The role of innate immunity in atherogenesis
2008; Elsevier BV; Volume: 50; Linguagem: Inglês
10.1194/jlr.r800100-jlr200
ISSN1539-7262
AutoresKarsten Hartvigsen, Meng-Yun Chou, Lotte F. Hansen, Peter X. Shaw, Sotirios Tsimikas, Christoph J. Binder, Joseph L. Witztum,
Tópico(s)Inflammasome and immune disorders
ResumoLipid peroxidation is a common event in health and is greatly accelerated in pro-inflammatory settings such as hypercholesterolemia. Consequently, oxidation-specific epitopes are generated, which are pro-inflammatory and immunogenic, leading to both adaptive and innate responses. Because innate immune mechanisms use conserved germline pattern recognition receptors (PRRs) that are preformed and present at birth, it is not obvious why they should bind to such epitopes. In this review, we put forward the hypothesis that because oxidation-specific epitopes are ubiquitous in both health and disease, and because they in essence represent “danger signals,” they constitute a class of pathogen-associated molecular patterns leading to the natural selection of multiple innate PRRs that target such epitopes. We suggest that apoptotic cells, and the blebs and microparticles released from such cells, which are rich in oxidation-specific epitopes and thus pro-inflammatory, constitute an endogenous set of selecting antigens. In turn, natural antibodies, scavenger receptors, and soluble innate proteins, such as pentraxins, all represent PRRs that target such epitopes. We discuss the evidence for this hypothesis and the consequences of such responses in health and disease, such as atherosclerosis. Lipid peroxidation is a common event in health and is greatly accelerated in pro-inflammatory settings such as hypercholesterolemia. Consequently, oxidation-specific epitopes are generated, which are pro-inflammatory and immunogenic, leading to both adaptive and innate responses. Because innate immune mechanisms use conserved germline pattern recognition receptors (PRRs) that are preformed and present at birth, it is not obvious why they should bind to such epitopes. In this review, we put forward the hypothesis that because oxidation-specific epitopes are ubiquitous in both health and disease, and because they in essence represent “danger signals,” they constitute a class of pathogen-associated molecular patterns leading to the natural selection of multiple innate PRRs that target such epitopes. We suggest that apoptotic cells, and the blebs and microparticles released from such cells, which are rich in oxidation-specific epitopes and thus pro-inflammatory, constitute an endogenous set of selecting antigens. In turn, natural antibodies, scavenger receptors, and soluble innate proteins, such as pentraxins, all represent PRRs that target such epitopes. We discuss the evidence for this hypothesis and the consequences of such responses in health and disease, such as atherosclerosis. Hypercholesterolemia not only leads to enhanced binding of apolipoprotein B (apoB) containing lipoproteins in the arterial intima but also initiates the pro-inflammatory and pro-oxidant conditions that play an obligatory role in the perpetuation and progression of the disease. Inflammation is mediated by immune mechanisms, which profoundly impact atherogenesis, accelerating but providing atheroprotective influences as well (1Binder C.J. Chang M.K. Shaw P.X. Miller Y.I. Hartvigsen K. Dewan A. Witztum J.L. Innate and acquired immunity in atherogenesis.Nat. Med. 2002; 8: 1218-1226Crossref PubMed Scopus (588) Google Scholar, 2Hansson G.K. Libby P. The immune response in atherosclerosis: a double-edged sword.Nat. Rev. Immunol. 2006; 6: 508-519Crossref PubMed Scopus (1789) Google Scholar, 3Getz G.S. Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis.J. Lipid Res. 2005; 46: 1-10Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 4Binder C.J. Shaw P.X. Chang M.K. Boullier A. Hartvigsen K. Miller S.Ho¨rkko¨, Y.I. Woelkers D.A. Corr M. Witztum J.L. The role of natural antibodies in atherogenesis.J. Lipid Res. 2005; 46: 1353-1363Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Why should immune mechanisms be involved in the response to hypercholesterolemia? Immunity is most often thought of in the context of responses to infectious pathogens, but evidence to support other than a minor role for direct involvement of bacterial or viral agents in atherosclerosis is lacking. Indeed, atherogenesis can proceed in mice maintained even in a completely sterile environment (5Wright S.D. Burton C. Hernandez M. Hassing H. Montenegro J. Mundt S. Patel S. Card D.J. Bergstrom A.Hermanowski-Vosatka, J.D. al et Infectious agents are not necessary for murine atherogenesis.J. Exp. Med. 2000; 191: 1437-1442Crossref PubMed Scopus (150) Google Scholar). In this review, we will develop the hypothesis that the enhanced lipid peroxidation that occurs with hypercholesterolemia, and the consequent generation of “oxidation-specific” epitopes, leads to activation of immune responses that impact atherogenesis. Understanding these mechanisms will lead to new insights into atherogenesis and may lead to novel immunoregulatory therapies to modulate disease progression. Adaptive immunity is the active response to perceived changes that are outside the realm of “self,” such as the wide variety of epitopes presented by foreign pathogens. Indeed, the essence of adaptive immunity is the generation of an almost limitless number of high-affinity B-cell and T-cell receptors (∼1014 to 1018) through somatic mutations and induced junctional diversity at VDJ gene recombination sites to produce both cellular (via T-cells) and humoral immunity [via secreted antibodies (Abs) from B-cell-derived plasma cells] against selecting pathogens. Although the adaptive response is delayed in time due to the selection and maturation of T- and B-cell responses, it provides a specific and high-affinity response to newly recognized pathogens. A variety of potential antigens have been described in the atherosclerotic lesion that could serve to activate such adaptive immune responses, including bacterial and viral antigens. However, among these, oxidation-specific epitopes, as occur when LDL is oxidized (OxLDL), are the ones most widely studied to date (4Binder C.J. Shaw P.X. Chang M.K. Boullier A. Hartvigsen K. Miller S.Ho¨rkko¨, Y.I. Woelkers D.A. Corr M. Witztum J.L. The role of natural antibodies in atherogenesis.J. Lipid Res. 2005; 46: 1353-1363Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Multiple oxidative mechanisms are present in the vascular wall that can lead to the generation of highly reactive oxidized lipids. In turn, these can modify proteins and lipids present not only on LDL, for example, but on a wide variety of extracellular and cellular components as well. We have termed these oxidation-specific epitopes to indicate that common modifications could be produced under widely different inflammatory settings and on widely different proteins or even lipids. For example, the common oxidation product, malondialdehyde (MDA), and its many complex condensation products, can modify proteins and lipids leading to common oxidation-specific neo-epitopes that are immunogenic and, importantly, are recognized in a hapten-specific manner. Thus, as we have shown, an MDA adduct formed on apoB of OxLDL could lead to hapten-specific MDA monoclonal antibodies [such as MDA2 and E014 (6Palinski W. Rosenfeld S.Yla¨-Herttuala, M.E. Butler S.W. Socher S.A. Parthasarathy S. Curtiss L.K. Witztum J.L. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein.Arteriosclerosis. 1990; 10: 325-335Crossref PubMed Google Scholar, 7Palinski W. Miller S.Ho¨rkko¨, E. Steinbrecher U.P. Powell H.C. Curtiss L.K. Witztum J.L. 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. 1996; 98: 800-814Crossref PubMed Scopus (501) Google Scholar)] that not only recognize MDA epitopes in atherosclerotic plaques (8Rosenfeld M.E. Palinski W. Butler S.Yla¨-Herttuala, S. Witztum J.L. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits.Arteriosclerosis. 