Low Levels of Apolipoprotein B-100 Autoantibodies Are Associated with Increased Risk of Coronary Events

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 36, Issue 4, 2016, Pages 765-771

  Björkbacka, Harry ^a   Alm, Ragnar ^a   Persson, Margaretha ^a   Hedblad, Bo ^a   Nilsson, Jan ^a   Fredrikson, Gunilla Nordin ^a  

^a LUND UNIVERSITY HOSPITAL   (Sweden)

Author keywords

apolipoproteins; autoantibodies; cardiovascular disease; immune responses; peptides

Indexed keywords

APOLIPOPROTEIN B100; APOLIPOPROTEIN B100 P210; APOLIPOPROTEIN B100 P45; IMMUNOGLOBULIN G ANTIBODY; IMMUNOGLOBULIN M ANTIBODY; UNCLASSIFIED DRUG; APOB PROTEIN, HUMAN; AUTOANTIBODY; BIOLOGICAL MARKER; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M;

ADULT; AGED; ARTICLE; BRAIN HEMORRHAGE; BRAIN ISCHEMIA; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CONTROLLED STUDY; ECHOGRAPHY; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; FOLLOW UP; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; MAJOR CLINICAL STUDY; MALE; PRIORITY JOURNAL; PROSPECTIVE STUDY; BLOOD; CHI SQUARE DISTRIBUTION; CORONARY ARTERY DISEASE; DISEASE FREE SURVIVAL; EPIDEMIOLOGY; IMMUNOLOGY; INCIDENCE; KAPLAN MEIER METHOD; MIDDLE AGED; MORTALITY; ODDS RATIO; PROPORTIONAL HAZARDS MODEL; PROTECTION; RISK ASSESSMENT; RISK FACTOR; STATISTICAL MODEL; SWEDEN; TIME FACTOR;

AGED; APOLIPOPROTEIN B-100; AUTOANTIBODIES; BIOMARKERS; CHI-SQUARE DISTRIBUTION; CORONARY ARTERY DISEASE; DISEASE-FREE SURVIVAL; FEMALE; HUMANS; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M; INCIDENCE; KAPLAN-MEIER ESTIMATE; LINEAR MODELS; LOGISTIC MODELS; MALE; MIDDLE AGED; ODDS RATIO; PROPORTIONAL HAZARDS MODELS; PROSPECTIVE STUDIES; PROTECTIVE FACTORS; RISK ASSESSMENT; RISK FACTORS; SWEDEN; TIME FACTORS;

EID: 84959233918     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.115.306938     Document Type: Article

References (41)

