Journal of Clinical Immunology

, Volume 34, Supplement 1, pp 12–21 | Cite as

Natural IgM: Beneficial Autoantibodies for the Control of Inflammatory and Autoimmune Disease

  • Caroline GrönwallEmail author
  • Gregg J. Silverman


Natural IgM are highly represented in the circulation at birth, and these often autoreactive antibodies have been postulated to have innate-like properties and play crucial roles in apoptotic cell clearance, tissue homeostasis, and immune modulation. This review summarizes the known properties of these IgM autoantibodies, and the evidence that these anti-apoptotic cell IgM natural antibodies can regulate inflammatory responses through ancient pathways of the innate immune system that first arose long before the initial emergence of the adaptive immune system. While the regulatory contributions of these natural IgM autoantibodies are certainly not an essential and fundamental component of host defenses, these provide an additional layer to further protect the host. More importantly, these IgM antibody responses are highly inducible and their up-regulation can be a powerful means for the host to survive in a setting of chronic inflammation. The observed beneficial clinical associations for cardiovascular disease and autoimmunity, as well as opportunities for potential therapeutic implications are discussed.


Immunoglobulin protective IgM apoptotic cells autoimmunity inflammation homeostasis 


  1. 1.
    Ehrlich P. On immunity with special reference to cell life. Proc R Soc Lond. 1900;66:424–48.Google Scholar
  2. 2.
    Avrameas S. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’. Immunol Today. 1991;12:154–9.PubMedGoogle Scholar
  3. 3.
    Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, Woelkers D, Shaw PX, et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest. 2009;119:1335–49.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Meffre E, Salmon JE. Autoantibody selection and production in early human life. J Clin Invest. 2007;117:598–601.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest. 2007;117:712–8.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Silverman GJ, Srikrishnan R, Germar K, Goodyear CS, Andrews KA, Ginzler EM, et al. Genetic imprinting of autoantibody repertoires in systemic lupus erythematosus patients. Clin Exp Immunol. 2008;153:102–16.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Haury M, Sundblad A, Grandien A, Barreau C, Coutinho A, Nobrega A. The repertoire of serum IgM in normal mice is largely independent of external antigenic contact. Eur J Immunol. 1997;27:1557–63.PubMedGoogle Scholar
  8. 8.
    Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011;11:34–46.PubMedGoogle Scholar
  9. 9.
    Baumgarth N, Herman OC, Jager GC, Brown L, Herzenberg LA. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc Natl Acad Sci U S A. 1999;96:2250–5.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Holodick NE, Tumang JR, Rothstein TL. Immunoglobulin secretion by B1 cells: differential intensity and IRF4-dependence of spontaneous IgM secretion by peritoneal and splenic B1 cells. Eur J Immunol. 2010;40:3007–16.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Hayakawa K, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, et al. Positive selection of natural autoreactive B cells. Science. 1999;285:113–6.PubMedGoogle Scholar
  12. 12.
    Pillai S, Cariappa A, Moran ST. Positive selection and lineage commitment during peripheral B-lymphocyte development. Immunol Rev. 2004;197:206–18.PubMedGoogle Scholar
  13. 13.
    Hardy RR, Carmack CE, Shinton SA, Riblet RJ, Hayakawa K. A single VH gene is utilized predominantly in anti-BrMRBC hybridomas derived from purified Ly-1 B cells. Definition of the VH11 family. J Immunol. 1989;142:3643–51.PubMedGoogle Scholar
  14. 14.
    Mercolino TJ, Locke AL, Afshari A, Sasser D, Travis WW, Arnold LW, et al. Restricted immunoglobulin variable region gene usage by normal Ly-1 (CD5+) B cells that recognize phosphatidyl choline. J Exp Med. 1989;169:1869–77.PubMedGoogle Scholar
  15. 15.
    Rowley B, Tang L, Shinton S, Hayakawa K, Hardy RR. Autoreactive B-1 B cells: constraints on natural autoantibody B cell antigen receptors. J Autoimmun. 2007;29:236–45.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Wang H, Clarke SH. Positive selection focuses the VH12 B-cell repertoire towards a single B1 specificity with survival function. Immunol Rev. 2004;197:51–9.PubMedGoogle Scholar
  17. 17.