1990; 10: 336-349Crossref PubMed Scopus (413) Google Scholar), but MDA modified proteins in diabetic kidneys (9Horie K. Miyata T. Maeda K. Miyata S. Sugiyama S. Sakai H. Strihou C.Y. Monnier V.M. Witztum J.L. Kurokawa K. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy.J. Clin. Invest. 1997; 100: 2995-3004Crossref PubMed Scopus (385) Google Scholar) and Heyman nephritis (10Neale T.J. Ojha P.P. Exner M. Poczewski H. Ruger B. Witztum J.L. Davis P. Kerjaschki D. Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen.J. Clin. Invest. 1994; 94: 1577-1584Crossref PubMed Scopus (138) Google Scholar), as well as in Alzheimer plaques (11Dei R. Takeda A. Niwa H. Li M. Nakagomi Y. Watanabe M. Inagaki T. Washimi Y. Yasuda Y. Horie K. al et Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease.Acta Neuropathol. 2002; 104: 113-122Crossref PubMed Scopus (136) Google Scholar). Because lipid peroxidation is a common process even in health, and is greatly accelerated in inflammatory diseases, such oxidation-specific epitopes are ubiquitous in both health and disease. Indeed, cells undergoing apoptosis, which are under intense pro-oxidant stress, display a variety of immunogenic oxidation-specific epitopes on their surface (as discussed below) (12Chang M.K. Bergmark C. Laurila A. Han S.Ho¨rkko¨, K.H. Friedman P. Dennis E.A. Witztum J.L. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: Evidence that oxidation-specific epitopes mediate macrophage recognition.Proc. Natl. Acad. Sci. USA. 1999; 96: 6353-6358Crossref PubMed Scopus (396) Google Scholar). In turn, these “neo-self” epitopes are recognized as “foreign” by adaptive immune surveillance. Evidence for humoral and cell-mediated immunity to a variety of oxidation-specific epitopes, such as autoantibodies to OxLDL and MDA-modified LDL (MDA-LDL), has been documented in both animal models of atherosclerosis and in humans (4Binder C.J. Shaw P.X. Chang M.K. Boullier A. Hartvigsen K. Miller S.Ho¨rkko¨, Y.I. Woelkers D.A. Corr M. Witztum J.L. The role of natural antibodies in atherogenesis.J. Lipid Res. 2005; 46: 1353-1363Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 13Tsimikas S. Brilakis E.S. Lennon R.J. Miller E.R. Witztum J.L. McConnell J.P. Kornman K.S. Berger P.B. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events.J. Lipid Res. 2007; 48: 425-433Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). While the originating immunogen that elicited such responses may be varied in a generalized setting of inflammation, as occurs in hypercholesterolemia, the ensuing adaptive immune responses have been shown to profoundly modulate the rate of atherosclerotic lesion progression, where an abundance of such epitopes are found. For example, as first demonstrated in our lab (14Binder C.J. Hartvigsen K. Witztum J.L. Promise of immune modulation to inhibit atherogenesis.J. Am. Coll. Cardiol. 2007; 50: 547-550Crossref PubMed Scopus (25) Google Scholar) and confirmed and extended by others (15Nilsson J. Hansson G.K. Shah P.K. Immunomodulation of atherosclerosis: implications for vaccine development.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 18-28Crossref PubMed Scopus (45) Google Scholar), immunization with homologous MDA-LDL, OxLDL, or mimics of oxidation epitopes (16Caligiuri G. Vandaele J.Khallou-Laschet, M. Gaston A.T. Delignat S. Mandet C. Kohler H.V. Kaveri S.V. Nicoletti A. Phosphorylcholine-targeting immunization reduces atherosclerosis.J. Am. Coll. Cardiol. 2007; 50: 540-546Crossref PubMed Scopus (143) Google Scholar) can reduce the progression of atherosclerosis in animal models of atherosclerosis, even in the presence of marked hypercholesterolemia. Lymphocytes in general have been found to modulate murine atherosclerosis (1Binder C.J. Chang M.K. Shaw P.X. Miller Y.I. Hartvigsen K. Dewan A. Witztum J.L. Innate and acquired immunity in atherogenesis.Nat. Med. 2002; 8: 1218-1226Crossref PubMed Scopus (588) Google Scholar, 2Hansson G.K. Libby P. The immune response in atherosclerosis: a double-edged sword.Nat. Rev. Immunol. 