1. Nilsson J, Hansson GK. Autoimmunity in atherosclerosis: a protective response losing control? J Intern Med. 2008;263:464-478. doi: 10.1111/j.1365-2796.2008.01945.x.
2. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204-212. doi: 10.1038/ni.2001.
3. Palinski W, Witztum JL. Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis. J Intern Med. 2000;247:371-380.
4. Frostegård J, Wu R, Giscombe R, Holm G, Lefvert AK, Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein. Arterioscler Thromb. 1992;12:461-467.
5. Ylä-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994;14:32-40.
6. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995;92:3893-3897.
7. Gonçalves I, Nitulescu M, Ares MP, Fredrikson GN, Jansson B, Li ZC, Nilsson J. Identification of the target for therapeutic recombinant anti-apoB-100 peptide antibodies in human atherosclerotic lesions. Atherosclerosis. 2009;205:96-100. doi: 10.1016/j. atherosclerosis.2008.11.020.
8. Fredrikson GN, Hedblad B, Berglund G, Alm R, Ares M, Cercek B, Chyu KY, Shah PK, Nilsson J. Identification of immune responses against aldehyde-modified peptide sequences in apoB associated with cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003;23:872-878. doi: 10.1161/01.ATV.0000067935.02679.B0.
9. Hansson GK, Libby P. The immune response in atherosclerosis: a doubleedged sword. Nat Rev Immunol. 2006;6:508-519. doi: 10.1038/nri1882.
10. Nilsson J, Björkbacka H, Fredrikson GN. Apolipoprotein B100 autoimmunity and atherosclerosis - disease mechanisms and therapeutic potential. Curr Opin Lipidol. 2012;23:422-428. doi: 10.1097/ MOL.0b013e328356ec7c.
11. Ameli S, Hultgårdh-Nilsson A, Regnström J, Calara F, Yano J, Cercek B, Shah PK, Nilsson J. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol. 1996;16:1074-1079.
12. Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde- modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995;92:821-825.
13. Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med. 2003;9:736-743. doi: 10.1038/nm876.
14. Fredrikson GN, Söderberg I, Lindholm M, Dimayuga P, Chyu KY, Shah PK, Nilsson J. Inhibition of atherosclerosis in apoE-null mice by immunization with apoB-100 peptide sequences. Arterioscler Thromb Vasc Biol. 2003;23:879-884. doi: 10.1161/01.ATV.0000067937.93716.DB.
15. Schiopu A, Bengtsson J, Söderberg I, Janciauskiene S, Lindgren S, Ares MP, Shah PK, Carlsson R, Nilsson J, Fredrikson GN. Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis. Circulation. 2004;110:2047-2052. doi: 10.1161/01.CIR.0000143162.56057.B5.
16. Schiopu A, Frendéus B, Jansson B, Söderberg I, Ljungcrantz I, Araya Z, Shah PK, Carlsson R, Nilsson J, Fredrikson GN. Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice. J Am Coll Cardiol. 2007;50:2313-2318. doi: 10.1016/j.jacc.2007.07.081.
17. Gonçalves I, Gronholdt ML, Söderberg I, Ares MP, Nordestgaard BG, Bentzon JF, Fredrikson GN, Nilsson J. Humoral immune response against defined oxidized low-density lipoprotein antigens reflects structure and disease activity of carotid plaques. Arterioscler Thromb Vasc Biol. 2005;25:1250-1255. doi: 10.1161/01.ATV.0000166518.96137.38.
18. Fredrikson GN, Anand DV, Hopkins D, Corder R, Alm R, Bengtsson E, Shah PK, Lahiri A, Nilsson J. Associations between autoantibodies against apolipoprotein B-100 peptides and vascular complications in patients with type 2 diabetes. Diabetologia. 2009;52:1426-1433. doi: 10.1007/ s00125-009-1377-9.
19. Fredrikson GN, Schiopu A, Berglund G, Alm R, Shah PK, Nilsson J. Autoantibody against the amino acid sequence 661-680 in apo B-100 is associated with decreased carotid stenosis and cardiovascular events. Atherosclerosis. 2007;194:e188-e192. doi: 10.1016/j. atherosclerosis.2006.12.014.
20. Sjögren P, Fredrikson GN, Samnegard A, Ericsson CG, Ohrvik J, Fisher RM, Nilsson J, Hamsten A. High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction. Eur Heart J. 2008;29:2218-2226. doi: 10.1093/eurheartj/ehn336.
21. McLeod O, Silveira A, Fredrikson GN, et al. Plasma autoantibodies against apolipoprotein B-100 peptide 210 in subclinical atherosclerosis. Atherosclerosis. 2014;232:242-248. doi: 10.1016/j. atherosclerosis.2013.11.041.
22. Fagerberg B, Prahl Gullberg U, Alm R, Nilsson J, Fredrikson GN. Circulating autoantibodies against the apolipoprotein B-100 peptides p45 and p210 in relation to the occurrence of carotid plaques in 64-yearold women. PLoS One. 2015;10:e0120744. doi: 10.1371/journal. pone.0120744.
