Skip to main content
Log in

Innate and adaptive immunity in atherosclerosis

Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Atherosclerosis, a chronic inflammatory disorder, involves both the innate and adaptive arms of the immune response that mediate the initiation, progression, and ultimate thrombotic complications of atherosclerosis. Most fatal thromboses, which may manifest as acute myocardial infarction or ischemic stroke, result from frank rupture or superficial erosion of the fibrous cap overlying the atheroma, processes that occur in inflammatorily active, rupture-prone plaques. Appreciation of the inflammatory character of atherosclerosis has led to the application of C-reactive protein as a biomarker of cardiovascular risk and the characterization of the anti-inflammatory and immunomodulatory actions of the statin class of drugs. An improved understanding of the pathobiology of atherosclerosis and further studies of its immune mechanisms provide avenues for the development of future strategies directed toward better risk stratification of patients as well as the identification of novel anti-inflammatory therapies. This review retraces leukocyte subsets involved in innate and adaptive immunity and their contributions to atherogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6:508–519. doi:10.1038/nri1882

    Article  CAS  PubMed  Google Scholar 

  2. Weber C, Zernecke A, Libby P (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8:802–815. doi:10.1038/nri2415

    Article  CAS  PubMed  Google Scholar 

  3. Libby P (2001) Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 104:365–372

    CAS  PubMed  Google Scholar 

  4. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT (2003) From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 108:1664–1672. doi:10.1161/01.CIR.0000087480.94275.97

    Article  PubMed  Google Scholar 

  5. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT (2003) From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 108:1772–1778. doi:10.1161/01.CIR.0000087481.55887.C9

    Article  PubMed  Google Scholar 

  6. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR (2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347:1557–1565. doi:10.1056/NEJMoa021993

    Article  CAS  PubMed  Google Scholar 

  7. Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118. doi:10.1146/annurev.pharmtox.45.120403.095748

    Article  CAS  PubMed  Google Scholar 

  8. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E (1999) Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100:230–235

    CAS  PubMed  Google Scholar 

  9. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr (2001) Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 344:1959–1965. doi:10.1056/NEJM200106283442601

    Article  CAS  PubMed  Google Scholar 

  10. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E (2005) C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352:20–28. doi:10.1056/NEJMoa042378

    Article  CAS  PubMed  Google Scholar 

  11. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71:343–353. doi:10.1016/0092-8674(92)90362-G

    Article  CAS  PubMed  Google Scholar 

  12. Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK (1994) Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 93:1885–1893. doi:10.1172/JCI117179

    Article  CAS  PubMed  Google Scholar 

  13. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417:750–754. doi:10.1038/nature00804

    Article  CAS  PubMed  Google Scholar 

  14. Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516. doi:10.1016/S0092-8674(01)00238-0

    Article  CAS  PubMed  Google Scholar 

  15. Cybulsky MI, Gimbrone MA Jr (1991) Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251:788–791. doi:10.1126/science.1990440

    Article  CAS  PubMed  Google Scholar 

  16. Li H, Cybulsky MI, Gimbrone MA Jr, Libby P (1993) An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb 13:197–204

    PubMed  Google Scholar 

  17. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone DS (2001) A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 107:1255–1262. doi:10.1172/JCI11871

    Article  CAS  PubMed  Google Scholar 

  18. Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J, Hynes RO, Schaefer EJ, Wagner DD (1997) Absence of P-selectin delays fatty streak formation in mice. J Clin Invest 99:1037–1043. doi:10.1172/JCI119231

    Article  CAS  PubMed  Google Scholar 

  19. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2:275–281. doi:10.1016/S1097-2765(00)80139-2

    Article  CAS  PubMed  Google Scholar 

  20. Boring L, Gosling J, Cleary M, Charo IF (1998) Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394:894–897. doi:10.1038/29788

    Article  CAS  PubMed  Google Scholar 

  21. Amorino GP, Hoover RL (1998) Interactions of monocytic cells with human endothelial cells stimulate monocytic metalloproteinase production. Am J Pathol 152:199–207

    CAS  PubMed  Google Scholar 

  22. Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA (1998) A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 101:353–363. doi:10.1172/JCI1195

    Article  CAS  PubMed  Google Scholar 

  23. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rosenzweig A (1999) MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398:718–723. doi:10.1038/19546

    Article  CAS  PubMed  Google Scholar 

  24. Lesnik P, Haskell CA, Charo IF (2003) Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J Clin Invest 111:333–340

    CAS  PubMed  Google Scholar 

  25. Combadiere C, Potteaux S, Gao JL, Esposito B, Casanova S, Lee EJ, Debre P, Tedgui A, Murphy PM, Mallat Z (2003) Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 107:1009–1016. doi:10.1161/01.CIR.0000057548.68243.42

    Article  CAS  PubMed  Google Scholar 

  26. Cheng C, Tempel D, van Haperen R, de Boer HC, Segers D, Huisman M, van Zonneveld AJ, Leenen PJ, van der Steen A, Serruys PW, de Crom R, Krams R (2007) Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest 117:616–626. doi:10.1172/JCI28180

    Article  CAS  PubMed  Google Scholar 

  27. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J (2003) Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A 100:4736–4741. doi:10.1073/pnas.0730843100

    Article  CAS  PubMed  Google Scholar 

  28. Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ (1990) Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 344:254–257. doi:10.1038/344254a0

    Article  CAS  PubMed  Google Scholar 

  29. Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe DW, Libby P (1992) Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol 140:301–316

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Monaco C, Andreakos E, Kiriakidis S, Mauri C, Bicknell C, Foxwell B, Cheshire N, Paleolog E, Feldmann M (2004) Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proc Natl Acad Sci U S A 101:5634–5639. doi:10.1073/pnas.0401060101

    Article  CAS  PubMed  Google Scholar 

  32. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA (2000) Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 164:13–17

    CAS  PubMed  Google Scholar 

  33. Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, Luthringer D, Xu XP, Rajavashisth TB, Yano J, Kaul S, Arditi M (2001) Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 104:3103–3108. doi:10.1161/hc5001.100631

    Article  CAS  PubMed  Google Scholar 

  34. Miller YI, Viriyakosol S, Binder CJ, Feramisco JR, Kirkland TN, Witztum JL (2003) 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. doi:10.1074/jbc.M209634200

    Article  CAS  PubMed  Google Scholar 

  35. Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 10:416–421. doi:10.1038/nm1008

