title: Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis.
abstract: Oxidation-specific epitopes (OSE), present on oxidized LDL (OxLDL), apoptotic cells, cell debris and modified proteins in the vessel wall, accumulate in response to hypercholesterolemia, and generate potent pro-inflammatory, disease-specific antigens. They represent an important class of 'danger associated molecular patterns' (DAMPs), against which a concerted innate immune response is directed. OSE are recognized by innate 'pattern recognition receptors', such as scavenger receptors present on dendritic cells and monocyte/macrophages, as well as by innate proteins, such as IgM natural antibodies and soluble proteins, such as C-reactive protein and complement factor H. These innate immune responses provide a first line of defense against atherosclerosis-specific DAMPs, and engage adaptive immune responses, provided by T and B-2 cells, which provide a more specific and definitive response. Such immune responses are ordinarily directed to remove foreign pathogens, such as those found on microbial pathogens, but when persistent or maladaptive, lead to host damage. In this context, atherosclerosis can be considered as a systemic chronic inflammatory disease initiated by the accumulation of OSE type DAMPs and perpetuated by maladaptive response of the innate and adaptive immune system. Understanding this paradigm leads to new approaches to defining cardiovascular risk and suggests new modes of therapy. Therefore, OSE have become potential targets of diagnostic and therapeutic agents. Human and murine OSE-targeting antibodies have been developed and are now being used as biomarkers in human studies and experimentally in translational applications of non-invasive molecular imaging of oxidation-rich plaques and immunotherapeutics.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Leibundgut
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D050197:Atherosclerosis / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy; D015415:Biomarkers; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D057054:Molecular Imaging; D010084:Oxidation-Reduction
chemical_list: D000906:Antibodies; D015415:Biomarkers; D000939:Epitopes
references.citation: J Clin Invest. 2005 Aug;115(8):2072-5
references.pmid: 16075051
references.citation: Eur J Immunol. 2011 Sep;41(9):2515-8
references.pmid: 21952808
references.citation: J Clin Invest. 2011 Dec;121(12):4861-9
references.pmid: 22105168
references.citation: J Am Coll Cardiol. 2007 Dec 11;50(24):2313-8
references.pmid: 18068040
references.citation: J Clin Invest. 2005 Aug;115(8):2192-201
references.pmid: 16075060
references.citation: J Lipid Res. 2012 Dec;53(12):2773-90
references.pmid: 22969153
references.citation: Immunol Rev. 2007 Oct;219:187-203
references.pmid: 17850490
references.citation: J Am Coll Cardiol. 2011 Oct 11;58(16):1715-27
references.pmid: 21982317
references.citation: Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2311-6
references.pmid: 21084697
references.citation: Circ Res. 2010 Sep 17;107(6):737-46
references.pmid: 20651288
references.citation: Free Radic Biol Med. 2011 Nov 15;51(10):1903-9
references.pmid: 21925592
references.citation: Arterioscler Thromb Vasc Biol. 2003 Apr 1;23(4):630-6
references.pmid: 12615690
references.citation: J Lipid Res. 2012 Oct;53(10):2126-2132
references.pmid: 22822027
references.citation: Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):605-12
references.pmid: 22223728
references.citation: Atherosclerosis. 2007 Feb;190(2):298-305
references.pmid: 16677655
references.citation: Atherosclerosis. 2006 Nov;189(1):83-90
references.pmid: 16386745
references.citation: J Am Coll Cardiol. 2012 Apr 17;59(16):1438-40
references.pmid: 22497822
references.citation: Eur Heart J. 2010 Dec;31(23):2844-53
references.pmid: 20965889
references.citation: Biomark Med. 2011 Oct;5(5):673-94
references.pmid: 22003918
references.citation: Cell. 2012 Sep 28;151(1):138-52
references.pmid: 23021221
references.citation: Semin Immunopathol. 2009 Jun;31(1):5-22
references.pmid: 19449008
references.citation: Curr Opin Pharmacol. 2010 Apr;10(2):197-202
references.pmid: 20207195
references.citation: J Clin Invest. 2009 May;119(5):1335-49
