Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies

Abstract

Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA+ MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE+ MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD. Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA+ MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE+ MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD. Inflammation and immunity are recognized as important modulators of CVDs. A large body of evidence supports a role for oxidized LDL (OxLDL) as mediator of the inflammatory responses that propagates atherosclerotic lesion formation (1Libby P. Lichtman A.H. Hansson G.K. Immune effector mechanisms implicated in atherosclerosis: from mice to humans.Immunity. 2013; 38: 1092-1104Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar). IgGs to OxLDL are present in lesions, and their titers in plasma have been found to be positively (though inconsistently) associated with CVD risk (2Tsiantoulas D. Diehl C.J. Witztum J.L. Binder C.J. B cells and humoral immunity in atherosclerosis.Circ. Res. 2014; 114: 1743-1756Crossref PubMed Scopus (198) Google Scholar). On the other hand, increasing epidemiological evidence demonstrates that high levels of IgM antibodies to OxLDL are inversely associated with CVD, suggesting a protective role for these antibodies (3Karvonen J. Paivansalo M. Kesaniemi Y.A. Horkko S. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis.Circulation. 2003; 108: 2107-2112Crossref PubMed Scopus (229) Google Scholar, 4Tsimikas 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, 5Fiskesund R. Stegmayr B. Hallmans G. Vikstrom M. Weinehall L. de Faire U. Frostegard J. Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden.Stroke. 2010; 41: 607-612Crossref PubMed Scopus (55) Google Scholar, 6Grönlund H. Hallmans G. Jansson J.H. Boman K. Wikstrom M. de Faire U. Frostegard J. Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden.Eur. J. Cardiovasc. Prev. Rehabil. 2009; 16: 382-386Crossref PubMed Scopus (55) Google Scholar, 7Tsimikas S. Willeit P. Willeit J. Santer P. Mayr M. Xu Q. Mayr A. Witztum J.L. Kiechl S. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.J. Am. Coll. Cardiol. 2012; 60: 2218-2229Crossref PubMed Scopus (164) Google Scholar). Moreover, a number of experimental studies in mouse models of atherosclerosis support a protective role for IgM (8Binder C.J. Horkko S. Dewan 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, 9Kyaw T. Tay C. Krishnamurthi S. Kanellakis P. Agrotis A. Tipping P. Bobik A. Toh B.H. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions.Circ. Res. 2011; 109: 830-840Crossref PubMed Scopus (230) Google Scholar, 10Lewis M.J. Malik T.H. Ehrenstein M.R. Boyle J.J. Botto M. Haskard D.O. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice.Circulation. 2009; 120: 417-426Crossref PubMed Scopus (188) Google Scholar). Most anti-OxLDL IgMs are believed to be so-called natural antibodies (NAbs), which are preexisting antibodies with germ-line or near germ-line encoded variable regions (2Tsiantoulas D. Diehl C.J. Witztum J.L. Binder C.J. B cells and humoral immunity in atherosclerosis.Circ. Res. 2014; 114: 1743-1756Crossref PubMed Scopus (198) Google Scholar). However, it is not known how anti-OxLDL IgM NAbs confer protection and if OxLDL itself represents the actual/only target antigen of such antibodies in vivo. Anti-OxLDL NAbs have specificity for various oxidation-specific epitopes (OSEs). OSEs are generated by the modification of proteins and lipids with reactive breakdown products resulting from lipid peroxidation. Prominent examples include oxidized glycerophospholipids (OxGPs) or malondialdehyde (MDA) and 4-hydroxynonenal. We have previously shown that up to 30% of IgM NAbs have specificity for OSEs (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar). the OSEs found on OxLDL have been shown to be present in various inflammatory (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, K. R. Perkmann T. G. M. R. H. of and as a of acute Full Text Full Text PDF PubMed Scopus Google Scholar, L. J. R. G. H. Binder C.J. Witztum J.L. H. in 2011; PubMed Scopus Google and on the surface of apoptotic cells (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, M.K. C. A. Horkko S. P. Witztum