    Article  PubMed  CAS  Google Scholar 

  36. Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) 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 U S A 101:10679–10684. doi:10.1073/pnas.0403249101

    Article  CAS  PubMed  Google Scholar 

  37. Kawakami A, Osaka M, Aikawa M, Uematsu S, Akira S, Libby P, Shimokado K, Sacks FM, Yoshida M (2008) Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation. Circ Res 103:1402–1409. doi:10.1161/CIRCRESAHA.108.178426

    Article  CAS  PubMed  Google Scholar 

  38. Mullick AE, Tobias PS, Curtiss LK (2005) Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 115:3149–3156. doi:10.1172/JCI25482

    Article  CAS  PubMed  Google Scholar 

  39. Tobias PS, Curtiss LK (2008) TLR2 in murine atherosclerosis. Semin Immunopathol 30:23–27. doi:10.1007/s00281-007-0102-3

    Article  CAS  PubMed  Google Scholar 

  40. Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U (2002) Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med 195:245–257. doi:10.1084/jem.20011022

    Article  CAS  PubMed  Google Scholar 

  41. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 117:195–205. doi:10.1172/JCI29950

    Article  CAS  PubMed  Google Scholar 

  42. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ (2007) Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 117:185–194. doi:10.1172/JCI28549

    Article  CAS  PubMed  Google Scholar 

  43. Amento EP, Ehsani N, Palmer H, Libby P (1991) Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb 11:1223–1230

    CAS  PubMed  Google Scholar 

  44. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P (1999) Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 99:2503–2509

    CAS  PubMed  Google Scholar 

  45. Herman MP, Sukhova GK, Libby P, Gerdes N, Tang N, Horton DB, Kilbride M, Breitbart RE, Chun M, Schonbeck U (2001) Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation 104:1899–1904. doi:10.1161/hc4101.097419

    Article  CAS  PubMed  Google Scholar 

  46. Deguchi JO, Aikawa E, Libby P, Vachon JR, Inada M, Krane SM, Whittaker P, Aikawa M (2005) Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. Circulation 112:2708–2715. doi:10.1161/CIRCULATIONAHA.105.562041

    Article  CAS  PubMed  Google Scholar 

  47. Schneider F, Sukhova GK, Aikawa M, Canner J, Gerdes N, Tang SM, Shi GP, Apte SS, Libby P (2008) Matrix-metalloproteinase-14 deficiency in bone-marrow-derived cells promotes collagen accumulation in mouse atherosclerotic plaques. Circulation 117:931–939. doi:10.1161/CIRCULATIONAHA.107.707448

    Article  CAS  PubMed  Google Scholar 

  48. Galis ZS, Sukhova GK, Lark MW, Libby P (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–2503. doi:10.1172/JCI117619

    Article  CAS  PubMed  Google Scholar 

  49. Fabunmi RP, Sukhova GK, Sugiyama S, Libby P (1998) Expression of tissue inhibitor of metalloproteinases-3 in human atheroma and regulation in lesion-associated cells: a potential protective mechanism in plaque stability. Circ Res 83:270–278

    CAS  PubMed  Google Scholar 

  50. Newby AC (2008) Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol 28:2108–2114. doi:10.1161/ATVBAHA.108.173898

    Article  CAS  PubMed  Google Scholar 

  51. Dollery CM, Owen CA, Sukhova GK, Krettek A, Shapiro SD, Libby P (2003) Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circulation 107:2829–2836. doi:10.1161/01.CIR.0000072792.65250.4A

    Article  CAS  PubMed  Google Scholar 

  52. Fukumoto Y, Deguchi JO, Libby P, Rabkin-Aikawa E, Sakata Y, Chin MT, Hill CC, Lawler PR, Varo N, Schoen FJ, Krane SM, Aikawa M (2004) Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques. Circulation 110:1953–1959. doi:10.1161/01.CIR.0000143174.41810.10

    Article  CAS  PubMed  Google Scholar 

  53. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP (2004) Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol 24:1359–1366. doi:10.1161/01.ATV.0000134530.27208.41

    Article  CAS  PubMed  Google Scholar 

  54. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P (1998) Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest 102:576–583. doi:10.1172/JCI181

    Article  CAS  PubMed  Google Scholar 

  55. Jormsjo S, Wuttge DM, Sirsjo A, Whatling C, Hamsten A, Stemme S, Eriksson P (2002) Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 161:939–945

    PubMed  Google Scholar 

  56. Sukhova GK, Zhang Y, Pan JH, Wada Y, Yamamoto T, Naito M, Kodama T, Tsimikas S, Witztum JL, Lu ML, Sakara Y, Chin MT, Libby P, Shi GP (2003) Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest 111:897–906

    CAS  PubMed  Google Scholar 

  57. Kitamoto S, Sukhova GK, Sun J, Yang M, Libby P, Love V, Duramad P, Sun C, Zhang Y, Yang X, Peters C, Shi GP (2007) Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation 115:2065–2075. doi:10.1161/CIRCULATIONAHA.107.688523

    Article  CAS  PubMed  Google Scholar 

  58. Lutgens E, Lutgens SP, Faber BC, Heeneman S, Gijbels MM, de Winther MP, Frederik P, van der Made I, Daugherty A, Sijbers AM, Fisher A, Long CJ, Saftig P, Black D, Daemen MJ, Cleutjens KB (2006) Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113:98–107. doi:10.1161/CIRCULATIONAHA.105.561449

    Article  CAS  PubMed  Google Scholar 

  59. Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, Ridker PM, Libby P, Chapman HA (1999) Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 104:1191–1197. doi:10.1172/JCI7709

    Article  CAS  PubMed  Google Scholar 

  60. Jonsson-Rylander AC, Nilsson T, Fritsche-Danielson R, Hammarstrom A, Behrendt M, Andersson JO, Lindgren K, Andersson AK, Wallbrandt P, Rosengren B, Brodin P, Thelin A, Westin A, Hurt-Camejo E, Lee-Sogaard CH (2005) Role of ADAMTS-1 in atherosclerosis: remodeling of carotid artery, immunohistochemistry, and proteolysis of versican. Arterioscler Thromb Vasc Biol 25:180–185

    PubMed  Google Scholar 

  61. Wagsater D, Bjork H, Zhu C, Bjorkegren J, Valen G, Hamsten A, Eriksson P (2008) ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis 196:514–522. doi:10.1016/j.atherosclerosis.2007.05.018

