Naturally Occurring IgM Antibodies to Oxidation-Specific Epitopes

  • Christoph J. Binder
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 750)

Abstract

Naturally occurring antibodies (NAbs) have specificity for both microbial and self antigens, which allows them to act in the first line defense against invading pathogens, as well as in tissue homeostasis by mediating the clearance of cellular debris. This latter recognition of self by NAbs was often thought to reflect the polyreactivity of low affinity antibodies. The finding that oxidation-specific epitopes are dominant targets of naturally occurring IgM antibodies shed light on this and provided novel insights into the understanding of the house keeping functions of NAbs. Oxidation-specific epitopes represent stress-induced or altered self structures that are generated as a consequence of lipidperoxidation during many physiological and pathological situations. Importantly, the same structures have been found in the membranes of dying cells. Only oxidized lipids and dying cells—but not native membrane lipids or viable cells—are recognized by this set of NAbs. Thus, oxidation-specific epitopes represent ideal marks that identify biological waste for its clearance and the neutralization of its pro-inflammatory properties. Furthermore, this binding property of NAbs has also important implications for various chronic inflammatory diseases, including atherosclerosis.

Keywords

Arthritis Foam Pneumonia Aldehyde Polysaccharide 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 2005; 26:347–62. PMID: 15633017 doi:10.1007/s00281-004-0182-2PubMedCrossRefGoogle Scholar
  2. 2.
    Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 2011; 11:34–46. PMID:21151033 doi:10.1038/nri2901PubMedCrossRefGoogle Scholar
  3. 3.
    Boes M. Role of natural and immune IgM antibodies in immune responses. Mol Immunol 2000; 37:1141–9. PMID:11451419 doi:10.1016/S0161-5890(01)00025-6PubMedCrossRefGoogle Scholar
  4. 4.
    Bendelac A, Bonneville M, Kearney JF. Autoreactivity by design: innate B and T lymphocytes. Nat Rev Immunol 2001; 1:177–86. PMID:11905826 doi:10.1038/35105052PubMedCrossRefGoogle Scholar
  5. 5.
    Lutz HU, Binder CJ, Kaveri S. Naturally occurring auto-antibodies in homeostasis and disease. Trends Immunol 2009; 30:43–51. PMID:19058756 doi:10.1016/j.it.2008.10.002PubMedCrossRefGoogle Scholar
  6. 6.
    Boes M, Schmidt T, Linkemann K et al. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci USA 2000; 97:1184–9. PMID:10655505 doi:10.1073/pnas.97.3.1184PubMedCrossRefGoogle Scholar
  7. 7.
    Chen GY, Nunez G. Sterile inflammation: sensing andreactingto damage. Nat Rev Immunol 2010; 10:826–37. PMID:21088683 doi:10.1038/nri2873PubMedCrossRefGoogle Scholar
  8. 8.
    Miller YI, Choi SH, Wiesner P et al. Oxidation-specific epitopes are danger-associated molecular patterns recognizedbypattern recognition receptors of innate immunity. CircRes 2011; 108:235–48. PMID:21252151 doi:10.1161/CIRCRESAHA.1 10.223875Google Scholar
  9. 9.
    Chou MY, Hartvigsen K, Hansen LF et al. Oxidation-specific epitopes are important targets of innate immunity. J Intern Med 2008; 263:479–88. PMID:18410591 doi:10.1111/j.1365-2796.2008.01968.xPubMedCrossRefGoogle Scholar
  10. 10.
    Chang MK, Bergmark C, Laurila A et al. Monoclonal antibodies against oxidized low-density lipoproteinbind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci USA 1999; 96:6353–8. PMID: 10339591 doi: 10.1073/pnas.96.11.6353PubMedCrossRefGoogle Scholar
  11. 11.
    Chang MK, Binder CJ, Miller YI et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. JExp Med 2004; 200:1359–70. PMID:15583011 doi:10.1084/jem.20031763CrossRefGoogle Scholar
  12. 12.
    Binder CJ. Natural IgM antibodies against oxidation-specific epitopes. J Clin Immunol 2010; 30(Suppl 1):S56–60. PMID:20387104 doi:10.1007/s10875-010-9396-3PubMedCrossRefGoogle Scholar
  13. 13.
    Witztum JL, Steinbrecher UP, Kesaniemi YA et al. Autoantibodies to glucosylated proteins in the plasma of patients with diabetes mellitus. Proc Natl Acad Sci USA 1984; 81:3204–8. PMID:6587346 doi:10.1073/pnas.81.10.3204PubMedCrossRefGoogle Scholar
