Immunologic Research

, 51:97

Antigenic specificity and expression of a natural idiotope on human pentameric and hexameric IgM polymers

  • Vladimir Petrušić
  • Irena Živković
  • Marijana Stojanović
  • Ivana Stojićević
  • Emilija Marinković
  • Aleksandra Inić-Kanada
  • Ljiljana Dimitijević


Natural antibodies (NAbs) are present in circulation even before the exposure to antigen and they exert various biological functions. They are polyreactive and mainly represented by immunoglobulin M (IgM), which is the first antibody produced in an ongoing immune response to infection and/or immunization. IgM is always secreted as a polymer with predominant pentameric structure, although other polymeric forms such as hexamer can be also formed. The biological functions of hexameric IgM are still not known and it is proposed that its existence as a NAb could be deleterious. However, the nature of IgM hexamers has not been investigated yet. In this paper, we have tested the expression of natural idiotope and antigenic specificities of pentameric and hexameric IgM polymers originating from sera of patients with Waldenström’s macroglobulinemia, as well as patients suffering from recurrent urinary bacterial infections. We demonstrate that although pentameric IgM polymers can exist as natural and immune antibodies, IgM hexamers are exclusively immune and do not exist as NAbs.


Hexamer IgM Immune antibodies Natural antibodies Natural idiotope Pentamer 











Oligodeoxynucleotides with CpG motifs




  1. 1.
    Boes M. Role of natural and immune IgM antibodies in immune responses. Mol Immunol. 2000;37:1141–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Racine R, Winslow GM. IgM in microbial infections: taken for granted? Immunol Lett. 2009;125:79–85.PubMedCrossRefGoogle Scholar
  3. 3.
    Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Op Immunol. 1995;7:812–8.CrossRefGoogle Scholar
  4. 4.
    Avrameas S, Ternynck T, Tsonis T, Lymberi P. Naturally occuring B-cell autoreactivity: a critical overview. J Autoimmun. 2007;29:213–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Hardy RR, Hayakawa K. CD5 B cells, a fetal B cell lineage. Adv Immunol. 1994;55:297–339.PubMedCrossRefGoogle Scholar
  6. 6.
    Kantor AB, Herzenberg LA. Origin of murine B cell lineages. Annu Rev Immunol. 1993;11:501–38.PubMedCrossRefGoogle Scholar
  7. 7.
    Radulović M, Ćirić B, Jurišić A, Jankov R, Apostolski S, Živančević-Simonović S, Dimitrijević L. Expression of Y7 idiotope on IgM molecules from cord sera. In: Lukić M, Čolić M, Mostarica-Stojković M, editors. Immunoregulation in health and disease. Massachusetts: Academic Press; 1997. p. 205–11.CrossRefGoogle Scholar
  8. 8.
    Duan B, Morel L. Role of B-1a cells in autoimmunity. Autoimmun Rev. 2006;5:403–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Cattaneo A, Neuberger MS. Polymeric immunoglobulin M is secreted by transfectants of non-lymphoid cells in the absence of immunoglobulin J chain. EMBO J. 1987;6:2753–8.PubMedGoogle Scholar
  10. 10.
    Niles MJ, Matsuuchi L, Koshland ME. Polymer IgM assembly and secretion in lymphoid and nonlymphoid cell lines: evidence that J chain is required for pentamer IgM synthesis. Proc Nail Acad Sci USA. 1995;92:2884–8.CrossRefGoogle Scholar
  11. 11.
    Randall TD, Brewer JW, Corley RB. Direct evidence that J chain regulates the polymeric structure of IgM in antibody-secreting B cells. J Biol Chem. 1992;267:18002–7.PubMedGoogle Scholar
  12. 12.
    Randall TD, Parkhouse RME, Corley RB. J chain synthesis and secretion of hexameric IgM is differentially regulated by lipopolysaccharide and interleukin 5. Proc Nail Acad Sci USA. 1992;89:962–6.CrossRefGoogle Scholar
  13. 13.
    Randall TD, King LB, Corley RB. The biological effects of IgM hexamer formation. Eur J Immunol. 1990;20:1971–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Davis A, Shulman MJ. IgM—molecular requirements for its assembly and function. Immunol Today. 1989;14:118–22.CrossRefGoogle Scholar
  15. 15.
    Fudenberg HH, Kunkel HG. Physical properties of the red cell agglutinins in acquired hemolytic anemia. J Exp Med. 1957;106:689–702.PubMedCrossRefGoogle Scholar
  16. 16.
    Mehrotra TN, Charlwood PA. Physico-chemical characterization of the cold auto-antibodies of acquired haemolytic anaemia. Immunology. 1960;3:254–64.Google Scholar
  17. 17.
    Eskeland T, Christenssen TB. IgM molecules with and without J chain in serum and after purification, studied by ultracentrifugation, electrophoresis, and electron microscopy. Scan J Immunol. 1975;4:217–28.CrossRefGoogle Scholar
  18. 18.
    Kownatski E. Reassociation of IgM subunits in the presence and absence of J chain. Immummunol Commun. 1973;2:105–13.Google Scholar
  19. 19.
    Brewer JW, Randall TD, Parkhouse RME, Corley RB. Mechanism and subcellular localization of secretory IgM polymer assembly. J Biol Chem. 1994;269:17338–48.PubMedGoogle Scholar
  20. 20.
    Collins C, Tsui FWL, Shulman MJ. Differential activation of human and guinea pig complement by pentameric and hexameric IgM. Eur J Immunol. 2002;32:1802–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Davis AC, Roux KH, Shulman MJ. On the structure of polymeric IgM. Eur J Immunol. 1988;18:1001–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Wiersma EJ, Collins C, Fazel S, Shulman MJ. Structural and functional analysis of J chain-deficient IgM. J Immunol. 1998;160:5979–89.PubMedGoogle Scholar