    Kantor AB, Merrill CE, Herzenberg LA, Hillson JL. An unbiased analysis of V(H)-D-J(H) sequences from B-1a, B-1b, and conventional B cells. J Immunol. 1997;158:1175–86.PubMedGoogle Scholar
  18. 18.
    Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med. 2011;208:67–80.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Griffin DO, Rothstein TL. Human b1 cell frequency: isolation and analysis of human b1 cells. Front Immunol. 2012;3:122.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Griffin DO, Rothstein TL. Human “orchestrator” CD11b(+) B1 cells spontaneously secrete interleukin-10 and regulate T-cell activity. Mol Med. 2012;18:1003–8.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Schroeder Jr HW, Mortari F, Shiokawa S, Kirkham PM, Elgavish RA, Bertrand 3rd FE. Developmental regulation of the human antibody repertoire. Ann N Y Acad Sci. 1995;764:242–60.PubMedGoogle Scholar
  22. 22.
    Souto-Carneiro MM, Sims GP, Girschik H, Lee J, Lipsky PE. Developmental changes in the human heavy chain CDR3. J Immunol. 2005;175:7425–36.PubMedGoogle Scholar
  23. 23.
    Casali P, Notkins AL. CD5+ B lymphocytes, polyreactive antibodies and the human B-cell repertoire. Immunol Today. 1989;10:364–8.PubMedGoogle Scholar
  24. 24.
    Casali P, Schettino EW. Structure and function of natural antibodies. Curr Top Microbiol Immunol. 1996;210:167–79.PubMedGoogle Scholar
  25. 25.
    Rogosch T, Kerzel S, Hoss K, Hoersch G, Zemlin C, Heckmann M, et al. IgA response in preterm neonates shows little evidence of antigen-driven selection. J Immunol. 2012;189:5449–56.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Madi A, Bransburg-Zabary S, Kenett DY, Ben-Jacob E, Cohen IR. The natural autoantibody repertoire in newborns and adults: a current overview. Adv Exp Med Biol. 2012;750:198–212.PubMedGoogle Scholar
  27. 27.
    Madi A, Hecht I, Bransburg-Zabary S, Merbl Y, Pick A, Zucker-Toledano M, et al. Organization of the autoantibody repertoire in healthy newborns and adults revealed by system level informatics of antigen microarray data. Proc Natl Acad Sci U S A. 2009;106:14484–9.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Chen ZJ, Wheeler CJ, Shi W, Wu AJ, Yarboro CH, Gallagher M, et al. Polyreactive antigen-binding B cells are the predominant cell type in the newborn B cell repertoire. Eur J Immunol. 1998;28:989–94.PubMedGoogle Scholar
  29. 29.
    Wang C, Turunen SP, Kummu O, Veneskoski M, Lehtimaki J, Nissinen AE, et al. Natural antibodies of newborns recognize oxidative stress-related malondialdehyde acetaldehyde adducts on apoptotic cells and atherosclerotic plaques. Int Immunol. 2013;25:575–87.PubMedGoogle Scholar
  30. 30.
    Perlmutter RM, Kearney JF, Chang SP, Hood LE. Developmentally controlled expression of immunoglobulin VH genes. Science. 1985;227:1597–601.PubMedGoogle Scholar
  31. 31.
    Ochsenbein AF, Fehr T, Lutz C, Suter M, Brombacher F, Hengartner H, et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science. 1999;286:2156–9.PubMedGoogle Scholar
  32. 32.
    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.PubMedGoogle Scholar
  33. 33.
    de Cathelineau AM, Henson PM. The final step in programmed cell death: phagocytes carry apoptotic cells to the grave. Essays Biochem. 2003;39:105–17.Google Scholar
  34. 34.
    Devitt A, Marshall LJ. The innate immune system and the clearance of apoptotic cells. J Leukoc Biol. 2011;90:447–57.PubMedGoogle Scholar
  35. 35.
    Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol. 2007;7:964–74.PubMedGoogle Scholar
  36. 36.
    Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol. 2010;6:280–9.PubMedGoogle Scholar
  37. 37.