  14. 14.
    Steinbrecher UP, Fisher M, Witztum JL et al. Immunogenicity of homologous low density lipoprotein after methylation, ethylation, acetylation, or carbamylation: generation of antibodies specific for derivatized lysine. J Lipid Res 1984; 25:1109–16. PMID:6439810PubMedGoogle Scholar
  15. 15.
    Palinski W, Rosenfeld ME, Yla-Herttuala S et al. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci USA 1989; 86:1372–6. PMID:2465552 doi:10.1073/pnas.86.4.1372PubMedCrossRefGoogle Scholar
  16. 16.
    Palinski W, Yla-Herttuala S, Rosenfeld ME et al. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis 1990; 10:325–35. PMID: 1693068PubMedCrossRefGoogle Scholar
  17. 17.
    Hörkko S, Binder CJ, Shaw PX et al. Immunological responses to oxidized LDL. Free Radic Biol Med 2000; 28:1771–9. PMID:10946219 doi:10.1016/S0891-5849(00)00333-6PubMedCrossRefGoogle Scholar
  18. 18.
    Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30:2311–6. PMID:21084697 doi:10.1161/ATVBAHA.108.179697PubMedCrossRefGoogle Scholar
  19. 19.
    Bochkov VN, Oskolkova OV, Birukov KG et al. Generation and biological activities ofoxidizedphospholipids. Antioxid Redox Signal 2010; 12:1009–59. PMID: 19686040 doi: 10.1089/ars.2009.2597PubMedCrossRefGoogle Scholar
  20. 20.
    Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 1991; 11:81–128. PMID:1937131 doi:10.1016/0891-584 9(91)90192-6PubMedCrossRefGoogle Scholar
  21. 21.
    Palinski W, Ord VA, Plump AS et al. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysinein serum. Arterioscler Thromb 1994; 14:605–16. PMID:7511933 doi:10.1161/01. ATV. 14.4.605PubMedCrossRefGoogle Scholar
  22. 22.
    Palinski W, Tangirala RK, Miller E et al. Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15:1569–76. PMID:7583529 doi:10.1161/01.ATV.15.10.1569PubMedCrossRefGoogle Scholar
  23. 23.
    Chou MY, Fogelstrand L, Hartvigsen K et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest 2009; 119:1335–49. PMID:19363291 doi:10.1172/JCI36800PubMedCrossRefGoogle Scholar
  24. 24.
    Palinski W, Horkko S, Miller E et al. 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; 98:800–14. PMID:8698873 doi:10.1172/JCI118853PubMedCrossRefGoogle Scholar
  25. 25.
    Hörkko S, Bird DA, Miller E et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. JClin Invest 1999; 103:117–28. PMID:9884341 doi:10.1172/JCI4533CrossRefGoogle Scholar
  26. 26.
    Shaw PX, Horkko S, Chang MK et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 2000; 105:1731–40. PMID:10862788 doi:10.1172/JCI8472PubMedCrossRefGoogle Scholar
  27. 27.
    Claflin JL, Cubberley M. Clonal nature of the immune response to phosphocholine. VII. Evidence throughout inbred mice for molecular similarities among antibodies bearing the T15 idiotype. J Immunol 1980; 125:551–8. PMID:7391569PubMedGoogle Scholar
  28. 28.
    Briles DE, Forman C, Hudak S et al. Anti-phosphorylcholine antibodies of the T15 idiotype are optimally protective against Streptococcus pneumoniae. JExpMed 1982; 156:1177–85. PMID:7153709 doi:10.1084/jem. 156.4.1177CrossRefGoogle Scholar
  29. 29.
    Binder CJ, Shaw PX, Chang MK et al. The role of natural antibodies in atherogenesis. J Lipid Res 2005; 46:1353–63. PMID:15897601 doi:10.1194/jlr.R500005-JLR200PubMedCrossRefGoogle Scholar
  30. 30.
    Tuominen A, Miller YI, Hansen LF et al. A natural antibody to oxidized cardiolipin binds to oxidized low-density lipoprotein, apoptotic cells, and atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2006; 26:2096–102. PMID:16794225 doi:10.1161/01.ATV.0000233333.07991.4aPubMedCrossRefGoogle Scholar
  31. 31.
    Merbl Y, Zucker-Toledano M, Quintana FJ et al. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest 2007; 117:712–8. PMID: 17332892 doi:10.1172/JCI29943PubMedCrossRefGoogle Scholar
  32. 32.
    Notkins AL. Polyreactivity of antibody molecules. Trends Immunol 2004; 25:174–9. PMID: 15039043 doi:10.1016/j.it.2004.02.004PubMedCrossRefGoogle Scholar
  33. 33.
    Ogden CA, Kowalewski R, Peng Y et al. IgM is required for efficient complement mediated phagocytosis of apoptoticcellsinvivo. Autoimmunity 2005; 38:259–64. PMID:16206508 doi:10.1080/08916930500124452PubMedCrossRefGoogle Scholar