  23. 23.
    Brewer JW, Randall TD, Parkhouse RME, Corley RB. IgM hexamers? Immunol Today. 1994;15:165–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Petrusic V, Stojanovic M, Zivkovic I, Inic-Kanada A, Dimitrijevic L. Changes in composition of IgM polymers in patients suffering from recurrent urinary bacterial infections after bacterial immunization treatment. Immunol Invest. 2010;39:781–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Stojanovic M, Inic-Kanada A, Popovic Z, Zivkovic I, Dimitrijevic L. Changes in pools of autoantibodies and anti-bacterial antibodies in patients suffering from recurrent infections of the urinary tract and undergoing bacterial immunization treatment. Immunol Lett. 2004;94:123–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Kornfeld R, Keller J, Baenziger J, Kornfeld S. The structure of the glycopeptide of human gamma G myeloma proteins. J Biol Chem. 1971;246:3259–68.PubMedGoogle Scholar
  27. 27.
    Bradford M. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Burr FA, Burr B. Slab Gel system for the resolution of oligopeptides below molecular weight of 10,000. Meth Enzymol. 1983;96:239–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Swank RT, Munkres KD. Molecular weight analysis of oligopeptides by electrophoresis in polyacrylamide gel with sodium dodecyl sulfate. Anal Biochem. 1971;39:462–77.PubMedCrossRefGoogle Scholar
  30. 30.
    Christensson B, Espersen F, Hedstrom SA, Kronvall G. Methodological aspects of Staphylococcus aureus peptidoglycan serology: comparisons between solid-phase radioimmunoassay and enzyme-linked immunosorbent assay. J Clin Microbiol. 1984;19:680–6.PubMedGoogle Scholar
  31. 31.
    Schiff DE, Wass CA, Cryz SJ Jr, Cross AS, Kim KS. Estimation of protective levels of anti-O-specific lipopolysaccharide immunoglobulin G antibody against experimental Escherichia coli infection. Infect Immun. 1993;61:975–80.PubMedGoogle Scholar
  32. 32.
    Verbrugh HA, Peters R, Rozenberg-Arska M, Peterson PK, Verhoef J. Antibodies to cell wall peptidoglycan of Staphylococcus aureus in patients with serious Staphylococcal infections. J Infect Dis. 1981;144:1–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Dimitrijevic L, Radulovic MI, Ciric BP, Petricevic MM, Inic AB, Nikolic DN, Apostolski S. Human monoclonal IgM DJ binds to ss DNA and human commensal bacteria. Human Antibodies. 1999;9:37–45.PubMedGoogle Scholar
  34. 34.
    Dimitrijevic L, Radulovic M, Ciric B, Odrljin T, Jankov RM, Marzari R. Immunochemical characterisation of a murine monoclonal anti-idiotypic antibody. J Immunoassay. 1992;13:181–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Avrameas S. Natural autoantibodies: from “horror autotoxicus” to “gnothi seauton”. Immunol Today. 1991;12:154–9.PubMedGoogle Scholar
  36. 36.
    Avrameas S, Ternyck T. The natural autoantibodies system: between hypotheses and facts. Mol Immunol. 1993;30:1133–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Avrameas S, Ternyck T. Natural autoantibodies: the other side of the immune system. Res Immunol. 1995;146:235–48.PubMedCrossRefGoogle Scholar
  38. 38.
    Bouvet JP, Dighiero G. From natural polyreactive autoantibodies to a la carte monoreactive antibodies to infectious agents: is it a small world after all? Infect Immun. 1998;66:1–4.PubMedGoogle Scholar
  39. 39.
    Parkhouse RME, Askonas BA, Dourmashkin RR. Electron microscopic studies of mouse immunoglobulin M; structure and reconstitution following reduction. Immunology. 1970;18:575–84.PubMedGoogle Scholar
  40. 40.
    Binder CJ, Silverman GJ. Natural antibodies and the autoimmunity of atherosclerosis. Springer Semin Immun. 2005;26:385–404.CrossRefGoogle Scholar
  41. 41.
    Jaffe ES. Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and genetics: tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001. p. 132–5.Google Scholar
  42. 42.
    Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulous MA. Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol. 2003;30:110–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Shoenfeld Y, Isenberg D. Antiphospholipids as natural autoantibodies. In: Shoenfeld Y, Isenberg D, editors. Natural autoantibodies: their physiological role and regulatory significance. Boca Raton: CRC Press, Inc.; 2000. p. 259–68.Google Scholar
  44. 44.
    Botazzi B, Doni A, Garlanda C, Mantovani A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol. 2010;28:157–83.CrossRefGoogle Scholar
  45. 45.
    Usharauli D. Chronic infections and the origin of adaptive immune system. Med Hypotheses. 2010;75:241–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Vladimir Petrušić
    • 1
  • Irena Živković
    • 1
  • Marijana Stojanović
    • 1
  • Ivana Stojićević
    • 1
  • Emilija Marinković
    • 1
  • Aleksandra Inić-Kanada
    • 1
  • Ljiljana Dimitijević
    • 1
  1. 1.Department of Research and DevelopmentInstitute of Virology, Vaccines and Sera—TorlakBelgradeSerbia

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