Specificity, Polyspecificity and Heterospecificity of Antibody-Antigen Recognition

  • Marc H V Van Regenmortel


The concept of antibody specificity is analyzed and shown to reside in the ability of an antibody to discriminate between two antigens. Initially antibody specificity was attributed to sequence differences in complementarity-determining regions (CDRs) but as increasing numbers of crystallographic antibody-antigen complexes were elucidated, specificity was analyzed in terms of six antigen-binding regions (ABRs) that only roughly correspond to CDRs. It was found that each ABR differs significantly in its amino acid composition and tends to bind different types of amino acids at the surface of proteins. In spite of these differences, the combined preference of the six ABRs does not allow epitopes to be distinguished from the rest of the protein surface. These findings explain the poor success of past and newly proposed methods for predicting protein epitopes. Antibody polyspecificity refers to the ability of one antibody to bind a large variety of epitopes in different antigens and this property explains how the immune system develops an antibody repertoire that is able to recognize every antigen the system is likely to encounter. Antibody heterospecificity arises when an antibody reacts better with another antigen than with the one used to raise the antibody. As a result an antibody may sometimes appear to have been elicited by an antigen with which it is unable to react. The implications of antibody polyspecificity and heterospecificity in vaccine development are pointed out.


Antibody specificity Polyspecificity Heterospecificity Peptide hydropathic complementarity Epitope prediction Polyreactive antibodies Somatic hypermutation Autoimmunity Monogamous bivalent binding HIV-1 vaccines 


  1. Achour A, Biquard JM, Krsmanovic V, M’bika JP, Ficheux D, Sikorska M, Cozzone AJ. Induction of human immunodeficiency virus (HIV-1) envelope specific cell-mediated immunity by a non-homologous synthetic peptide. PLoS One. 2007;2(11):e1214.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Al Moudallal Z, Briand JP, Van Regenmortel MHV. Monoclonal antibodies as probes of the antigenic structure of tobacco mosaic virus. EMBO J. 1982;1:1005–10.PubMedPubMedCentralGoogle Scholar
  3. Almagro JC. Identification of differences in the specificity determining residues of antibodies that recognize antigens of different size: implications for the rational design of antibody repertoires. J Mol Recognit. 2004;17:132–43.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Batista FD, Neuberger MS. Affinity dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity. 1998;8:751–9.PubMedPubMedCentralGoogle Scholar
  5. Berek C, Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987;96:23–41. Scholar
  6. Berzofsky JA. Intrinsic and extrinsic factors in protein antigenic structure. Science. 1985;229:932–40.PubMedPubMedCentralGoogle Scholar
  7. Berzofsky JA, Schechter AN. The concepts of crossreactivity and specificity in immunology. Mol Immunol. 1981;18:751–63.PubMedPubMedCentralGoogle Scholar
  8. Bhattacharjee AK, Glaudemans CP. Dual binding specificities in MOPC 384 and 870 murine myeloma immunoglobulins. J Immunol. 1978;120:411–3.Google Scholar
  9. Biro JC. Seven fundamental, unsolved questions in molecular biology. Cooperative storage and bi-directional transfer of biological information by nucleic acids and proteins: an alternative to “central dogma”. Med Hypotheses. 2005;63:951–62.CrossRefGoogle Scholar
  10. Biro JC. The proteomic code: a molecular recognition code for proteins. Theor Biol Med Model. 2007;4:45.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Blalock JE, Bost KL. Binding of peptides that are specified by complementary RNAs. Biochem J. 1986;234:679–89.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Blythe MJ, Flower DR. Benchmarking B cell epitope prediction: underperformance of existing methods. Protein Sci. 2005;14:246–8.PubMedPubMedCentralGoogle Scholar
  13. Bouvet JP, Stahl D, Rose S, Quan CP, Kazatchkine MD, Kaveri SV. Induction of natural autoantibody activity following treatment of human immunoglobulin with dissociating agents. J Autoimmun. 2001;16:163–72.PubMedCrossRefGoogle Scholar
  14. Boyd WC, Bernard H. Quantitative changes in antibodies and globulin fractions in sera of rabbits injected with several antigens. J Immunol. 1937;33:111–22.Google Scholar