    Rosen A, Casciola-Rosen L. Autoantigens in systemic autoimmunity: critical partner in pathogenesis. J Intern Med. 2009;265:625–31.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Kim SJ, Gershov D, Ma X, Brot N, Elkon KB. I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. J Exp Med. 2002;196:655–65.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Chen Y, Khanna S, Goodyear CS, Park YB, Raz E, Thiel S, et al. Regulation of dendritic cells and macrophages by an anti-apoptotic cell natural antibody that suppresses TLR responses and inhibits inflammatory arthritis. J Immunol. 2009;183:1346–59.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Chen Y, Park YB, Patel E, Silverman GJ. IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells. J Immunol. 2009;182:6031–43.PubMedGoogle Scholar
  41. 41.
    Czajkowsky DM, Shao Z. The human IgM pentamer is a mushroom-shaped molecule with a flexural bias. Proc Natl Acad Sci U S A. 2009;106:14960–5.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Arnold JN, Dwek RA, Rudd PM, Sim RB. Mannan binding lectin and its interaction with immunoglobulins in health and in disease. Immunol Lett. 2006;106:103–10.PubMedGoogle Scholar
  43. 43.
    Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998;19:56–9.PubMedGoogle Scholar
  44. 44.
    Ogden CA, Kowalewski R, Peng Y, Montenegro V, Elkon KB. IGM is required for efficient complement mediated phagocytosis of apoptotic cells in vivo. Autoimmunity. 2005;38:259–64.PubMedGoogle Scholar
  45. 45.
    Quartier P, Potter PK, Ehrenstein MR, Walport MJ, Botto M. Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur J Immunol. 2005;35:252–60.PubMedGoogle Scholar
  46. 46.
    Stuart LM, Takahashi K, Shi L, Savill J, Ezekowitz RA. Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J Immunol. 2005;174:3220–6.PubMedGoogle Scholar
  47. 47.
    Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101:890–8.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Fadok VA, McDonald PP, Bratton DL, Henson PM. Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochem Soc Trans. 1998;26:653–6.PubMedGoogle Scholar
  49. 49.
    Stuart LM, Lucas M, Simpson C, Lamb J, Savill J, Lacy-Hulbert A. Inhibitory effects of apoptotic cell ingestion upon endotoxin-driven myeloid dendritic cell maturation. J Immunol. 2002;168:1627–35.PubMedGoogle Scholar
  50. 50.
    Gray M, Miles K, Salter D, Gray D, Savill J. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A. 2007;104:14080–5.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest. 2002;109:41–50.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Notley CA, Brown MA, Wright GP, Ehrenstein MR. Natural IgM is required for suppression of inflammatory arthritis by apoptotic cells. J Immunol. 2011;186:4967–72.PubMedGoogle Scholar
  53. 53.
    Gronwall C, Chen Y, Vas J, Khanna S, Thiel S, Corr M, et al. MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses. Proc Natl Acad Sci U S A. 2012;109:19745–50.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Vas J, Gronwall C, Marshak-Rothstein A, Silverman GJ. Natural antibody to apoptotic cell membranes inhibits the proinflammatory properties of lupus autoantibody immune complexes. Arthritis Rheum. 2012;64:3388–98.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83.PubMedGoogle Scholar
  56. 56.
    Asai T, Tena G, Plotnikova J, Willmann MR, Chiu WL, Gomez-Gomez L, et al. MAP kinase signalling cascade in Arabidopsis innate immunity. Nature. 2002;415:977–83.PubMedGoogle Scholar
  57. 57.
    Moncho-Amor V, Galardi-Castilla M, Perona R, Sastre L. The dual-specificity protein phosphatase MkpB, homologous to mammalian MKP phosphatases, is required for D. discoideum post-aggregative development and cisplatin response. Differentiation. 2011;81:199–207.PubMedGoogle Scholar
  58. 58.