    Article  PubMed  CAS  Google Scholar 

  62. Libby P, Theroux P (2005) Pathophysiology of coronary artery disease. Circulation 111:3481–3488. doi:10.1161/CIRCULATIONAHA.105.537878

    Article  PubMed  Google Scholar 

  63. Cairns A, Constantinides P (1954) Mast cells in human atherosclerosis. Science 120:31–32. doi:10.1126/science.120.3105.31

    Article  CAS  PubMed  Google Scholar 

  64. Jeziorska M, McCollum C, Woolley DE (1997) Mast cell distribution, activation, and phenotype in atherosclerotic lesions of human carotid arteries. J Pathol 182:115–122. doi:10.1002/(SICI)1096-9896(199705)182:1<115::AID-PATH806>3.0.CO;2-9

    Article  CAS  PubMed  Google Scholar 

  65. Kaartinen M, van der Wal AC, van der Loos CM, Piek JJ, Koch KT, Becker AE, Kovanen PT (1998) Mast cell infiltration in acute coronary syndromes: implications for plaque rupture. J Am Coll Cardiol 32:606–612. doi:10.1016/S0735-1097(98)00283-6

    Article  CAS  PubMed  Google Scholar 

  66. Kovanen PT, Kaartinen M, Paavonen T (1995) Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 92:1084–1088

    CAS  PubMed  Google Scholar 

  67. Libby P, Shi GP (2007) Mast cells as mediators and modulators of atherogenesis. Circulation 115:2471–2473. doi:10.1161/CIRCULATIONAHA.107.698480

    Article  PubMed  Google Scholar 

  68. Haley KJ, Lilly CM, Yang JH, Feng Y, Kennedy SP, Turi TG, Thompson JF, Sukhova GH, Libby P, Lee RT (2000) Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation. Circulation 102:2185–2189

    CAS  PubMed  Google Scholar 

  69. Sun J, Sukhova GK, Wolters PJ, Yang M, Kitamoto S, Libby P, MacFarlane LA, Mallen-St Clair J, Shi GP (2007) Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 13:719–724. doi:10.1038/nm1601

    Article  CAS  PubMed  Google Scholar 

  70. Bot I, de Jager SC, Zernecke A, Lindstedt KA, van Berkel TJ, Weber C, Biessen EA (2007) Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation 115:2516–2525. doi:10.1161/CIRCULATIONAHA.106.660472

    Article  CAS  PubMed  Google Scholar 

  71. Di Girolamo N, Wakefield D (2000) In vitro and in vivo expression of interstitial collagenase/MMP-1 by human mast cells. Dev Immunol 7:131–142. doi:10.1155/2000/82708

    Article  PubMed  Google Scholar 

  72. Baram D, Vaday GG, Salamon P, Drucker I, Hershkoviz R, Mekori YA (2001) Human mast cells release metalloproteinase-9 on contact with activated T cells: juxtacrine regulation by TNF-alpha. J Immunol 167:4008–4016

    CAS  PubMed  Google Scholar 

  73. Johnson JL, Jackson CL, Angelini GD, George SJ (1998) Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 18:1707–1715

    CAS  PubMed  Google Scholar 

  74. Tchougounova E, Lundequist A, Fajardo I, Winberg JO, Abrink M, Pejler G (2005) A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 280:9291–9296. doi:10.1074/jbc.M410396200

    Article  CAS  PubMed  Google Scholar 

  75. Lappalainen H, Laine P, Pentikainen MO, Sajantila A, Kovanen PT (2004) Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator. Arterioscler Thromb Vasc Biol 24:1880–1885. doi:10.1161/01.ATV.0000140820.51174.8d

    Article  CAS  PubMed  Google Scholar 

  76. Caughey GH, Raymond WW, Wolters PJ (2000) Angiotensin II generation by mast cell alpha- and beta-chymases. Biochim Biophys Acta 1480:245–257

    CAS  PubMed  Google Scholar 

  77. Heikkila HM, Latti S, Leskinen MJ, Hakala JK, Kovanen PT, Lindstedt KA (2008) Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha. Arterioscler Thromb Vasc Biol 28:309–314. doi:10.1161/ATVBAHA.107.151340

    Article  PubMed  CAS  Google Scholar 

  78. Wang Y, Shiota N, Leskinen MJ, Lindstedt KA, Kovanen PT (2001) Mast cell chymase inhibits smooth muscle cell growth and collagen expression in vitro: transforming growth factor-beta1-dependent and -independent effects. Arterioscler Thromb Vasc Biol 21:1928–1933. doi:10.1161/hq1201.100227

    Article  CAS  PubMed  Google Scholar 

  79. Leskinen MJ, Lindstedt KA, Wang Y, Kovanen PT (2003) Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol 23:238–243. doi:10.1161/01.ATV.0000051405.68811.4D

    Article  CAS  PubMed  Google Scholar 

  80. Leskinen MJ, Heikkila HM, Speer MY, Hakala JK, Laine M, Kovanen PT, Lindstedt KA (2006) Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling. Exp Cell Res 312:1289–1298. doi:10.1016/j.yexcr.2005.12.033

    Article  CAS  PubMed  Google Scholar 

  81. Steffel J, Akhmedov A, Greutert H, Luscher TF, Tanner FC (2005) Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 112:341–349. doi:10.1161/CIRCULATIONAHA.105.553735

    Article  CAS  PubMed  Google Scholar 

  82. Wang Y, Lindstedt KA, Kovanen PT (1995) Mast cell granule remnants carry LDL into smooth muscle cells of the synthetic phenotype and induce their conversion into foam cells. Arterioscler Thromb Vasc Biol 15:801–810

    CAS  PubMed  Google Scholar 

  83. Ma H, Kovanen PT (1995) IgE-dependent generation of foam cells: an immune mechanism involving degranulation of sensitized mast cells with resultant uptake of LDL by macrophages. Arterioscler Thromb Vasc Biol 15:811–819

    CAS  PubMed  Google Scholar 

  84. Kokkonen JO, Kovanen PT (1989) Proteolytic enzymes of mast cell granules degrade low density lipoproteins and promote their granule-mediated uptake by macrophages in vitro. J Biol Chem 264:10749–10755

    CAS  PubMed  Google Scholar 

  85. Lee M, Calabresi L, Chiesa G, Franceschini G, Kovanen PT (2002) Mast cell chymase degrades apoE and apoA-II in apoA-I-knockout mouse plasma and reduces its ability to promote cellular cholesterol efflux. Arterioscler Thromb Vasc Biol 22:1475–1481. doi:10.1161/01.ATV.0000029782.84357.68