2006; 6: 508-519Crossref PubMed Scopus (1789) Google Scholar, 3Getz G.S. Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis.J. Lipid Res. 2005; 46: 1-10Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). T-cells, especially interferon-γ-secreting Th1 cells, are considered pro-atherogenic, whereas several subsets of regulatory T-cells confer atheroprotection (see review by Mallat et al. in this issue). By contrast, B-cells, though not found in lesions, are nevertheless now thought to provide an overall protective function, in part through generation of Abs that bind to oxidation-specific epitopes (4Binder C.J. Shaw P.X. Chang M.K. Boullier A. Hartvigsen K. Miller S.Ho¨rkko¨, Y.I. Woelkers D.A. Corr M. Witztum J.L. The role of natural antibodies in atherogenesis.J. Lipid Res. 2005; 46: 1353-1363Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). In contrast with adaptive responses, innate immunity uses natural selection of receptors, which play a vital and nonredundant role in the initial defense against invading pathogens and in maintaining homeostasis against a variety of “self-antigens.” Because these receptors are preformed and are present at birth and/or matured via positive selection during the neonatal period or shortly thereafter, they are available for almost immediate defense against a perceived pathogen. Thus, innate receptors of necessity are focused on highly conserved motifs that are present on multiple pathogens as well as many neo-epitopes and even apparent “self-or neo-self epitopes.” These receptors are called pattern recognition receptors (PRRs) and the “conserved” patterns to which they bind are called pathogen-associated molecular patterns (PAMPs). In this review, we suggest that oxidation-specific epitopes are a major target of many innate PRRs. However, it is not apparent why such preformed PRRs should be involved in a disease process such as atherosclerosis, which would not be expected to exert evolutionary pressure. We put forward the hypothesis that because oxidation-specific epitopes are ubiquitous in both health and disease, and because they in essence represent “danger signals,” they constitute a class of PAMPs that has led to the natural selection of multiple PRRs that target such epitopes. This includes both cellular PRRs, such as scavenger receptors (SRs) and toll-like receptors on macrophages, and soluble PRRs, such as pentraxins and natural antibodies (NAbs). Furthermore, the fact that oxidation-specific epitopes often, if not frequently, share molecular identity with epitopes found on infectious pathogens as well provides further selecting pressure for receptors targeted to such epitopes. Thus, oxidation-specific epitopes are a major target of innate immunity. Our own appreciation that NAbs recognized oxidation-specific epitopes arose from studies in which we cloned a panel of hybridomas from cholesterol-fed apolipoprotein E-deficient mice, which have high IgM titers to such epitopes. We cloned eight hybridomas secreting IgM to OxLDL (7Palinski W. Miller S.Ho¨rkko¨, E. Steinbrecher U.P. Powell H.C. Curtiss L.K. Witztum J.L. 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. 1996; 98: 800-814Crossref PubMed Scopus (501) Google Scholar). Each of these, such as the prototypic E06, bound to both the lipid and apoB moiety of OxLDL and specifically to the phosphocholine (PC) headgroup of oxidized phospholipids (OxPLs), such as 1-palmitoyl-2-(5′-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), but not to the PC of native PL (17Ho¨rkko¨ S. Bird D.A. Miller E. Itabe H. Leitinger N. Subbanagounder G. Berliner J.A. Friedman P. Dennis E.A. Curtiss L.K. al et Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins.J. Clin. Invest. 1999; 103: 117-128Crossref PubMed Scopus (472) Google Scholar, 18Shaw P.X. Horkko S. Chang M.K. Curtiss L.K. Palinski W. Silverman G.J. Witztum J.L. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity.J. Clin. Invest. 