  34. 34.
    Chen Y, Park YB, Patel E et al. IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells. J Immunol 2009; 182:6031–43. PMID:19414754 doi: 10.4049/jimmunol.0804191PubMedCrossRefGoogle Scholar
  35. 35.
    Huber J, Vales A, Mitulovic G et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol 2002; 22:101–7. PMID:11788468 doi:10.1161/hq0102.101525PubMedCrossRefGoogle Scholar
  36. 36.
    Imai Y, Kuba K, Neely GG et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a keypathwayofacutelunginjury. Cell 2008; 133:235–49. PMID:18423196 doi:10.1016/j.cell.2008.02.043PubMedCrossRefGoogle Scholar
  37. 37.
    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685–95. PMID:15843671 doi:10.1056/NEJMra043430PubMedCrossRefGoogle Scholar
  38. 38.
    Binder CJ, Chang MK, Shaw PX et al. Innate and acquired immunity in atherogenesis. Nat Med 2002; 8:1218–26. PMID:12411948 doi:10.1038/nm1 102-1218PubMedCrossRefGoogle Scholar
  39. 39.
    Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12:204–12. PMID:21321594 doi:10.1038/ni.2001PubMedCrossRefGoogle Scholar
  40. 40.
    Lewis MJ, Malik TH, Ehrenstein MR et al. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2009; 120:417–26. PMID: 19620499 doi:10.1161/CIRCULATIONAHA.109.868158PubMedCrossRefGoogle Scholar
  41. 41.
    Binder CJ, Horkko S, Dewan A et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003; 9:736–43. PMID: 12740573 doi:10.1038/nm876PubMedCrossRefGoogle Scholar
  42. 42.
    Berland R, Wortis HH. Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 2002; 20:253–300. PMID:11861604 doi:10.1146/annurev.immunol.20.100301.064833PubMedCrossRefGoogle Scholar
  43. 43.
    Faria-Neto JR, Chyu KY, Li X et al. Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice. Atherosclerosis 2006; 189:83–90. PMID:16386745 doi:10.1016/j.atherosclerosis.2005.11.033PubMedCrossRefGoogle Scholar
  44. 44.
    Thorp E, Cui D, Schrijvers DM et al. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe—/— mice. Arterioscler Thromb Vasc Biol 2008; 28:1421–8. PMID:18451332 doi:10.1161/ATVBAHA.108.167197PubMedCrossRefGoogle Scholar
  45. 45.
    Reardon CA, Miller ER, Blachowicz L et al. Autoantibodies to OxLDL fail to alter the clearance of injected OxLDL in apolipoprotein E-deficient mice. JLipidRes 2004; 45:1347–54. PMID:15102879 doi:10.1194/jlr.M400075-JLR200Google Scholar
  46. 46.
    Salonen JT, Yla-Herttuala S, Yamamoto R et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339:883–7. PMID:1348295 doi:10.1016/0140-6736(92)90926-TPubMedCrossRefGoogle Scholar
  47. 47.
    Hulthe J. Antibodies to oxidized LDL in atherosclerosis development-clinical and animal studies. Clin Chim Acta 2004; 348:1–8. PMID:15369729 doi:10.1016/j.cccn.2004.05.021PubMedCrossRefGoogle Scholar
  48. 48.
    Karvonen J, Paivansalo M, Kesaniemi YA et al. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis. Circulation 2003; 108:2107–12. PMID: 14530200 doi:10.1161/01.CIR.0000092891.55157.A7PubMedCrossRefGoogle Scholar
  49. 49.
    Tsimikas S, Brilakis ES, Lennon RJ et al. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J Lipid Res 2007; 48:425–33. PMID: 17093289 doi:10.1194/jlr.M600361-JLR200PubMedCrossRefGoogle Scholar
  50. 50.
    Sjöberg BG, Su J, Dahlbom I et al. Low levels of IgM antibodies against phosphorylcholine-A potential risk marker for ischemic stroke in men. Atherosclerosis 2009; 203:528–32. PMID:18809177 doi:10.1016/j. atherosclerosis.2008.07.009PubMedCrossRefGoogle Scholar
  51. 51.
    Anania C, Gustafsson T, Hua X et al. Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus. Arthritis Res Ther 2010; 12:R214. PMID:21092251 doi:10.1186/ar3193PubMedCrossRefGoogle Scholar
  52. 52.
    Su J, Georgiades A, Wu R et al. Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension. Atherosclerosis 2006; 188:160–6. PMID: 16307748 doi:10.1016/j.atherosclerosis.2005.10.017PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Christoph J. Binder
    • 1
    • 2
  1. 1.Department of Laboratory MedicineMedical University of ViennaViennaAustria
  2. 2.Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria

Personalised recommendations