    Article  CAS  PubMed  Google Scholar 

  86. Lee M, Sommerhoff CP, von Eckardstein A, Zettl F, Fritz H, Kovanen PT (2002) Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol. Arterioscler Thromb Vasc Biol 22:2086–2091. doi:10.1161/01.ATV.0000041405.07367.B5

    Article  CAS  PubMed  Google Scholar 

  87. Yokoyama WM, Kim S, French AR (2004) The dynamic life of natural killer cells. Annu Rev Immunol 22:405–429. doi:10.1146/annurev.immunol.22.012703.104711

    Article  CAS  PubMed  Google Scholar 

  88. Millonig G, Malcom GT, Wick G (2002) Early inflammatory-immunological lesions in juvenile atherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study. Atherosclerosis 160:441–448. doi:10.1016/S0021-9150(01)00596-2

    Article  CAS  PubMed  Google Scholar 

  89. 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. doi:10.1161/01.ATV.0000124923.95545.2c

    Article  CAS  PubMed  Google Scholar 

  90. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE (2002) Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 106:2894–2900. doi:10.1161/01.CIR.0000042674.89762.20

    Article  PubMed  Google Scholar 

  91. Horne BD, Anderson JL, John JM, Weaver A, Bair TL, Jensen KR, Renlund DG, Muhlestein JB (2005) Which white blood cell subtypes predict increased cardiovascular risk? J Am Coll Cardiol 45:1638–1643. doi:10.1016/j.jacc.2005.02.054

    Article  PubMed  Google Scholar 

  92. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A, Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmani R (2003) Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 349:2316–2325. doi:10.1056/NEJMoa035655

    Article  CAS  PubMed  Google Scholar 

  93. Leclercq A, Houard X, Philippe M, Ollivier V, Sebbag U, Meilhac O, Michel JB (2007) Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment. J Leukoc Biol 82:1420–1429. doi:10.1189/jlb.1106671

    Article  CAS  PubMed  Google Scholar 

  94. Hemdahl AL, Gabrielsen A, Zhu C, Eriksson P, Hedin U, Kastrup J, Thoren P, Hansson GK (2006) Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol 26:136–142. doi:10.1161/01.ATV.0000193567.88685.f4

    Article  CAS  PubMed  Google Scholar 

  95. van Leeuwen M, Gijbels MJ, Duijvestijn A, Smook M, van de Gaar MJ, Heeringa P, de Winther MP, Tervaert JW (2008) Accumulation of myeloperoxidase-positive neutrophils in atherosclerotic lesions in LDLR−/− mice. Arterioscler Thromb Vasc Biol 28:84–89. doi:10.1161/ATVBAHA.107.154807

    Article  PubMed  CAS  Google Scholar 

  96. Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P (2004) Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol 24:1309–1314. doi:10.1161/01.ATV.0000131784.50633.4f

    Article  CAS  PubMed  Google Scholar 

  97. Podrez EA, Schmitt D, Hoff HF, Hazen SL (1999) Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest 103:1547–1560. doi:10.1172/JCI5549

    Article  CAS  PubMed  Google Scholar 

  98. Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM (2003) Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19:583–593. doi:10.1016/S1074-7613(03)00263-2

    Article  CAS  PubMed  Google Scholar 

  99. Zernecke A, Bot I, Djalali-Talab Y, Shagdarsuren E, Bidzhekov K, Meiler S, Krohn R, Schober A, Sperandio M, Soehnlein O, Bornemann J, Tacke F, Biessen EA, Weber C (2008) Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res 102:209–217. doi:10.1161/CIRCRESAHA.107.160697

    Article  CAS  PubMed  Google Scholar 

  100. Woollard KJ, Suhartoyo A, Harris EE, Eisenhardt SU, Jackson SP, Peter K, Dart AM, Hickey MJ, Chin-Dusting JP (2008) Pathophysiological levels of soluble P-selectin mediate adhesion of leukocytes to the endothelium through Mac-1 activation. Circ Res 103:1128–1138. doi:10.1161/CIRCRESAHA.108.180273

    Article  CAS  PubMed  Google Scholar 

  101. Bobryshev YV (2005) Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur Heart J 26:1700–1704. doi:10.1093/eurheartj/ehi282

    Article  PubMed  Google Scholar 

  102. Liu P, Yu YR, Spencer JA, Johnson AE, Vallanat CT, Fong AM, Patterson C, Patel DD (2008) CX3CR1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden. Arterioscler Thromb Vasc Biol 28:243–250. doi:10.1161/ATVBAHA.107.158675

    Article  CAS  PubMed  Google Scholar 

  103. Shaposhnik Z, Wang X, Weinstein M, Bennett BJ, Lusis AJ (2007) Granulocyte macrophage colony-stimulating factor regulates dendritic cell content of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 27:621–627. doi:10.1161/01.ATV.0000254673.55431.e6

    Article  CAS  PubMed  Google Scholar 

  104. Weis M, Schlichting CL, Engleman EG, Cooke JP (2002) Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases. Arterioscler Thromb Vasc Biol 22:1817–1823. doi:10.1161/01.ATV.0000036418.04998.D5

    Article  CAS  PubMed  Google Scholar 

  105. Aicher A, Heeschen C, Mohaupt M, Cooke JP, Zeiher AM, Dimmeler S (2003) Nicotine strongly activates dendritic cell-mediated adaptive immunity: potential role for progression of atherosclerotic lesions. Circulation 107:604–611. doi:10.1161/01.CIR.0000047279.42427.6D

    Article  CAS  PubMed  Google Scholar 

  106. 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. doi:10.1084/jem.20060245

    Article  CAS  PubMed  Google Scholar 

  107. 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 176:101–110. doi:10.1016/j.atherosclerosis.2004.04.027

    Article  CAS  PubMed  Google Scholar 

  108. 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. doi:10.1007/s00395-006-0636-x

    Article  CAS  PubMed  Google Scholar 

  109. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A 101:11779–11784. doi:10.1073/pnas.0403259101

    Article  CAS  PubMed  Google Scholar 

  110. Angeli V, Llodra J, Rong JX, Satoh K, Ishii S, Shimizu T, Fisher EA, Randolph GJ (2004) Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. Immunity 21:561–574. doi:10.1016/j.immuni.2004.09.003