2000; 105: 1731-1740Crossref PubMed Scopus (557) Google Scholar, 19Friedman P. Steinberg S.Ho¨rkko¨, D. Witztum J.L. Dennis E.A. Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids. Importance of Schiff base formation and aldol concentration.J. Biol. Chem. 2002; 277: 7010-7020Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). In the case of the apoB isolated from OxLDL, we showed that the OxPL was covalently linked to the lysines of apoB via the reactive aldehydes of the oxidized sn2 side chain, leaving the PC headgroup free to bind E06. E06 became of enormous interest when we found that it inhibited the uptake of OxLDL by macrophage scavenger receptors CD36 and SR-BI (20Boullier A. Gillotte K.L. Green S.Ho¨rkko¨, S.R. Friedman P. Dennis E.A. Witztum J.L. Steinberg D. Quehenberger O. The binding of oxidized low density lipoprotein to mouse CD36 is mediated in part by oxidized phospholipids that are associated with both the lipid and protein moieties of the lipoprotein.J. Biol. Chem. 2000; 275: 9163-9169Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 21Gillotte-Taylor K. Boullier A. Witztum J.L. Steinberg D. Quehenberger O. Scavenger receptor class B type I as a receptor for oxidized low density lipoprotein.J. Lipid Res. 2001; 42: 1474-1482Abstract Full Text Full Text PDF PubMed Google Scholar). Indeed, we demonstrated that both the lipid moiety of OxLDL, as well as the solubilized apoB of OxLDL, could bind to CD36 and that E06 could inhibit the binding of both. Furthermore, we showed that POVPC linked to BSA via its sn2 side chain also blocked the binding of OxLDL. These data strongly supported the interpretation that the PC moiety of OxPC was a sufficient ligand to mediate binding to CD36. This was confirmed by demonstrating the specific binding of the labeled POVPC peptide to CD36-transfected COS-7 cells (22Boullier A. Friedman P. Harkewicz R. Hartvigsen K. Green S.R. Almazan F. Dennis E.A. Steinberg D. Witztum J.L. Quehenberger O. Phosphocholine as a pattern recognition ligand for CD36.J. Lipid Res. 2005; 46: 969-976Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). NAbs are an essential layer of innate immunity (23Hardy R.R. Wei C.J. Hayakawa K. Selection during development of VH11+ B cells: a model for natural autoantibody-producing CD5+ B cells.Immunol. Rev. 2004; 197: 60-74Crossref PubMed Scopus (57) Google Scholar, 24Yang Y. Tung J.W. Ghosn E.E.B. Herzenberg L.A. Herzenberg L.A. Division and differentiation of natural antibody-producing cells in mouse spleen.Proc. Natl. Acad. Sci. USA. 2007; 104: 4542-4546Crossref PubMed Scopus (139) Google Scholar). In mice, a special subset of B-cells termed B-1 cells, secrete NAbs, which are predominantly IgM and IgA. In contrast with B-2 cells of adaptive immunity, which are negatively selected in fetal life producing anergy, B-1 cells are positively selected; thus, NAbs are present at birth or shortly thereafter and can be found in gnotobiotic mice reared in the complete absence of external antigenic stimulation. In uninfected mice, most, if not all, IgM in plasma are of B-1 origin, which are predominantly secreted from the spleen even in the absence of antigen. However, established B-1 cell clones can be expanded later in life by antigen exposure leading to increased IgM levels in plasma. B-1 cells have restricted use of VH genes that are minimally edited; thus, the IgM they generate are reflective of germline usage, with minimal to no mutations (25Binder C.J. Chou M.Y. Fogelstrand L. Hartvigsen K. Shaw P.X. Boullier A. Witztum J.L. Natural antibodies in murine atherosclerosis.Curr. Drug Targets. 2008; 9: 190-195Crossref PubMed Scopus (34) Google Scholar). Because they are conserved by natural selection, the presumption is that, fundamentally, NAbs provide advantageous properties maintaining homeostasis, such as their crucial role in immediate host defenses against “pathogens” (26Baumgarth N. Tung J.W. Herzenberg L.A. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion.Springer Semin. Immunopathol. 