  15. Brentani RR. Biological implications of complementary hydropathy of amino acids. J Theor Biol. 1988;135:495–9.PubMedCrossRefGoogle Scholar
  16. 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.<989::AID-IMMU989>3.0.CO;2-1.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chen J, Liu H, Yang J, Chou KC. Prediction of linear B cell epitope using amino acid pair antigenicity scale. Amino Acids. 2007;33:423–8.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Chen SW, Van Regenmortel MHV, Pellequer JL. Structure-activity relationships in peptide-antibody complexes: implications for epitope prediction and development of synthetic peptide vaccines. Curr Med Chem. 2009;16:953–64.Google Scholar
  19. Chothia C, Lesk AM. Canonical structures for the hypervariable regions of immunoglobulins. J Mol Biol. 1987;196:901–17.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Cohen IR, Hershberg U, Solomon S. Antigen-receptor degeneracy and immunological paradigms. Mol Immunol. 2004;40:993–6.Google Scholar
  21. Cohn M. A new concept of immune specificity emerges from a consideration of the self-nonself discrimination. Cell Immunol. 1997;181:103–8.Google Scholar
  22. Cohn M. Degeneracy, mimicry and cross-reactivity in immune recognition. Mol Immunol. 2005;42:651–5.Google Scholar
  23. Collis AV, Brouwer AP, Martin AC. Analysis of the antigen combining site: correlations between length and sequence composition of the hypervariable loops and the nature of the antigen. J Mol Biol. 2003;325:337–54.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol. 1995;7:812–8.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Day ED. Advanced immunochemistry. 2nd ed. New York, NY: Wiley; 1990. p. 1–291.Google Scholar
  26. De Vos-Cloetens C, Minsart-Baleriaux V, Urbain-Vansanten G. Possible relationships between antibodies and non-specific immunoglobulins simultaneously induced after antigenic stimulation. Immunology. 1971;20:955–8.PubMedPubMedCentralGoogle Scholar
  27. Dimitrov JD, Planchais C, Kang J, Pashov A, Vassilev TL, Kaveri SV, Lacroix-Desmazes S. Heterogeneous antigen recognition behavior of induced polyspecific antibodies. Biochem Biophys Res Commun. 2010;398:266–71.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Dimitrov JD, Planchais C, Roumenina LT, Vassilev TL, Kaveri SV, Lacroix-Desmazes S. Antibody polyreactivity in health and disease: Statuvariabilis. J Immunol. 2013;191:993–9.Google Scholar
  29. Ditzel HJ, Itoh K, Burton DR. Determinants of polyreactivity in a large panel of recombinant human antibodies from HIV-1 infection. J Immunol. 1996;157:739–49.PubMedPubMedCentralGoogle Scholar
  30. Edwards BM, Barash SC, Main SH, Choi GH, Minter R, Ullrich S, Williams E, DuFou L, Wilton J, Albert VR, et al. The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS. J Mol Biol. 2003;334:103–18.PubMedPubMedCentralGoogle Scholar
  31. Efroni S, Cohen IR. Simplicity belies a complex system: a response to the minimal model of immunity of Langman and Cohn. Cell Immunol. 2002;216:23–30.PubMedPubMedCentralGoogle Scholar
  32. Eisen HN. Specificity and degeneracy in antigen recognition: Yin and Yang in the immune system. Annu Rev Immunol. 2001;19:1–21.PubMedPubMedCentralGoogle Scholar
  33. Eisen HN, Chakraborty AK. Evolving concepts of specificity in immune reactions. Proc Natl Acad Sci U S A. 2010;107:22373–80. Scholar
  34. El-Manzalawy Y, Honavar V. Recent advances in B cell epitope prediction methods. Immunome Res. 2010;6(Suppl 2):1–9. Scholar
  35. Foote J, Eisen HN. Kinetic and affinity limits on antibodies produced during immune responses. Proc Natl Acad Sci U S A. 1995;92:1254–6.PubMedPubMedCentralGoogle Scholar
  36. Frison EA, Stace-Smith R. Cross-reacting and heterospecific monoclonal antibodies produced against arabis mosaic nepovirus. J Gen Virol. 1992;73:2525–30.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Gomara MJ, Haro I. Synthetic peptides for the immunodiagnosis of human diseases. Curr Med Chem. 2007;14:531–46.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Gonzalez S, González-Rodríguez AP, Suárez-Álvarez B, López-Soto A, Huergo-Zapico L, Lopez-Larrea C. Conceptual aspects of self and nonself discrimination. Self Nonself. 2011;2:19–25.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Greenbaum JA, Andersen PH, Blythe M, Bui H-H, Cachau RE, Crowe J, Davies M, Kolaskar AS, Lund O, Morrison S, et al. Towards a consensus on datasets and evaluation metrics for developing B-cell epitope prediction tools. J Mol Recognit. 2007;20:75–82.PubMedPubMedCentralGoogle Scholar