    Article  CAS  PubMed  Google Scholar 

  111. Packard RR, Maganto-Garcia 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 hypercholesterolemic conditions associated with atherosclerosis. Circ Res 103:965–973. doi:10.1161/CIRCRESAHA.108.185793

    Article  CAS  PubMed  Google Scholar 

  112. Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, Marks AR, Ron D, Tabas I (2003) The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5:781–792. doi:10.1038/ncb1035

    Article  CAS  PubMed  Google Scholar 

  113. Rivollier A, Perrin-Cocon L, Luche S, Diemer H, Strub JM, Hanau D, van Dorsselaer A, Lotteau V, Rabourdin-Combe C, Rabilloud T, Servet-Delprat C (2006) High expression of antioxidant proteins in dendritic cells: possible implications in atherosclerosis. Mol Cell Proteomics 5:726–736. doi:10.1074/mcp.M500262-MCP200

    CAS  PubMed  Google Scholar 

  114. Han JW, Shimada K, Ma-Krupa W, Johnson TL, Nerem RM, Goronzy JJ, Weyand CM (2008) Vessel wall-embedded dendritic cells induce T-cell autoreactivity and initiate vascular inflammation. Circ Res 102:546–553. doi:10.1161/CIRCRESAHA.107.161653

    Article  CAS  PubMed  Google Scholar 

  115. Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nat Rev Immunol 2:151–161. doi:10.1038/nri746

    Article  CAS  PubMed  Google Scholar 

  116. Niessner A, Sato K, Chaikof EL, Colmegna I, Goronzy JJ, Weyand CM (2006) Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Circulation 114:2482–2489. doi:10.1161/CIRCULATIONAHA.106.642801

    Article  CAS  PubMed  Google Scholar 

  117. Sato K, Niessner A, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM (2006) TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque. J Exp Med 203:239–250. doi:10.1084/jem.20051062

    Article  CAS  PubMed  Google Scholar 

  118. Niessner A, Shin MS, Pryshchep O, Goronzy JJ, Chaikof EL, Weyand CM (2007) Synergistic proinflammatory effects of the antiviral cytokine interferon-alpha and Toll-like receptor 4 ligands in the atherosclerotic plaque. Circulation 116:2043–2052. doi:10.1161/CIRCULATIONAHA.107.697789

    Article  CAS  PubMed  Google Scholar 

  119. Kalayoglu MV, Libby P, Byrne GI (2002) Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA 288:2724–2731. doi:10.1001/jama.288.21.2724

    Article  CAS  PubMed  Google Scholar 

  120. Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW, Litovsky S (2007) Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Tex Heart Inst J 34:11–18

    PubMed  Google Scholar 

  121. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, Lipp M (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33. doi:10.1016/S0092-8674(00)80059-8

    Article  CAS  PubMed  Google Scholar 

  122. Qu C, Edwards EW, Tacke F, Angeli V, Llodra J, Sanchez-Schmitz G, Garin A, Haque NS, Peters W, van Rooijen N, Sanchez-Torres C, Bromberg J, Charo IF, Jung S, Lira SA, Randolph GJ (2004) Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J Exp Med 200:1231–1241. doi:10.1084/jem.20032152

    Article  CAS  PubMed  Google Scholar 

  123. Gotsman I, Sharpe AH, Lichtman AH (2008) T-cell costimulation and coinhibition in atherosclerosis. Circ Res 103:1220–1231. doi:10.1161/CIRCRESAHA.108.182428

    Article  CAS  PubMed  Google Scholar 

  124. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548. doi:10.1146/annurev.immunol.23.021704.115611

    Article  PubMed  CAS  Google Scholar 

  125. Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68. doi:10.1146/annurev.immunol.23.021704.115839

    Article  CAS  PubMed  Google Scholar 

  126. Buono C, Pang H, Uchida Y, Libby P, Sharpe AH, Lichtman AH (2004) B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 109:2009–2015. doi:10.1161/01.CIR.0000127121.16815.F1

    Article  CAS  PubMed  Google Scholar 

  127. Dong C, Juedes AE, Temann UA, Shresta S, Allison JP, Ruddle NH, Flavell RA (2001) ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409:97–101. doi:10.1038/35051100

    Article  CAS  PubMed  Google Scholar 

  128. Gotsman I, Grabie N, Gupta R, Dacosta R, MacConmara M, Lederer J, Sukhova G, Witztum JL, Sharpe AH, Lichtman AH (2006) Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 114:2047–2055. doi:10.1161/CIRCULATIONAHA.106.633263

    Article  CAS  PubMed  Google Scholar 

  129. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8:239–245. doi:10.1038/ni1443

    Article  CAS  PubMed  Google Scholar 

  130. Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH (2007) Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J Clin Invest 117:2974–2982. doi:10.1172/JCI31344

    Article  CAS  PubMed  Google Scholar 

  131. Wang X, Ria M, Kelmenson PM, Eriksson P, Higgins DC, Samnegard A, Petros C, Rollins J, Bennet AM, Wiman B, de Faire U, Wennberg C, Olsson PG, Ishii N, Sugamura K, Hamsten A, Forsman-Semb K, Lagercrantz J, Paigen B (2005) Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat Genet 37:365–372. doi:10.1038/ng1524

    Article  CAS  PubMed  Google Scholar 

  132. van Wanrooij EJ, van Puijvelde GH, de Vos P, Yagita H, van Berkel TJ, Kuiper J (2007) Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) pathway attenuates atherogenesis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 27:204–210. doi:10.1161/01.ATV.0000251007.07648.81

    Article  PubMed  CAS  Google Scholar 

  133. Dawicki W, Bertram EM, Sharpe AH, Watts TH (2004) 4–1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J Immunol 173:5944–5951

    CAS  PubMed  Google Scholar 

  134. Olofsson PS, Soderstrom LA, Wagsater D, Sheikine Y, Ocaya P, Lang F, Rabu C, Chen L, Rudling M, Aukrust P, Hedin U, Paulsson-Berne G, Sirsjo A, Hansson GK (2008) CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117:1292–1301. doi:10.1161/CIRCULATIONAHA.107.699173

    Article  CAS  PubMed  Google Scholar 

  135. Hosono M, de Boer OJ, van der Wal AC, van der Loos CM, Teeling P, Piek JJ, Ueda M, Becker AE (2003) Increased expression of T cell activation markers (CD25, CD26, CD40L and CD69) in atherectomy specimens of patients with unstable angina and acute myocardial infarction. Atherosclerosis 168:73–80. doi:10.1016/S0021-9150(03)00024-8