2005; 26: 347-362Crossref PubMed Scopus (434) Google Scholar), which, as we show below, include endogenous pathogens bearing neo-self epitopes, such as oxidation-specific epitopes. We subsequently showed, by direct sequencing of the VH/VL chains and use of anti-idiotypic Abs, that all the hybridomas were 100% homologous to the classic germline-encoded NAb T15, secreted by a well-characterized B-1 cell clone described more than 30 years ago (18Shaw P.X. Horkko S. Chang M.K. Curtiss L.K. Palinski W. Silverman G.J. Witztum J.L. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity.J. Clin. Invest. 2000; 105: 1731-1740Crossref PubMed Scopus (557) Google Scholar). The T15 clone, which was a spontaneous murine plasmacytoma that secreted an IgA with the T15 idiotype, is considered the classic germline NAb. It was intensively studied because it binds to PC (not as part of a PL) covalently linked to the cell wall polysaccharide of pathogens and confers optimal protection to mice from lethal infection with Streptococcus pneumonia (27Mi Q.S. Zhou L. Schulze D.H. Fischer R.T. Lustig A. Rezanka L.J. Donovan D.M. Longo D.L. Kenny J.J. Highly reduced protection against Streptococcus pneumoniae after deletion of a single heavy chain gene in mouse.Proc. Natl. Acad. Sci. USA. 2000; 97: 6031-6036Crossref PubMed Scopus (49) Google Scholar). In further studies cited below, we went on to show that such OxPL were greatly increased in apoptotic cells as well (28Chang M.K. Binder C.J. Miller Y.I. Subbanagounder G. Silverman G.J. Berliner J.A. Witztum J.L. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.J. Exp. Med. 2004; 200: 1359-1370Crossref PubMed Scopus (282) Google Scholar). Thus, these studies demonstrated molecular (and immunological) mimicry between the PC of OxPL present on OxLDL and apoptotic cells on one hand and the PC moiety present on pneumococcus and many other infections pathogens on the other hand. This dual specificity for an endogenous self- or neo-self-antigen and an exogenous pathogen has been described as a characteristic of NAbs (26Baumgarth N. Tung J.W. Herzenberg L.A. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion.Springer Semin. Immunopathol. 2005; 26: 347-362Crossref PubMed Scopus (434) Google Scholar). Because immunization of mice with heat-inactivated PC-containing pneumococci was known to robustly expand T15 B-1 cell clones, and because such IgM blocked the uptake of OxLDL by macrophages, we immunized cholesterol-fed LDLR−/− mice with heat killed pneumococci to see if this would reduce atherosclerosis. Indeed, immunization induced high titers of E06/T15 IgM and significantly reduced atherosclerosis (29Binder C.J. Dewan S.Ho¨rkko¨, A. Chang M.K. Kieu E.P. Goodyear C.S. Shaw P.X. Palinski W. Witztum J.L. Silverman G.J. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.Nat. Med. 2003; 9: 736-743Crossref PubMed Scopus (603) Google Scholar). The atheroprotective property of anti-PC IgM was corroborated in a vein graft atherosclerosis model by Faria-Neto et al., in which they infused T15 IgM intravenously (30Faria-Neto J.R. Chyu K.Y. Li X. Dimayuga P.C. Ferreira C. Yano J. Cercek B. Shah P.K. Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice.Atherosclerosis. 2005; 189: 83-90Abstract Full Text Full Text PDF Scopus (146) Google Scholar), and by Caligiuri et al, who demonstrated that immunizing apoE−/− mice with PC-KLH was atheroprotective (16Caligiuri G. Vandaele J.Khallou-Laschet, M. Gaston A.T. Delignat S. Mandet C. Kohler H.V. Kaveri S.V. Nicoletti A. Phosphorylcholine-targeting immunization reduces atherosclerosis.J. Am. Coll. Cardiol. 2007; 50: 540-546Crossref PubMed Scopus (143) Google Scholar). Furthermore, we (28Chang M.K. Binder C.J. Miller Y.I. Subbanagounder G. Silverman G.J. Berliner J.A. Witztum J.L. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.J. Exp. Med. 2004; 200: 1359-1370Crossref PubMed Scopus (282) Google Scholar, 31Huber J. Vales A. Mitulovic G. Blumer M. Schmid R. Witztum J.L. Binder B.R. Leitinger N. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 101-107Crossref PubMed Scopus (247) Google Scholar) and others (32Imai Y. Kuba K. Neely G.G. Perkmann R.Yaghubian-Malhami, T. Loo G.van Ermolaeva M. Veldhuizen R. Leung Y.H.C. Wang H. al et Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury.Cell. 2008; 133: 235-249Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar) have shown that E06 can bind to and block pro-inflammatory effects of PC containing OxPL, and this property undoubtedly also contributes importantly to the anti-inflammatory and anti-atherogenic properties of these oxidation-specific IgM. However, the PC of OxPL is only one example of what are likely to be a wide variety of such oxidation-specific epitopes to which NAbs bind. For example, we cloned a NAb from LDLR−/− mice, termed LRO1, which bound to oxidized cardiolipin but not native cardiolipin (33Tuominen A. Miller Y.I. Hansen L.F. Kesaniemi Y.A. Witztum J.L. Ho¨rkko¨ S. A natural antibody to oxidized cardiolipin binds to oxidized low-density lipoprotein, apoptotic cells, and atherosclerotic lesions.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2096-2102Crossref PubMed Scopus (63) Google Scholar). LDL contains cardiolipin, and LRO1 also bound to OxLDL, but not native LDL, as well as to atherosclerotic lesions. LRO1 also bound to apoptotic cells but not viable cells. Cardiolipin is a major phospholipid of the inner leaflet of mitochondria, which is oxidized when cells undergo mitochondrial disruption that occurs during apoptosis (34Kagan V.E. Borisenko G.G. Tyurina Y.Y. Tyurin V.A. Jiang J. Potapovich A.I. Kini V. Amoscato A.A. Fujii Y. Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine.Free Radic. Biol. Med. 2004; 37: 1963-1985Crossref PubMed Scopus (296) Google Scholar). There are many oxidation-specific epitopes. Data developing in our laboratory suggest that in normal mice, 20% to 30% of all IgM derived from B-1 cell clones bind to such oxidation-specific epitopes (unpublished observations). Among these, we found a high prevalence of IgM to MDA and the complex structural adducts that occur when MDA is added to proteins. Remarkably, we previously documented a high titer of IgM to MDA-LDL even in wild-type C57BL/6 mice as well as in healthy adult humans (1Binder C.J. Chang M.K. Shaw P.X. Miller Y.I. Hartvigsen K. Dewan A. Witztum J.L. Innate and acquired immunity in atherogenesis.Nat. Med. 2002; 8: 1218-1226Crossref PubMed Scopus (588) Google Scholar, 13Tsimikas S. Brilakis E.S. Lennon R.J. Miller E.R. Witztum J.L. McConnell J.P. Kornman K.S. Berger P.B. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events.J. Lipid Res. 2007; 48: 425-433Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). Furthermore, in studies of newborn human umbilical cord blood, we found a high titer of IgM to MDA epitopes, and similar to such NAbs in mice, they bind apoptotic cells and atherosclerotic tissues. The role of NAbs in humans is not well defined, but since IgM do not cross the placenta, it is generally considered that such IgM represent the human equivalent of innate NAbs. These data suggest that oxidation-specific epitopes are an important target of innate NAbs in mice and humans. “Scavenger receptors” of macrophages were so named because they bound and internalized OxLDL, but not native LDL (35Goldstein J.L. Ho Y.K. Basu S.K. Brown M.S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition.Proc. Natl. Acad. Sci. USA. 1979; 76: 333-337Crossref PubMed Scopus (1948) Google Scholar), and to date, eight different classes of such receptors have been identified (36Pluddemann A. Neyen C. Gordon S. Macrophage scavenger receptors and host-derived ligands.Methods. 2007; 43: 207-217Crossref PubMed Scopus (239) Google Scholar). They are now recognized to be multifunctional receptors that bind and internalize ligands, which include polyanionic ligands and apoptotic cells, as well as mediate adhesion and present antigens. Via their ability
Referência(s)