  40. Haimovich J, Tarrab R, Sulica A, Sela M. Antibodies of different specificities in normal rabbit sera. J Immunol. 1970;104:1033–4.PubMedPubMedCentralGoogle Scholar
  41. Hans D, Young PR, Fairlie DP. Current status of short synthetic peptides as vaccines. Med Chem. 2006;2:627–46.PubMedPubMedCentralGoogle Scholar
  42. Haynes BF, Moody MA, Verkoczy L, Kelsoe G, Alam SM. Antibody polyspecificity and neutralization of HIV-1: a hypothesis. Hum Antibodies. 2005b;14:59–67.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Hopp TP. Retrospective: 12 years of antigenic determinant predictions, and more. Pept Res. 1993;6:183–90.Google Scholar
  44. Hopp TP, Woods KR. Prediction of protein antigenic determinants from amino acid sequences. Proc Natl Acad Sci U S A. 1981;78:3824–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Hunziker L, Recher M, Macpherson AJ, Ciurea A, Freigang S, Hengartner H, Zinkernagel RM. Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. Nat Immunol. 2003;4:343–9.PubMedCrossRefPubMedCentralGoogle Scholar
  46. James LC, Roversi P, Tawfik DS. Antibody multi-specificity mediated by conformational diversity. Science. 2003;299:1362–7.PubMedPubMedCentralGoogle Scholar
  47. Jimenez R, Salazar G, Baldridge KK, Romesberg FE. Flexibility and molecular recognition in the immune system. Proc Natl Acad Sci U S A. 2003;100:92–7.PubMedPubMedCentralGoogle Scholar
  48. Keskin O, Gursoy A, Ma B, Nussinov R. Principles of protein-protein interactions: what are the preferred ways for proteins to interact? Chem Rev 2008;108:1225–1244.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Khan T, Salunke DM. Structural elucidation of the mechanistic basis of degeneracy in the primary humoral response. J Immunol. 2012;188:1819–27.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Klein JS, Bjorkman PJ. Few and far between: how HIV may be evading antibody avidity. PLoS Pathog. 2010;6:e1000908.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Klein JS, Gnanapragasam PN, Galimidi RP, Foglesong CP, West AP Jr, Bjorkman PJ. Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10. Proc Natl Acad Sci U S A. 2009;106:7385–90.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Kringelum JV, Nielsen M, Padkjær SB, Lund O. Structural analysis of B-cell epitopes in antibody: protein complexes. Mol Immunol. 2013;53:24–34.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Kunik V, Ofran Y. The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops. Protein Eng Des Sel. 2013;26:599–609.Google Scholar
  54. Kunik V, Ashkenazi S, Ofran Y. Paratome: an online tool for systematic identification of antigen-binding regions in antibodies based on sequence or structure. Nucleic Acids Res. 2012a;40:W521–4.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kunik V, Peters B, Ofran Y. Structural consensus among antibodies defines the antigen binding site. PLoS Comput Biol. 2012b;8:e1002388.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Landsteiner K. The specificity of serological reactions. New York: Dover Publications; 1962. p. 330.Google Scholar
  57. Langman RE. The specificity of immunological reactions. Mol Immunol. 2000;37:555–61.Google Scholar
  58. Laune D, Molina F, Ferrieres G, Mani JC, Cohen P, Simon D, Bernardi T, Piechaczyk M, Pau B, Granier C. Systematic exploration of the antigen binding activity of synthetic peptides isolated from the variable regions of immunoglobulins. J Biol Chem. 1997;272:30937–44.PubMedPubMedCentralGoogle Scholar
  59. Lefranc MP. IMGT, the international ImMunoGeneTics database. Nucleic Acid Res. 2003;31:307–10.PubMedCrossRefPubMedCentralGoogle Scholar
  60. Lefranc MP, Giudicelli V, Kaas Q, Duprat E, Jabado-Michaloud J, Scaviner D, Ginestoux C, Clément O, Chaume D, Lefranc G. IMGT, the international ImMunoGeneTics information system. Nucleic Acids Res. 2005;33:D593–7.PubMedCrossRefPubMedCentralGoogle Scholar
  61. Li X, Song B, Chen X, Wang Z, Zeng M, Yu D, Hu D, Chen Z, Jin L, Yang S, Yang C, Chen B. Crystal structure of a four-layer aggregate of engineered TMV CP implies the importance of terminal residues for oligomer assembly. PLoS One. 2013;8:e77717.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Liang S, Zheng D, Zhang C, Zacharias M. Prediction of antigenic epitopes on protein surfaces by consensus scoring. BMC Bioinf. 2009;10:302.CrossRefGoogle Scholar