    Boes M, Schmidt T, Linkemann K, Beaudette BC, Marshak-Rothstein A, Chen J. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci U S A. 2000;97:1184–9.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Ehrenstein MR, Cook HT, Neuberger MS. Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies. J Exp Med. 2000;191:1253–8.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Lobo PI, Bajwa A, Schlegel KH, Vengal J, Lee SJ, Huang L, et al. Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17. J Immunol. 2012;188:1675–85.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Lewis MJ, Malik TH, Ehrenstein MR, Boyle JJ, Botto M, Haskard DO. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation. 2009;120:417–26.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Kyaw T, Tay C, Krishnamurthi S, Kanellakis P, Agrotis A, Tipping P, et al. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res. 2011;109:830–40.PubMedGoogle Scholar
  63. 63.
    Cesena FH, Dimayuga PC, Yano J, Zhao X, Kirzner J, Zhou J, et al. Immune-modulation by polyclonal IgM treatment reduces atherosclerosis in hypercholesterolemic apoE−/− mice. Atherosclerosis. 2011;220:59–65.PubMedGoogle Scholar
  64. 64.
    Binder CJ, Horkko S, Dewan A, Chang MK, Kieu EP, Goodyear CS, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med. 2003;9:736–43.PubMedGoogle Scholar
  65. 65.
    Jiang C, Zhao ML, Scearce RM, Diaz M. Activation-induced deaminase-deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis. Arthritis Rheum. 2011;63:1086–96.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Werwitzke S, Trick D, Kamino K, Matthias T, Kniesch K, Schlegelberger B, et al. Inhibition of lupus disease by anti-double-stranded DNA antibodies of the IgM isotype in the (NZB x NZW) F1 mouse. Arthritis Rheum. 2005;52:3629–38.PubMedGoogle Scholar
  67. 67.
    Stoehr AD, Schoen CT, Mertes MM, Eiglmeier S, Holecska V, Lorenz AK, et al. TLR9 in peritoneal B-1b cells is essential for production of protective self-reactive IgM to control Th17 cells and severe autoimmunity. J Immunol. 2011;187:2953–65.PubMedGoogle Scholar
  68. 68.
    Friedman P, Horkko S, Steinberg D, Witztum JL, Dennis EA. Dennis, Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids. Importance of Schiff base formation and aldol condensation. J Biol Chem. 2002;277:7010–20.PubMedGoogle Scholar
  69. 69.
    Suthers B, Hansbro P, Thambar S, McEvoy M, Peel R, Attia J. Pneumococcal vaccination may induce anti-oxidized low-density lipoprotein antibodies that have potentially protective effects against cardiovascular disease. Vaccine. 2012;30:3983–5.PubMedGoogle Scholar
  70. 70.
    Feizi T. Blood group antigens. Ii antigens. Proc R Soc Med. 1975;68:799–802.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Loomes LM, Uemura K, Feizi T. Interaction of Mycoplasma pneumoniae with erythrocyte glycolipids of I and i antigen types. Infect Immun. 1985;47:15–20.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Silberstein LE, Jefferies LC, Goldman J, Friedman D, Moore JS, Nowell PC, et al. Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens. Blood. 1991;78:2372–86.PubMedGoogle Scholar
  73. 73.
    Turunen SP, Kummu O, Harila K, Veneskoski M, Soliymani R, Baumann M, et al. Recognition of Porphyromonas gingivalis gingipain epitopes by natural IgM binding to malondialdehyde modified low-density lipoprotein. PLoS One. 2012;7:e34910.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Kroese FG, Bos NA. Peritoneal B-1 cells switch in vivo to IgA and these IgA antibodies can bind to bacteria of the normal intestinal microflora. Curr Top Microbiol Immunol. 1999;246:343–9. discussion 350.PubMedGoogle Scholar
  75. 75.
    Kroese FG, Butcher EC, Stall AM, Lalor PA, Adams S, Herzenberg LA. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. Int Immunol. 1989;1:75–84.PubMedGoogle Scholar
  76. 76.
    Shulzhenko N, Morgun A, Hsiao W, Battle M, Yao M, Gavrilova O, et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat Med. 2011;17:1585–93.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Stoel M, Jiang HQ, van Diemen CC, Bun JC, Dammers PM, Thurnheer MC, et al. Restricted IgA repertoire in both B-1 and B-2 cell-derived gut plasmablasts. J Immunol. 2005;174:1046–54.PubMedGoogle Scholar
  78. 78.
    Botto M, Walport MJ. C1q, autoimmunity and apoptosis. Immunobiology. 2002;205:395–406.PubMedGoogle Scholar
  79. 79.