references.pmid: 19363291
references.citation: Atherosclerosis. 2005 Sep;182(1):1-15
references.pmid: 15904923
references.citation: J Lipid Res. 2008 Oct;49(10):2230-9
references.pmid: 18594118
references.citation: Curr Opin Lipidol. 2013 Feb;24(1):78-85
references.pmid: 23298961
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S388-93
references.pmid: 19106070
references.citation: Clin Immunol. 2012 Aug;144(2):142-58
references.pmid: 22771788
references.citation: Circulation. 2011 Mar 15;123(10):1083-91
references.pmid: 21357823
references.citation: Cell. 2001 Feb 23;104(4):503-16
references.pmid: 11239408
references.citation: Curr Opin Lipidol. 2012 Dec;23(6):560-8
references.pmid: 23041907
references.citation: Circulation. 2004 Oct 5;110(14):2047-52
references.pmid: 15451805
references.citation: Arterioscler Thromb Vasc Biol. 2001 Aug;21(8):1333-9
references.pmid: 11498462
references.citation: Curr Opin Lipidol. 2012 Oct;23(5):422-8
references.pmid: 22814703
references.citation: J Clin Invest. 2004 Aug;114(3):427-37
references.pmid: 15286809
references.citation: Nat Rev Immunol. 2010 Jan;10(1):36-46
references.pmid: 19960040
references.citation: Circulation. 2007 Oct 16;116(16):1832-44
references.pmid: 17938300
references.citation: Circ Res. 2009 Jun 19;104(12):1355-63
references.pmid: 19461045
references.citation: J Clin Invest. 2013 Jan;123(1):27-36
references.pmid: 23281407
references.citation: J Am Coll Cardiol. 2012 Feb 7;59(6):616-26
references.pmid: 22300697
references.citation: Clin Immunol. 2010 Jan;134(1):66-79
references.pmid: 19666239
references.citation: J Am Coll Cardiol. 2012 Nov 20;60(21):2218-29
references.pmid: 23122790
references.citation: Nat Med. 2004 Apr;10(4):416-21
references.pmid: 15034566
references.citation: Cell. 2011 Apr 29;145(3):341-55
references.pmid: 21529710
references.citation: Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1788-95
references.pmid: 17541022
references.citation: Curr Cardiovasc Imaging Rep. 2011 Feb;4(1):4-16
references.pmid: 21297859
references.citation: Biochim Biophys Acta. 2012 Oct;1818(10):2465-75
references.pmid: 22305963
references.citation: J Exp Med. 2010 May 10;207(5):1081-93
references.pmid: 20439543
references.citation: Methods. 2007 Nov;43(3):207-17
references.pmid: 17920517
references.citation: Nat Med. 2003 Jun;9(6):736-43
references.pmid: 12740573
references.citation: Nature. 2011 May 19;473(7347):317-25
references.pmid: 21593864
references.citation: Circ Res. 2010 Jul 9;107(1):56-65
references.pmid: 20489162
references.citation: Circ Res. 2011 Sep 30;109(8):830-40
references.pmid: 21868694
references.citation: J Clin Invest. 2005 Nov;115(11):3149-56
references.pmid: 16211093
references.citation: J Am Coll Cardiol. 2011 Jan 18;57(3):337-47
references.pmid: 21106318
references.citation: J Lipid Res. 2011 Oct;52(10):1829-36
references.pmid: 21821825
references.citation: J Lipid Res. 2012 Jul;53(7):1316-26
references.pmid: 22508944
references.citation: J Am Coll Cardiol. 2012 Apr 17;59(16):1426-37
references.pmid: 22497821
references.citation: J Innate Immun. 2009;1(4):340-9
references.pmid: 20375591
references.citation: Circulation. 2009 Aug 4;120(5):417-26
references.pmid: 19620499
references.citation: Nature. 2011 Oct 05;478(7367):76-81
references.pmid: 21979047
references.citation: Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):821-5
references.pmid: 7846059
references.citation: Circ Res. 2012 Aug 31;111(6):778-99
references.pmid: 22935534
references.citation: J Lipid Res. 2005 Aug;46(8):1582-90
references.pmid: 15961784
references.citation: J Lipid Res. 2005 Jul;46(7):1353-63
references.pmid: 15897601
references.citation: Circ Res. 2011 Jan 21;108(2):235-48
references.pmid: 21252151
references.citation: J Am Coll Cardiol. 2010 Sep 14;56(12):946-55
references.pmid: 20828647
references.citation: Nat Immunol. 2011 Mar;12(3):204-12
references.pmid: 21321594
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1213-9
references.pmid: 15718493
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10679-84
references.pmid: 15249654
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S340-5
references.pmid: 18980945
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13043-8
references.pmid: 12244213