J.L. antibodies against oxidized low-density lipoprotein to apoptotic cells and their by evidence that oxidation-specific epitopes mediate PubMed Scopus Google Scholar, M.K. Binder C.J. Miller Y.I. G. Silverman G.J. Witztum J.L. cells with oxidation-specific epitopes are and Med. PubMed Scopus Google Scholar). it for by the OSEs have been shown to inflammatory responses in and cells the of interleukin M.K. Binder C.J. Miller Y.I. G. Silverman G.J. Witztum J.L. cells with oxidation-specific epitopes are and Med. PubMed Scopus Google Scholar, D. Hartvigsen K. P. M. H. S. C. malondialdehyde epitopes and from 2011; PubMed Scopus Google Scholar, Y.I. Choi P. L. R. Hartvigsen K. A. A. Diehl C.J. epitopes are danger-associated molecular patterns recognized by of innate Res. 2011; 108: PubMed Scopus Google Scholar). are as small vesicles that are released from activated or cells including cells and monocytes and are present in the G. A. A. and Res. 2011; 109: PubMed Scopus Google Scholar). MPs are membrane is resulting in in and Res. 2011; 108: PubMed Scopus Google Scholar). levels of circulating MPs have been shown to be associated with CVD G. A. A. and Res. 2011; 109: PubMed Scopus Google Scholar, in and Res. 2011; 108: PubMed Scopus Google Scholar, L. F. a in the between immunity, and 2011; PubMed Scopus Google Scholar). plasma MPs are in patients with acute coronary H. B. J. A. levels of membrane microparticles with in the circulating of patients with acute coronary PubMed Scopus Google and with high as as in patients with L. F. a in the between immunity, and 2011; PubMed Scopus Google Scholar). studies found as as for on MPs by of in and Res. 2011; 108: PubMed Scopus Google Scholar). Moreover, MPs in can in and Res. 2011; 108: PubMed Scopus Google Scholar). MPs can cells cell surface the carry on their surface, or can and to cells, their C. of a novel for Res. 2010; PubMed Scopus Google Scholar). MPs isolated from human atherosclerotic were shown to mediate on by B. C. D. G. G. S. from human atherosclerotic and Res. 2011; 108: PubMed Scopus Google Scholar). MPs were found to and other of the to resulting in the of cell and K. J.P. microparticles cells in an 2011; PubMed Scopus Google Scholar). the of MPs are from lipid have been to be D. of and cells by lipids in PubMed Scopus Google Scholar). We have previously that apoptotic cells are bound by OSE-specific IgM which their in and their in (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, K. R. Perkmann T. G. M. R. H. of and as a of acute Full Text Full Text PDF PubMed Scopus Google Scholar). we investigated whether circulating MPs isolated from healthy and patients with acute myocardial infarction carry OSEs. We the of a novel subset of circulating MPs in healthy and patients that is characterized by the of MDA of these MPs carry OSE-specific suggesting a novel by which OSE-specific IgM from CVD. were from the of healthy of healthy with a of and and healthy and with and Moreover, were from a to as and from the coronary of patients primary for ST-segment elevation myocardial infarction as K. C. J. S. D. C. M. to the site of formation in acute myocardial 2009; PubMed Scopus Google Scholar). are shown in and were with to an activated A of with a or the at the site of to of a of the to were for were were at for at to plasma with of resulting plasma the cell of the plasma at and the to and at for at to plasma for at to and to the plasma and MPs were and with at for at Finally, MPs were in and at for studies were or healthy the of the of the of and in the of were if of the at the of coronary associated with ST-segment elevation in or flow in a culprit coronary artery and an of of the coronary of and with the of isolated MPs were with to in the of OSEs on their surface, isolated MPs were with of or of antibodies in of the IgM primary as for oxidized and and which are against including (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, W. Horkko S. Miller Witztum J.L. of monoclonal autoantibodies to epitopes of oxidized from of epitopes of oxidized low density lipoprotein in human PubMed Scopus Google Scholar, S. Miller H. G. P. autoantibodies for oxidized or oxidized of oxidized low-density PubMed Scopus Google Scholar, S. Hartvigsen K. A. G. S. Witztum J.L. Binder C.J. of malondialdehyde epitopes for in cardiovascular Lipid Res. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). were with the antibodies for at MPs were at for were and to or IgM to at a of or and for in at identify MPs that carry MDA and MPs were with IgM at by and IgM human MPs were with an or with the and for in at identify the MPs were with to or from and for in at with MPs were at for and the were with for in at circulating MPs in the and coronary of plasma were with were on a for at low and were at MPs were as with using with a of as in to to were on a were with were by from the of of the of and with of in for at to the cells and were by at and for the and MPs were and with and at for at Finally, MPs were in and at for using the were with of or an for at in cells were at and with of for in at were and were on a and were using and circulating MPs were in and with a at the were to with an molecular of and against specificity of and is in the (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, W. Horkko S. Miller Witztum J.L. of monoclonal autoantibodies to epitopes of oxidized from of epitopes of oxidized low density lipoprotein in human PubMed Scopus Google Scholar, S. Miller H. G. P. autoantibodies for oxidized or oxidized of oxidized low-density PubMed Scopus Google Scholar, S. Hartvigsen K. A. G. S. Witztum J.L. Binder C.J. of malondialdehyde epitopes for in cardiovascular Lipid Res. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). these with the we studies to or different of MDA using as (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar). IgM and IgM antibodies to LDL and MDA-modified LDL were as previously (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar). of and in and were to and at were with for at with of plasma or in were and at were with and of the IgM antibodies with an IgM in an of at the were as by a with of a 30% in the were on a and as the of were with of the IgM and IgM in plasma or in were as of IgM IgM for the IgM antibodies against in the and coronary of the plasma in and to as were to in the and coronary the specificity of the an using or as were in and with of or and to as from the of healthy as monocytes were isolated using by using to the of the different by flow cytometry using were with a and were using the of found to be the of MPs in THP-1 or primary human monocytes for in were with of in generated MPs for at in MPs were with or of or the of the were by the cells in a at for levels were in the by using a were using for were using or or by were as the are as A of We and have previously shown that of and cells by various such as and results in the formation of OSEs on the surface of these cells (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, M.K. C. A. Horkko S. P. Witztum J.L. antibodies against oxidized low-density lipoprotein to apoptotic cells and their by evidence that oxidation-specific epitopes mediate PubMed Scopus Google Scholar, M.K. Binder C.J. Miller Y.I. G. Silverman G.J. Witztum J.L. cells with oxidation-specific epitopes are and Med. PubMed Scopus Google Scholar, S. Hartvigsen K. A. G. S. Witztum J.L. Binder C.J. of malondialdehyde epitopes for in cardiovascular Lipid Res. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Miller Y.I. Hansen L.F. Kesaniemi Y.A. Witztum J.L. Horkko S. A natural to oxidized to oxidized low-density apoptotic cells, and atherosclerotic PubMed Scopus Google Scholar). Moreover, in and of as as of THP-1 cells with have been found to carry OSEs J. A. G. M. R. Witztum J.L. Binder membrane vesicles and from apoptotic cells oxidized that PubMed Scopus Google Scholar, R. J.L. membrane as novel carriers of molecular mechanisms of and 2012; PubMed Scopus Google Scholar). whether OSEs are present on MPs in we isolated MPs from plasma of healthy by and the of OSEs on the surface of MPs by flow cytometry using previously characterized monoclonal anti-OxLDL IgM NAbs with specificity for and epitopes and (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, W. Horkko S. Miller Witztum J.L. of monoclonal autoantibodies to epitopes of oxidized from of epitopes of oxidized low density lipoprotein in human PubMed Scopus Google Scholar, S. Miller H. G. P. autoantibodies for oxidized or oxidized of oxidized low-density PubMed Scopus Google Scholar, S. Hartvigsen K. A. G. S. Witztum J.L. Binder C.J. of malondialdehyde epitopes for in cardiovascular Lipid Res. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). These NAbs OxLDL and a specificity for OSEs (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, W. Horkko S. Miller Witztum J.L. of monoclonal autoantibodies to epitopes of oxidized from of epitopes of oxidized low density lipoprotein in human PubMed Scopus Google Scholar, S. Miller H. G. P. autoantibodies for oxidized or oxidized of oxidized low-density PubMed Scopus Google Scholar, S. Hartvigsen K. A. G. S. Witztum J.L. Binder C.J. of malondialdehyde epitopes for in cardiovascular Lipid Res. 2012; Full Text Full Text PDF PubMed Scopus Google A subset of circulating MPs of were bound by OSE-specific an On of MPs were bound by the and of MPs with the antibodies and (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar, W. Horkko S. Miller Witztum J.L. of monoclonal autoantibodies to epitopes of oxidized from of epitopes of oxidized low density lipoprotein in human PubMed Scopus Google Scholar). the bound of suggesting specificity for a different type of MDA A of MPs found in the plasma of a cohort of healthy Moreover, of circulating MPs with and antibodies that epitopes are present on MPs that the of OSEs to to the in to as of to plasma has been shown to of LDL C.J. of on LDL A PubMed Scopus Google Scholar). of plasma with not the of OSEs circulating MPs from different cells, we investigated the of the which using antibodies for and Consistent with L. F. a in the between immunity, and 2011; PubMed Scopus Google a majority of MPs were of were and were from MPs were present of the of MPs results and to whether MDA epitopes can be in the of we generated MPs from by the not to the surface of a large of MPs generated from these cells OSEs are a target of IgM NAbs (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google we whether of the isolated MPs were bound by IgM. we found that of circulating MPs IgM bound on their surface we IgM from MPs and the to and for in to circulating IgM in plasma of the of IgM to IgM that IgM antibodies to of IgM in plasma IgM to of IgM findings are with that IgMs represent of IgM NAbs in mice (11Chou M.Y. Fogelstrand L. Hartvigsen K. Hansen L.F. Woelkers D. Shaw P.X. Choi J. Perkmann T. Backhed F. Miller Y.I. epitopes are of innate natural antibodies in mice and 2009; PubMed Scopus Google Scholar). specificity of the IgM for in in which LDL for the to inhibited the by IgMs are of IgM with specificity for These are with the of OSEs on a subset of circulating MPs and support the that MDA are We and have previously shown that responses in various cells, including by THP-1 cells D. Hartvigsen K. P. M. H. S. C. malondialdehyde epitopes and from 2011; PubMed Scopus Google Scholar, M.J. proteins and responses by PubMed Google Scholar). whether MPs MDA we by THP-1 cells or primary human monocytes that were with MPs in the of the IgM or an A subset of MPs were bound by not an of by THP-1 and primary human with the not an inhibited by and in THP-1 cells and primary found in primary monocytes be by previously between THP-1 cells and primary monocytes in their responses and that primary monocytes are to of THP-1 cells as a for the and of monocytes and in the 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). not the with the A not these demonstrate the of natural IgM antibodies to inflammatory of MPs and that the of MPs are to a by studies have that patients with have levels of circulating which could the inflammatory responses of we whether MPs isolated from the and coronary of patients with carry MDA epitopes. from the artery and from the site of of the coronary of the patients levels were in the coronary with the site of the the of isolated MPs from the and coronary the of MPs between the MPs were MPs in the coronary with the Moreover, the of MPs by of low and not different between the of MPs of were for not of MPs from not a of MPs in the coronary levels of IgM at Moreover, the of MPs found in MPs not MPs the number and of MPs are elevated in the coronary of we a subset of circulating MPs that carry OSEs and are at the site of coronary of patients with STE-MI. OSE+ MPs are recognized by OxLDL-specific IgM which have the to of is evidence from epidemiological and experimental studies that humoral immunity an important role in CVD (2Tsiantoulas D. Diehl C.J. Witztum J.L. Binder C.J. B cells and humoral immunity in atherosclerosis.Circ. Res. 2014; 114: 1743-1756Crossref PubMed Scopus (198) Google Scholar). IgM antibodies in atheroprotective as mice in IgM atherosclerosis M.J. Malik T.H. Ehrenstein M.R. Boyle J.J. Botto M. Haskard D.O. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice.Circulation. 2009; 120: 417-426Crossref PubMed Scopus (188) Google Scholar). with this, low plasma IgM antibodies to and are associated with carotid and an risk of a coronary in (3Karvonen J. Paivansalo M. Kesaniemi Y.A. Horkko S. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis.Circulation. 2003; 108: 2107-2112Crossref PubMed Scopus (229) Google Scholar, 4Tsimikas 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). Moreover, high levels of OSE-specific IgM antibodies have been shown to predict a risk of cardiovascular R. Stegmayr B. Hallmans G. Vikstrom M. Weinehall L. de Faire U. Frostegard J. Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden.Stroke. 2010; 41: 607-612Crossref PubMed Scopus (55) Google Scholar, 6Grönlund H. Hallmans G. Jansson J.H. Boman K. Wikstrom M. de Faire U. Frostegard J. Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden.Eur. J. Cardiovasc. Prev. Rehabil. 2009; 16: 382-386Crossref PubMed Scopus (55) Google Scholar). a of the which for that high IgM titers to and were associated with a risk of cardiovascular S. Willeit P. Willeit J. Santer P. Mayr M. Xu Q. Mayr A. Witztum J.L. Kiechl S. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.J. Am. Coll. Cardiol. 2012; 60: 2218-2229Crossref PubMed Scopus (164) Google Scholar). Our findings that MPs carry OSEs and are recognized by the antibodies that and a novel atheroprotective mechanism for OxLDL-specific IgM. with were found to have circulating MPs of H. B. J. A. levels of membrane microparticles with in the circulating of patients with acute coronary PubMed Scopus Google Scholar). Moreover, in a study of the number of MPs in the to the coronary with an of the culprit coronary artery found to be with MPs in the from the artery M. Choi in microparticles from the of culprit coronary in patients with ST-segment elevation myocardial 2013; Full Text Full Text PDF PubMed Scopus (55) Google Scholar). We that patients have of MPs at the coronary suggesting that MPs are generated from and cells at these MPs to and responses We have by and the of including a of as as on from on protection A. G. M.Y. M. A. Miller Y.I. and of oxidized and oxidized coronary and in Am. Coll. Cardiol. 2014; PubMed Scopus Google Scholar). MDA-modified proteins the of such as in monocytes and D. Hartvigsen K. P. M. H. S. C. malondialdehyde epitopes and from 2011; PubMed Scopus Google Scholar, J.L. S. R. of products in PubMed Scopus Google Scholar). MPs carry MDA by inflammatory responses the these can be inhibited by IgM antibodies. be by other OSEs present on including of which we found to be present on epitopes have been found to mediate present on apoptotic cells or M.K. Binder C.J. Miller Y.I. G. Silverman G.J. Witztum J.L. cells with oxidation-specific epitopes are and Med. PubMed Scopus Google Scholar, J. A. G. M. R. Witztum J.L. Binder membrane vesicles and from apoptotic cells oxidized that PubMed Scopus Google Scholar). has been previously shown that MPs can and D. of and cells by lipids in PubMed Scopus Google Scholar). that MDA-modified lipids or proteins on the surface of MPs to these of has been shown to MDA and in LDL S. P. of and of human PubMed Scopus Google Scholar, J. M. of low density to in human PubMed Scopus Google Scholar). OSE-specific IgM could with the of MPs and formation to be a subset of circulating MPs carry OSEs that are recognized by IgM which in their and their the of the between MPs and IgM antibodies to identify novel and for CVD. M. and for and and patients for their monoclonal antibodies and have been generated at J. L. and a can be to with acute coronary acute myocardial infarction low density lipoprotein cell interleukin malondialdehyde MDA-modified LDL natural oxidation-specific oxidized low density lipoprotein oxidized primary cell ST-segment elevation myocardial infarction