytoid dendritic cells and beyond. J Exp Med 202:461–465

    Article  CAS  PubMed  Google Scholar 

  56. Decker T, Muller M, Stockinger S (2005) The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol 5:675–687

    Article  CAS  PubMed  Google Scholar 

  57. Van Vré EA, Hoymans VY, Bult H, Lenjou M, Van Bockstaele DR, Vrints CJ, Bosmans JM (2006) Decreased number of circulating plasmacytoid dendritic cells in patients with atherosclerotic coronary artery disease. Coron Artery Dis 17:243–248

    Article  PubMed  Google Scholar 

  58. Bobryshev YV, Lord RS (2005) Co-accumulation of dendritic cells and natural killer T cells within rupture-prone regions in human atherosclerotic plaques. J Histochem Cytochem 53:781–785

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. Caligiuri G, Rudling M, Ollivier V, Jacob MP, Michel JB, Hansson GK, Nicoletti A (2003) Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med 9:10–17

    CAS  PubMed  Google Scholar 

  62. Pinderski L, Fyfe A, Hedrick C, Olvera T (1999) Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Atheroscler ThrombVasc Biol 19:2847–2853

    Google Scholar 

  63. Aslanian A, Chapman H, Charo I (2005) Transient role for CD1d-restricted natural killer T cells in the formation of atherosclerotic lesions. Atheroscler ThrombVasc Biol 25:628–632

    Article  CAS  Google Scholar 

  64. Whitman SC, Rateri DL, Szilvassy SJ, Yokoyama W, Daugherty A (2004) Depletion of natural killer cell function decreases atherosclerosis in low-density lipoprotein receptor null mice. Arterioscler Thromb Vasc Biol 24:1049–1054

    Article  CAS  PubMed  Google Scholar 

  65. Van Kaer L (2007) NKT cells: T lymphocytes with innate effector functions. Curr Opin Immunol 19:354–364

    Article  PubMed  Google Scholar 

  66. Bezbradica JS, Stanic AK, Matsuki N, Bour-Jordan H, Bluestone JA, Thomas JW, Unutmaz D, Van Kaer L, Joyce S (2005) Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo. J Immunol 174:4694–4705

    Google Scholar 

  67. Schmieg J, Yang G, Franck RW, Van Rooijen N, Tsuji M (2005) Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc Natl Acad Sci USA 102:1127–1132

    Article  CAS  PubMed  Google Scholar 

  68. Van Kaer L (2004) Natural killer T cells as targets for immunotherapy of autoimmune diseases. Immunol Cell Biol 82:315–322

    Article  PubMed  Google Scholar 

  69. Hansson G, Nilsson J (2009) Vaccination against atherosclerosis? Induction of atheroprotective immunity. Semin Immunopathol 31:95–101

    Article  CAS  PubMed  Google Scholar 

  70. Palinski W, Milller E, Witztum J (1995) Immunisation of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA 92:821–825

    Article  CAS  PubMed  Google Scholar 

  71. Binder CJ, Hartvigsen K, Witztum JL (2007) Promise of immune modulation to inhibit atherogenesis. J Am Coll Cardiol 50:547–550

    Article  PubMed  Google Scholar 

  72. Nilsson J, Nordin Fredrikson G, Schiopu A, Shah PK, Jansson B, Carlsson R (2007) Oxidized LDL antibodies in treatment and risk assessment of atherosclerosis and associated cardiovascular disease. Curr Pharm Des 13:1021–1030

    Article  CAS  PubMed  Google Scholar 

  73. Fredrikson GN, Björkbacka H, Söderberg I, Ljungcrantz I, Nilsson J (2008) Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B-100 transgenic mice without inducing an increase in peptide-specific antibodies. J Intern Med 264:563–570

    Article  CAS  PubMed  Google Scholar 

  74. van Leeuwen M, Damoiseaux J, Duijvestijn A, Tervaert JW (2009) The therapeutic potential of targeting B cells and anti-oxLDL antibodies in atherosclerosis. Autoimmun Rev 9:53–57

    Article  PubMed  Google Scholar 

  75. Bobryshev YV (2001) Can dendritic cells be exploited for therapeutic intervention in atherosclerosis? Atherosclerosis 154:511–512

    Article  CAS  PubMed  Google Scholar 

  76. Markiewicz M, Kast W (2004) Progress in the development of immunotherapy of cancer using ex vivo-generated dendritic cells expressing multiple tumor antigen epitopes. Cancer Investig 22:417–434

    Article  CAS  Google Scholar 

  77. Dubsky P, Ueno H, Piqueras B, Connolly J, Banchereau J, Palucka AK (2005) Human dendritic cell subsets for vaccination. J Clin Immunol 25:551–572

    Article  PubMed  Google Scholar 

  78. Benko S, Magyarics Z, Szabó A, Rajnavölgyi E (2008) Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors. Biol Chem 389:469–485

    Article  CAS  PubMed  Google Scholar 

  79. Steinman RM (2008) Dendritic cells in vivo: a key target for a new vaccine science. Immunity 29:319–324

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Faculty of Medicine, University of New South Wales, Sydney, Australia, for support.

Conflict of interest statement

We have no commercial associations (i.e. pharmaceutical stock ownership, consultancy, advisory board membership or relevant patents) that might pose a conflict of interest. We declare that we have no conflict of interest.

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Perrins, CJ., Bobryshev, Y.V. Current advances in understanding of immunopathology of atherosclerosis. Virchows Arch 458, 117–123 (2011). https://doi.org/10.1007/s00428-010-1006-5

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