    Inoue T, Okumura Y, Shirama M, Ishibashi H, Kashiwagi S, Okubo H. Selective partial IgM deficiency: functional assessment of T and B lymphocytes in vitro. J Clin Immunol. 1986;6:130–5.PubMedGoogle Scholar
  80. 80.
    Takeuchi T, Nakagawa T, Maeda Y, Hirano S, Sasaki-Hayashi M, Makino S, et al. Functional defect of B lymphocytes in a patient with selective IgM deficiency associated with systemic lupus erythematosus. Autoimmunity. 2001;34:115–22.PubMedGoogle Scholar
  81. 81.
    Perrazio SF, Salomao R, Silva NP, Carneiro-Sampaio M, Andrade LEC. Serial screening shows that 28% of systemic lupus erythematosus adult patients carry an underlying primary immunodeficiency. Arthritis Rheum. 2012;64:S284.Google Scholar
  82. 82.
    Senaldi G, Ireland R, Bellingham AJ, Vergani D, Veerapan K, Wang F. IgM reduction in systemic lupus erythematosus. Arthritis Rheum. 1988;31:1213.PubMedGoogle Scholar
  83. 83.
    Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M. High levels of circulating early apoptic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus. 1998;7:113–8.PubMedGoogle Scholar
  84. 84.
    Gronwall C, Akhter E, Oh C, Burlingame RW, Petri M, Silverman GJ. IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE. Clin Immunol. 2012;142:390–8.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Padilla ND, Ciurana C, van Oers J, Ogilvie AC, Hack CE. Levels of natural IgM antibodies against phosphorylcholine in healthy individuals and in patients undergoing isolated limb perfusion. J Immunol Methods. 2004;293:1–11.PubMedGoogle Scholar
  86. 86.
    Ajeganova S, Fiskesund R, de Faire U, Hafstrom I, Frostegard J. Effect of biological therapy on levels of atheroprotective antibodies against phosphorylcholine and apolipoproteins in rheumatoid arthritis - a one year study. Clin Exp Rheumatol. 2011;29:942–50.PubMedGoogle Scholar
  87. 87.
    Shaw PX, Horkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest. 2000;105:1731–40.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Horkko S, Bird DA, Miller E, Itabe H, Leitinger N, Subbanagounder G, et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest. 1999;103:117–28.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Su J, Hua X, Concha H, Svenungsson E, Cederholm A, Frostegard J. Natural antibodies against phosphorylcholine as potential protective factors in SLE. Rheumatology (Oxford). 2008;47:1144–50.Google Scholar
  90. 90.
    Nishinarita S, Sawada S, Horie T. Phosphorylcholine antibodies in pulmonary infection. Med Microbiol Immunol. 1990;179:205–14.PubMedGoogle Scholar
  91. 91.
    Schenkein HA, Gunsolley JC, Best AM, Harrison MT, Hahn CL, Wu J, et al. Antiphosphorylcholine antibody levels are elevated in humans with periodontal diseases. Infect Immun. 1999;67:4814–8.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Dunlap NE, Ballinger S, Reed T, Christian JC, Koopman WJ, Briles DE. The use of monozygotic and dizygotic twins to estimate the effects of inheritance on the levels of immunoglobulin isotypes and antibodies to phosphocholine. Clin Immunol Immunopathol. 1993;66:176–80.PubMedGoogle Scholar
  93. 93.
    Rahman I, Atout R, Pedersen NL, de Faire U, Frostegard J, Ninio E, et al. Genetic and environmental regulation of inflammatory CVD biomarkers Lp-PLA2 and IgM anti-PC. Atherosclerosis. 2011;218:117–22.PubMedGoogle Scholar
  94. 94.
    Anania C, Gustafsson T, Hua X, Su J, Vikstrom M, de Faire U, 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.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Fiskesund R, Su J, Bulatovic I, Vikstrom M, de Faire U, Frostegard J. IgM phosphorylcholine antibodies inhibit cell death and constitute a strong protection marker for atherosclerosis development, particularly in combination with other auto-antibodies against modified LDL. Results Immunol. 2012;2:13–8.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Su J, Georgiades A, Wu R, Thulin T, de Faire U, Frostegard J. Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension. Atherosclerosis. 2006;188:160–6.PubMedGoogle Scholar
  97. 97.