    Article  CAS  PubMed  Google Scholar 

  136. Roselaar SE, Kakkanathu PX, Daugherty A (1996) Lymphocyte populations in atherosclerotic lesions of apoE −/− and LDL receptor −/− mice. Decreasing density with disease progression. Arterioscler Thromb Vasc Biol 16:1013–1018

    CAS  Google Scholar 

  137. Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby P, Luster AD (1999) Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J Clin Invest 104:1041–1050. doi:10.1172/JCI6993

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  139. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK (1995) T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A 92:3893–3897. doi:10.1073/pnas.92.9.3893

    Article  CAS  PubMed  Google Scholar 

  140. Xu Q, Kleindienst R, Waitz W, Dietrich H, Wick G (1993) Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest 91:2693–2702. doi:10.1172/JCI116508

    Article  CAS  PubMed  Google Scholar 

  141. Song L, Leung C, Schindler C (2001) Lymphocytes are important in early atherosclerosis. J Clin Invest 108:251–259

    CAS  PubMed  Google Scholar 

  142. 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 

  143. Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P (1985) Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57:65–73. doi:10.1016/0021-9150(85)90138-8

    Article  CAS  PubMed  Google Scholar 

  144. Schulte S, Sukhova GK, Libby P (2008) Genetically programmed biases in Th1 and Th2 immune responses modulate atherogenesis. Am J Pathol 172:1500–1508. doi:10.2353/ajpath.2008.070776

    Article  CAS  PubMed  Google Scholar 

  145. Buono C, Binder CJ, Stavrakis G, Witztum JL, Glimcher LH, Lichtman AH (2005) T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci U S A 102:1596–1601. doi:10.1073/pnas.0409015102

    Article  CAS  PubMed  Google Scholar 

  146. Laurat E, Poirier B, Tupin E, Caligiuri G, Hansson GK, Bariety J, Nicoletti A (2001) In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 104:197–202

    CAS  PubMed  Google Scholar 

  147. Lee TS, Yen HC, Pan CC, Chau LY (1999) The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 19:734–742

    CAS  PubMed  Google Scholar 

  148. Davenport P, Tipping PG (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

    CAS  PubMed  Google Scholar 

  149. Hauer AD, Uyttenhove C, de Vos P, Stroobant V, Renauld JC, van Berkel TJ, van Snick J, Kuiper J (2005) Blockade of interleukin-12 function by protein vaccination attenuates atherosclerosis. Circulation 112:1054–1062. doi:10.1161/CIRCULATIONAHA.104.533463

    Article  CAS  PubMed  Google Scholar 

  150. Elhage R, Jawien J, Rudling M, Ljunggren HG, Takeda K, Akira S, Bayard F, Hansson GK (2003) Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc Res 59:234–240. doi:10.1016/S0008-6363(03)00343-2

    Article  CAS  PubMed  Google Scholar 

  151. Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B, Humbert Y, Chvatchko Y, Tedgui A (2001) Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 89:E41–E45. doi:10.1161/hh1901.098735

    Article  CAS  PubMed  Google Scholar 

  152. Buono C, Come CE, Stavrakis G, Maguire GF, Connelly PW, Lichtman AH (2003) Influence of interferon-gamma on the extent and phenotype of diet-induced atherosclerosis in the LDLR-deficient mouse. Arterioscler Thromb Vasc Biol 23:454–460. doi:10.1161/01.ATV.0000059419.11002.6E

    Article  CAS  PubMed  Google Scholar 

  153. Gupta S, Pablo AM, Jiang X, Wang N, Tall AR, Schindler C (1997) IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest 99:2752–2761. doi:10.1172/JCI119465

    Article  CAS  PubMed  Google Scholar 

  154. Whitman SC, Ravisankar P, Elam H, Daugherty A (2000) Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E−/− mice. Am J Pathol 157:1819–1824

    CAS  PubMed  Google Scholar 

  155. Hansson GK, Hellstrand M, Rymo L, Rubbia L, Gabbiani G (1989) Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells. J Exp Med 170:1595–1608. doi:10.1084/jem.170.5.1595

    Article  CAS  PubMed  Google Scholar 

  156. Friesel R, Komoriya A, Maciag T (1987) Inhibition of endothelial cell proliferation by gamma-interferon. J Cell Biol 104:689–696. doi:10.1083/jcb.104.3.689

    Article  CAS  PubMed  Google Scholar 

  157. Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK (1999) Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145:33–43. doi:10.1016/S0021-9150(99)00011-8

    Article  CAS  PubMed  Google Scholar 

  158. Tellides G, Tereb DA, Kirkiles-Smith NC, Kim RW, Wilson JH, Schechner JS, Lorber MI, Pober JS (2000) Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature 403:207–211. doi:10.1038/35003221

    Article  CAS  PubMed  Google Scholar 

  159. Bavendiek U, Libby P, Kilbride M, Reynolds R, Mackman N, Schonbeck U (2002) Induction of tissue factor expression in human endothelial cells by CD40 ligand is mediated via activator protein 1, nuclear factor kappa B, and Egr-1. J Biol Chem 277:25032–25039. doi:10.1074/jbc.M204003200

    Article  CAS  PubMed  Google Scholar 

  160. Schonbeck U, Mach F, Sukhova GK, Herman M, Graber P, Kehry MR, Libby P (2000) CD40 ligation induces tissue factor expression in human vascular smooth muscle cells. Am J Pathol 156:7–14

    CAS  PubMed  Google Scholar 

  161. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P (1997) Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation 96:396–399

    CAS  PubMed  Google Scholar 

  162. Zirlik A, Maier C, Gerdes N, MacFarlane L, Soosairajah J, Bavendiek U, Ahrens I, Ernst S, Bassler N, Missiou A, Patko Z, Aikawa M, Schonbeck U, Bode C, Libby P, Peter K (2007) CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1. Circulation 115:1571–1580. doi:10.1161/CIRCULATIONAHA.106.683201

    Article  CAS  PubMed  Google Scholar 

  163. Grewal IS, Flavell RA (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16:111–135. doi:10.1146/annurev.immunol.16.1.111

    Article  CAS  PubMed  Google Scholar 

  164. Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS, Libby P (1997) Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A 94:1931–1936. doi:10.1073/pnas.94.5.1931