23. Asciutto G, Dias NV, Edsfeldt A, Alm R, Fredrikson GN, Gonçalves I, Nilsson J. Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy. Atherosclerosis. 2015;239:289-294. doi: 10.1016/j. atherosclerosis.2015.01.023.
24. Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmö, Sweden. Diabet Med. 2000;17:299-307.
25. Nilsson J, Kovanen PT. Will autoantibodies help to determine severity and progression of atherosclerosis? Curr Opin Lipidol. 2004;15:499-503.
26. Svenungsson E, Engelbertsen D, Wigren M, Gustafsson JT, Gunnarsson I, Elvin K, Jensen-Urstad K, Fredrikson GN, Nilsson J. Decreased levels of autoantibodies against apolipoprotein B-100 antigens are associated with cardiovascular disease in systemic lupus erythematosus. Clin Exp Immunol. 2015;181:417-426. doi: 10.1111/cei.12651.
27. Kyaw T, Tay C, Hosseini H, Kanellakis P, Gadowski T, MacKay F, Tipping P, Bobik A, Toh BH. Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PLoS One. 2012;7:e29371. doi: 10.1371/ journal.pone.0029371.
28. Kyaw T, Tay C, Krishnamurthi S, Kanellakis P, Agrotis A, Tipping P, Bobik A, Toh BH. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res. 2011;109:830-840. doi: 10.1161/ CIRCRESAHA.111.248542.
29. Sage AP, Tsiantoulas D, Baker L, Harrison J, Masters L, Murphy D, Loinard C, Binder CJ, Mallat Z. BAFF receptor deficiency reduces the development of atherosclerosis in mice-brief report. Arterioscler Thromb Vasc Biol. 2012;32:1573-1576. doi: 10.1161/ATVBAHA.111.244731.
30. Engelbertsen D, Vallejo J, Quách TD, Fredrikson GN, Alm R, Hedblad B, Björkbacka H, Rothstein TL, Nilsson J, Bengtsson E. Low Levels of IgM Antibodies against an Advanced Glycation Endproduct-Modified Apolipoprotein B100 Peptide Predict Cardiovascular Events in Nondiabetic Subjects. J Immunol. 2015;195:3020-3025. doi: 10.4049/ jimmunol.1402869.
31. Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ. B cells and humoral immunity in atherosclerosis. Circ Res. 2014;114:1743-1756. doi: 10.1161/CIRCRESAHA.113.301145.
32. Kyaw T, Tipping P, Bobik A, Toh BH. Protective role of natural IgMproducing B1a cells in atherosclerosis. Trends Cardiovasc Med. 2012;22:48-53. doi: 10.1016/j.tcm.2012.06.011.
33. Caligiuri G, Khallou-Laschet J, Vandaele M, Gaston AT, Delignat S, Mandet C, Kohler HV, Kaveri SV, Nicoletti A. Phosphorylcholinetargeting immunization reduces atherosclerosis. J Am Coll Cardiol. 2007;50:540-546. doi: 10.1016/j.jacc.2006.11.054.
34. Faria-Neto JR, Chyu KY, Li X, Dimayuga PC, Ferreira C, Yano J, Cercek B, Shah PK. Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice. Atherosclerosis. 2006;189:83-90. doi: 10.1016/j.atherosclerosis.2005.11.033.
35. Binder CJ, Hartvigsen K, Chang MK, Miller M, Broide D, Palinski W, Curtiss LK, Corr M, Witztum JL. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest. 2004;114:427-437. doi: 10.1172/JCI20479.
36. Grönlund H, Hallmans G, Jansson JH, Boman K, Wikström M, de Faire U, Frostegård J. Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a populationbased cohort from northern Sweden. Eur J Cardiovasc Prev Rehabil. 2009;16:382-386. doi: 10.1097/HJR.0b013e32832a05df.
37. Fiskesund R, Stegmayr B, Hallmans G, Vikström M, Weinehall L, de Faire U, Frostegård J. Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden. Stroke. 2010;41:607-612. doi: 10.1161/STROKEAHA.109.558742.
38. Engelbertsen D, Anand DV, Fredrikson GN, Hopkins D, Corder R, Shah PK, Lahiri A, Nilsson J, Bengtsson E. High levels of IgM against methylglyoxal- modified apolipoprotein B100 are associated with less coronary artery calcification in patients with type 2 diabetes. J Intern Med. 2012;271:82-89. doi: 10.1111/j.1365-2796.2011.02411.x.
39. Smith CJ, Lawrence CB, Rodriguez-Grande B, Kovacs KJ, Pradillo JM, Denes A. The immune system in stroke: clinical challenges and their translation to experimental research. J Neuroimmune Pharmacol. 2013;8:867-887. doi: 10.1007/s11481-013-9469-1.
40. Matusik P, Guzik B, Weber C, Guzik TJ. Do we know enough about the immune pathogenesis of acute coronary syndromes to improve clinical practice? Thromb Haemost. 2012;108:443-456. doi: 10.1160/ TH12-05-0341.
41. Fredrikson GN, Hedblad B, Berglund G, Alm R, Nilsson JA, Schiopu A, Shah PK, Nilsson J. Association between IgM against an aldehyde-modified peptide in apolipoprotein B-100 and progression of carotid disease. Stroke. 2007;38:1495-1500. doi: 10.1161/STROKEAHA.106.474577.