    Fiskesund R, Stegmayr B, Hallmans G, Vikstrom M, Weinehall L, de Faire U, et al. Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden. Stroke. 2010;41:607–12.PubMedGoogle Scholar
  98. 98.
    Sjoberg BG, Su J, Dahlbom I, Gronlund H, Wikstrom M, Hedblad B, et al. Low levels of IgM antibodies against phosphorylcholine-A potential risk marker for ischemic stroke in men. Atherosclerosis. 2009;203:528–32.PubMedGoogle Scholar
  99. 99.
    Gronlund H, Hallmans G, Jansson JH, Boman K, Wikstrom M, de Faire U, et al. 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;16:382–6.PubMedGoogle Scholar
  100. 100.
    de Faire U, Frostegard J. Natural antibodies against phosphorylcholine in cardiovascular disease. Ann N Y Acad Sci. 2009;1173:292–300.PubMedGoogle Scholar
  101. 101.
    Caidahl K, Hartford M, Karlsson T, Herlitz J, Pettersson K, de Faire U, et al. IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes. Int J Cardiol. 2013;167:464–9.PubMedGoogle Scholar
  102. 102.
    Carrero JJ, Hua X, Stenvinkel P, Qureshi AR, Heimburger O, Barany P, et al. Low levels of IgM antibodies against phosphorylcholine-A increase mortality risk in patients undergoing haemodialysis. Nephrol Dial Transplant. 2009;24:3454–60.PubMedGoogle Scholar
  103. 103.
    Sobel M, Moreno KI, Yagi M, Kohler TR, Tang GL, Clowes AW, et al. Low levels of a natural IgM antibody are associated with vein graft stenosis and failure. J Vasc Surg. 2013;58:997–1005. e1001-1002.PubMedGoogle Scholar
  104. 104.
    Eriksson UK, Sjoberg BG, Bennet AM, de Faire U, Pedersen NL, Frostegard J. Low levels of antibodies against phosphorylcholine in Alzheimer’s disease. J Alzheimers Dis. 2010;21:577–84.PubMedGoogle Scholar
  105. 105.
    Fukumoto M, Shoji T, Emoto M, Kawagishi T, Okuno Y, Nishizawa Y. Antibodies against oxidized LDL and carotid artery intima-media thickness in a healthy population. Arterioscler Thromb Vasc Biol. 2000;20:703–7.PubMedGoogle Scholar
  106. 106.
    Karvonen J, Paivansalo M, Kesaniemi YA, Horkko S. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis. Circulation. 2003;108:2107–12.PubMedGoogle Scholar
  107. 107.
    Garrido-Sanchez L, Chinchurreta P, Garcia-Fuentes E, Mora M, Tinahones FJ. A higher level of IgM anti-oxidized LDL antibodies is associated with a lower severity of coronary atherosclerosis in patients on statins. Int J Cardiol. 2010;145:263–4.PubMedGoogle Scholar
  108. 108.
    Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Wardemann H. Autoreactivity in human IgG + memory B cells. Immunity. 2007;26:205–13.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Barrett DJ, Ayoub EM. IgG2 subclass restriction of antibody to pneumococcal polysaccharides. Clin Exp Immunol. 1986;63:127–34.PubMedCentralPubMedGoogle Scholar
  110. 110.
    von Gunten S, Smith DF, Cummings RD, Riedel S, Miescher S, Schaub A, et al. Intravenous immunoglobulin contains a broad repertoire of anticarbohydrate antibodies that is not restricted to the IgG2 subclass. J Allergy Clin Immunol. 2009;123:1268–76. e1215.Google Scholar
  111. 111.
    Anthony RM, Wermeling F, Ravetch JV. Novel roles for the IgG Fc glycan. Ann N Y Acad Sci. 2012;1253:170–80.PubMedGoogle Scholar
  112. 112.