    Article  CAS  PubMed  Google Scholar 

  165. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594. doi:10.1038/35393

    Article  CAS  PubMed  Google Scholar 

  166. Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, Koteliansky VE, Flavell RA (1999) Requirement for CD154 in the progression of atherosclerosis. Nat Med 5:1313–1316. doi:10.1038/15271

    Article  CAS  PubMed  Google Scholar 

  167. Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P (1998) Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394:200–203. doi:10.1038/28204

    Article  CAS  PubMed  Google Scholar 

  168. Nadareishvili ZG, Koziol DE, Szekely B, Ruetzler C, LaBiche R, McCarron R, DeGraba TJ (2001) Increased CD8(+) T cells associated with Chlamydia pneumoniae in symptomatic carotid plaque. Stroke 32:1966–1972. doi:10.1161/hs0901.095633

    Article  CAS  PubMed  Google Scholar 

  169. Henderson EL, Geng YJ, Sukhova GK, Whittemore AD, Knox J, Libby P (1999) Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation 99:96–104

    CAS  PubMed  Google Scholar 

  170. Park SH, Bendelac A (2000) CD1-restricted T-cell responses and microbial infection. Nature 406:788–792. doi:10.1038/35021233

    Article  CAS  PubMed  Google Scholar 

  171. Melian A, Geng YJ, Sukhova GK, Libby P, Porcelli SA (1999) CD1 expression in human atherosclerosis. A potential mechanism for T cell activation by foam cells. Am J Pathol 155:775–786

    CAS  PubMed  Google Scholar 

  172. Tupin E, Nicoletti A, Elhage R, Rudling M, Ljunggren HG, Hansson GK, Berne GP (2004) CD1d-dependent activation of NKT cells aggravates atherosclerosis. J Exp Med 199:417–422. doi:10.1084/jem.20030997

    Article  CAS  PubMed  Google Scholar 

  173. Nakai Y, Iwabuchi K, Fujii S, Ishimori N, Dashtsoodol N, Watano K, Mishima T, Iwabuchi C, Tanaka S, Bezbradica JS, Nakayama T, Taniguchi M, Miyake S, Yamamura T, Kitabatake A, Joyce S, Van Kaer L, Onoe K (2004) Natural killer T cells accelerate atherogenesis in mice. Blood 104:2051–2059. doi:10.1182/blood-2003-10-3485

    Article  CAS  PubMed  Google Scholar 

  174. Major AS, Wilson MT, McCaleb JL, Ru Su Y, Stanic AK, Joyce S, Van Kaer L, Fazio S, Linton MF (2004) Quantitative and qualitative differences in proatherogenic NKT cells in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 24:2351–2357. doi:10.1161/01.ATV.0000147112.84168.87

    Article  CAS  PubMed  Google Scholar 

  175. Aslanian AM, Chapman HA, Charo IF (2005) Transient role for CD1d-restricted natural killer T cells in the formation of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 25:628–632. doi:10.1161/01.ATV.0000153046.59370.13

    Article  CAS  PubMed  Google Scholar 

  176. Carding SR, Egan PJ (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2:336–345. doi:10.1038/nri797

    Article  CAS  PubMed  Google Scholar 

  177. Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G (1993) Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol 142:1927–1937

    CAS  PubMed  Google Scholar 

  178. Elhage R, Gourdy P, Brouchet L, Jawien J, Fouque MJ, Fievet C, Huc X, Barreira Y, Couloumiers JC, Arnal JF, Bayard F (2004) Deleting TCR alpha beta+ or CD4+ T lymphocytes leads to opposite effects on site-specific atherosclerosis in female apolipoprotein E-deficient mice. Am J Pathol 165:2013–2018

    PubMed  Google Scholar 

  179. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336. doi:10.1038/ni904

    Article  CAS  PubMed  Google Scholar 

  180. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787. doi:10.1016/j.cell.2008.05.009

    Article  CAS  PubMed  Google Scholar 

  181. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A (1999) Protective role of interleukin-10 in atherosclerosis. Circ Res 85:e17–e24

    CAS  PubMed  Google Scholar 

  182. Pinderski Oslund LJ, Hedrick CC, Olvera T, Hagenbaugh A, Territo M, Berliner JA, Fyfe AI (1999) Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol 19:2847–2853

    CAS  PubMed  Google Scholar 

  183. Pinderski LJ, Fischbein MP, Subbanagounder G, Fishbein MC, Kubo N, Cheroutre H, Curtiss LK, Berliner JA, Boisvert WA (2002) Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ Res 90:1064–1071. doi:10.1161/01.RES.0000018941.10726.FA

    Article  CAS  PubMed  Google Scholar 

  184. Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R, Fradelizi D, Tedgui A (2001) Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 89:930–934. doi:10.1161/hh2201.099415

    Article  CAS  PubMed  Google Scholar 

  185. Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, Daemen MJ (2002) Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol 22:975–982. doi:10.1161/01.ATV.0000019729.39500.2F

    Article  CAS  PubMed  Google Scholar 

  186. Robertson AK, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK (2003) Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 112:1342–1350

    CAS  PubMed  Google Scholar 

  187. Gojova A, Brun V, Esposito B, Cottrez F, Gourdy P, Ardouin P, Tedgui A, Mallat Z, Groux H (2003) Specific abrogation of transforming growth factor-beta signaling in T cells alters atherosclerotic lesion size and composition in mice. Blood 102:4052–4058. doi:10.1182/blood-2003-05-1729

    Article  CAS  PubMed  Google Scholar 

  188. Ovchinnikova O, Robertson AK, Wagsater D, Folco EJ, Hyry M, Myllyharju J, Eriksson P, Libby P, Hansson GK (2009) T-cell activation leads to reduced collagen maturation in atherosclerotic plaques of Apoe(−/−) mice. Am J Pathol 174:693–700. doi:10.2353/ajpath.2009.080561

    Article  CAS  PubMed  Google Scholar 

  189. 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. doi:10.1038/nm1343

    Article  CAS  PubMed  Google Scholar 

  190. Mor A, Luboshits G, Planer D, Keren G, George J (2006) Altered status of CD4(+) CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 27:2530–2537. doi:10.1093/eurheartj/ehl222

    Article  CAS  PubMed  Google Scholar 

  191. 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. doi:10.1161/01.CIR.0000089083.61317.A1