    Anthony RM, Kobayashi T, Wermeling F, Ravetch JV. Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature. 2011;475:110–3.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Hess C, Winkler A, Lorenz AK, Holecska V, Blanchard V, Eiglmeier S, et al. T cell-independent B cell activation induces immunosuppressive sialylated IgG antibodies. J Clin Invest. 2013;123:3788–96.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol. 2008;4:491–8.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Ferreira R, Barreto M, Santos E, Pereira C, Martins B, Andreia R, et al. Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production. J Autoimmun. 2005;25:155–63.PubMedGoogle Scholar
  116. 116.
    Pascual V, Victor K, Lelsz D, Spellerberg MB, Hamblin TJ, Thompson KM, et al. Nucleotide sequence analysis of the V regions of two IgM cold agglutinins. Evidence that the VH4-21 gene segment is responsible for the major cross-reactive idiotype. J Immunol. 1991;146:4385–91.PubMedGoogle Scholar
  117. 117.
    Jenks SA, Palmer EM, Marin EY, Hartson L, Chida AS, Richardson C, et al. 9G4+ autoantibodies are an important source of apoptotic cell reactivity associated with high levels of disease activity in systemic lupus erythematosus. Arthritis Rheum. 2013;65:3165–75.PubMedGoogle Scholar
  118. 118.
    Pugh-Bernard AE, Silverman GJ, Cappione AJ, Villano ME, Ryan DH, Insel RA, et al. Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J Clin Invest. 2001;108:1061–70.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Richardson C, Chida AS, Adlowitz D, Silver L, Fox E, Jenks SA, et al. Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. J Immunol. 2013;191:4926–39.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Bhat NM, Lee LM, van Vollenhoven RF, Teng NN, Bieber MM. VH4-34 encoded antibody in systemic lupus erythematosus: effect of isotype. J Rheumatol. 2002;29:2114–21.PubMedGoogle Scholar
  121. 121.
    Bayry J, Negi VS, Kaveri SV. Intravenous immunoglobulin therapy in rheumatic diseases. Nat Rev Rheumatol. 2011;7:349–59.PubMedGoogle Scholar
  122. 122.
    Kaveri SV. Intravenous immunoglobulin: exploiting the potential of natural antibodies. Autoimmun Rev. 2012;11:792–4.PubMedGoogle Scholar
  123. 123.
    Wu R, Shoenfeld Y, Sherer Y, Patnaik M, Matsuura E, Gilburd B, et al. Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations–possible immunomodulation of atherosclerosis. Autoimmunity. 2003;36:91–7.PubMedGoogle Scholar
  124. 124.
    Bieber AJ, Warrington A, Asakura K, Ciric B, Kaveri SV, Pease LR, et al. Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia. 2002;37:241–9.PubMedGoogle Scholar
  125. 125.
    Hurez V, Kazatchkine MD, Vassilev T, Ramanathan S, Pashov A, Basuyaux B, et al. Pooled normal human polyspecific IgM contains neutralizing anti-idiotypes to IgG autoantibodies of autoimmune patients and protects from experimental autoimmune disease. Blood. 1997;90:4004–13.PubMedGoogle Scholar
  126. 126.
    Rieben R, Roos A, Muizert Y, Tinguely C, Gerritsen AF, Daha MR. Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation. Blood. 1999;93:942–51.PubMedGoogle Scholar
  127. 127.
    Vassilev T, Yamamoto M, Aissaoui A, Bonnin E, Berrih-Aknin S, Kazatchkine MD, et al. Normal human immunoglobulin suppresses experimental myasthenia gravis in SCID mice. Eur J Immunol. 1999;29:2436–42.PubMedGoogle Scholar
  128. 128.
    Alejandria MM, Lansang MA, Dans LF, Mantaring 3rd JB. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;9, CD001090.PubMedGoogle Scholar
  129. 129.
    Tugrul S, Ozcan PE, Akinci O, Seyhun Y, Cagatay A, Cakar N, et al. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis [ISRCTN28863830]. Crit Care. 2002;6:357–62.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Watzlawik JO, Wootla B, Painter MM, Warrington AE, Rodriguez M. Cellular targets and mechanistic strategies of remyelination-promoting IgMs as part of the naturally occurring autoantibody repertoire. Expert Rev Neurother. 2013;13:1017–29.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of MedicineNew York University School of MedicineNew YorkUSA

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