    Article  CAS  PubMed  Google Scholar 

  192. Ait-Oufella H, Horvat B, Kerdiles Y, Herbin O, Gourdy P, Khallou-Laschet J, Merval R, Esposito B, Tedgui A, Mallat Z (2007) Measles virus nucleoprotein induces a regulatory immune response and reduces atherosclerosis in mice. Circulation 116:1707–1713. doi:10.1161/CIRCULATIONAHA.107.699470

    Article  PubMed  Google Scholar 

  193. Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clement K, Holvoet P, Tedgui A, Mallat Z (2007) Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. Arterioscler Thromb Vasc Biol 27:2691–2698. doi:10.1161/ATVBAHA.107.149567

    Article  CAS  PubMed  Google Scholar 

  194. Heller EA, Liu E, Tager AM, Yuan Q, Lin AY, Ahluwalia N, Jones K, Koehn SL, Lok VM, Aikawa E, Moore KJ, Luster AD, Gerszten RE (2006) Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation 113:2301–2312. doi:10.1161/CIRCULATIONAHA.105.605121

    Article  CAS  PubMed  Google Scholar 

  195. Steffens S, Burger F, Pelli G, Dean Y, Elson G, Kosco-Vilbois M, Chatenoud L, Mach F (2006) Short-term treatment with anti-CD3 antibody reduces the development and progression of atherosclerosis in mice. Circulation 114:1977–1984. doi:10.1161/CIRCULATIONAHA.106.627430

    Article  CAS  PubMed  Google Scholar 

  196. van Puijvelde GH, Hauer AD, de Vos P, van den Heuvel R, van Herwijnen MJ, van der Zee R, van Eden W, van Berkel TJ, Kuiper J (2006) Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114:1968–1976. doi:10.1161/CIRCULATIONAHA.106.615609

    Article  PubMed  CAS  Google Scholar 

  197. van Puijvelde GH, van Es T, van Wanrooij EJ, Habets KL, de Vos P, van der Zee R, van Eden W, van Berkel TJ, Kuiper J (2007) Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 27:2677–2683. doi:10.1161/ATVBAHA.107.151274

    Article  PubMed  CAS  Google Scholar 

  198. Maron R, Sukhova G, Faria AM, Hoffmann E, Mach F, Libby P, Weiner HL (2002) 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. doi:10.1161/01.CIR.0000029750.99462.30

    Article  CAS  PubMed  Google Scholar 

  199. Harats D, Yacov N, Gilburd B, Shoenfeld Y, George J (2002) 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. doi:10.1016/S0735-1097(02)02135-6

    Article  CAS  PubMed  Google Scholar 

  200. George J, Yacov N, Breitbart E, Bangio L, Shaish A, Gilburd B, Shoenfeld Y, Harats D (2004) Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I. Cardiovasc Res 62:603–609. doi:10.1016/j.cardiores.2004.01.028

    Article  CAS  PubMed  Google Scholar 

  201. Watanabe M, Sangawa A, Sasaki Y, Yamashita M, Tanaka-Shintani M, Shintaku M, Ishikawa Y (2007) Distribution of inflammatory cells in adventitia changed with advancing atherosclerosis of human coronary artery. J Atheroscler Thromb 14:325–331

    PubMed  Google Scholar 

  202. Moos MP, John N, Grabner R, Nossmann S, Gunther B, Vollandt R, Funk CD, Kaiser B, Habenicht AJ (2005) The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:2386–2391. doi:10.1161/01.ATV.0000187470.31662.fe

    Article  CAS  PubMed  Google Scholar 

  203. Zhou X, Hansson GK (1999) Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein E knockout mice. Scand J Immunol 50:25–30. doi:10.1046/j.1365-3083.1999.00559.x

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  205. Palinski W, Rosenfeld ME, Yla-Herttuala S, Gurtner GC, Socher SS, Butler SW, Parthasarathy S, Carew TE, Steinberg D, Witztum JL (1989) Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A 86:1372–1376. doi:10.1073/pnas.86.4.1372

    Article  CAS  PubMed  Google Scholar 

  206. Palinski W, Horkko S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK, Witztum JL (1996) Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest 98:800–814. doi:10.1172/JCI118853

    Article  CAS  PubMed  Google Scholar 

  207. Shaw PX, Horkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, Witztum JL (2000) Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 105:1731–1740. doi:10.1172/JCI8472

    Article  CAS  PubMed  Google Scholar 

  208. Binder CJ, Horkko S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ (2003) Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 9:736–743. doi:10.1038/nm876

    Article  CAS  PubMed  Google Scholar 

  209. Perschinka H, Mayr M, Millonig G, Mayerl C, van der Zee R, Morrison SG, Morrison RP, Xu Q, Wick G (2003) Cross-reactive B-cell epitopes of microbial and human heat shock protein 60/65 in atherosclerosis. Arterioscler Thromb Vasc Biol 23:1060–1065. doi:10.1161/01.ATV.0000071701.62486.49

    Article  CAS  PubMed  Google Scholar 

  210. Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G (1992) Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb 12:789–799

    CAS  PubMed  Google Scholar 

  211. Afek A, George J, Gilburd B, Rauova L, Goldberg I, Kopolovic J, Harats D, Shoenfeld Y (2000) 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. doi:10.1006/jaut.1999.0351

    Article  CAS  PubMed  Google Scholar 

  212. Schett G, Xu Q, Amberger A, Van der Zee R, Recheis H, Willeit J, Wick G (1995) Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest 96:2569–2577. doi:10.1172/JCI118320

    Article  CAS  PubMed  Google Scholar 

  213. Packard RR, Libby P (2008) Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem 54:24–38. doi:10.1373/clinchem.2007.097360

    Article  CAS  PubMed  Google Scholar 

  214. Libby P (2005) The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 46:1225–1228. doi:10.1016/j.jacc.2005.07.006

    Article  PubMed  Google Scholar 

  215. Libby P (2006) Inflammation in cardiovascular disease. In: Morrow DA (ed) Contemporary Cardiology. Humana Press, Inc, Totowa, NJ, pp 205–219

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter Libby.

Additional information

This work was supported by the Fondation Leducq, Paris, France (Dr. Libby) and by NIH HL087282 (Dr. Lichtman) and HL36436 (Dr. Libby).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Packard, R.R.S., Lichtman, A.H. & Libby, P. Innate and adaptive immunity in atherosclerosis. Semin Immunopathol 31, 5–22 (2009). https://doi.org/10.1007/s00281-009-0153-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-009-0153-8

Keywords

Navigation