  63. Loor F. On the existence of heterospecific antibodies in sera from rabbits immunized against tobacco mosaic virus determinants. Immunology. 1971;21:557–64.PubMedPubMedCentralGoogle Scholar
  64. Ludewig B, Krebs P, Metters H, Tatzel J, Türeci O, Sahin U. Molecular characterization of virus-induced autoantibody responses. J Exp Med. 2004;200:637–46.PubMedPubMedCentralCrossRefGoogle Scholar
  65. MacCallum RM, Martin AC, Thornton JM. Antibody-antigen interactions: contact analysis and binding site topography. J Mol Biol. 1996;262:732–45.PubMedCrossRefPubMedCentralGoogle Scholar
  66. Mäkelä O. Single lymph node cells producing heteroclitic bacteriophage antibody. J Immunol. 1965;95:378–86.PubMedPubMedCentralGoogle Scholar
  67. Manivel V, Bayiroglu F, Siddiqui Z, Salunke DM, Rao KV. The primary antibody repertoire represents a linked network of degenerate antigen specificities. J Immunol. 2002;169:888–97.PubMedPubMedCentralGoogle Scholar
  68. Marchalonis JJ, Kaveri S, Lacroix-Desmazes S, Kazatchkine MD. Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system. FASEB J. 2002;16:842–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Mariuzza RA. Multiple paths to multispecificity. Immunity. 2006;24:359–61.Google Scholar
  70. Markus G, Tritsch GL, Parthasarathy R. A model for hydropathybased peptide interactions. Arch Biochem Biophys. 1989;272:433–9.PubMedCrossRefPubMedCentralGoogle Scholar
  71. Mayr E. The growth of biological thought. Diversity, evolution, and inheritance. Cambridge, MA: Harvard University Press; 1982. p. 974.Google Scholar
  72. Mazumdar PH. Species and specificity. Cambridge: Cambridge University Press; 1995.Google Scholar
  73. Mc Farland BJ, Strong RK. Thermodynamic analysis of degenerate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation. Immunity. 2003;19:803–12.CrossRefGoogle Scholar
  74. Mc Lennan IC. Germinal centers. Annu Rev Immunol. 1994;12:117–39.CrossRefGoogle Scholar
  75. McMahon MJ, O’Kennedy R. Polyreactivity as an acquired artefact, rather than a physiologic property, of antibodies: evidence that monoreactive antibodies may gain the ability to bind to multiple antigens after exposure to low pH. J Immunol Methods. 2000;241:1–10.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Moticka EJ. The non-specific stimulation of immunoglobulin secretion following specific stimulation of the immune system. Immunology. 1974;27:401–12.PubMedPubMedCentralGoogle Scholar
  77. Mouquet H, Nussenzweig MC. Polyreactive antibodies in adaptive immune responses to viruses. Cell Mol Life Sci. 2012;69:1435–45.PubMedCrossRefPubMedCentralGoogle Scholar
  78. Mouquet H, Scheid JF, Zoller MJ, Krogsgaard M, Ott RG, Shukair S, Artyomov MN, Pietzsch J, Connors M, Pereyra F, Walker BD, Ho DD, Wilson PC, Seaman MS, Eisen HN, Chakraborty AK, Hope TJ, Ravetch JV, Wardemann H, Nussenzweig MC. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature. 2010;467:591–5.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Muller S. Use of antipeptide antibodies in molecular and cellular biology. In: Van Regenmortel MHV, Muller S, editors. Synthetic peptides as antigens. Amsterdam: Elsevier; 1999b. p. 215–35.Google Scholar
  80. Münz C, Lünemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9:246–58.PubMedPubMedCentralCrossRefGoogle Scholar
  81. North B, Lehmann A, Dunbrack RL Jr. A new clustering of antibody CDR loop conformations. J Mol Biol. 2011;406:228–56.PubMedCrossRefPubMedCentralGoogle Scholar
  82. Notkins AL. Polyreactivity of antibody molecules. Trends Immunol. 2004;25:174–9.CrossRefGoogle Scholar
  83. Ochsenbein AF, Fehr T, Lutz C, Suter M, Brombacher F, Hengartner H, Zinkernagel RM. Control of early viral and bacterial distribution and disease by natural antibodies. Science. 1999;286:2156–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. Ofran Y, Schlessinger A, Rost B. Automated identification of complementarity determining regions (CDRs) reveals peculiar characteristics of CDRs and B cell epitopes. J Immunol. 2008;181:6230–5.PubMedCrossRefPubMedCentralGoogle Scholar
  85. Oppezzo P, Dumas G, Bouvet JP, Robello C, Cayota A, Pizarro JC, Dighiero G, Pritsch O. Somatic mutations can lead to a loss of superantigenic and polyreactive binding. Eur J Immunol. 2004;34:1423–32.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Padlan EA, Abergel C, Tipper JP. Identification of specificity determining residues in antibodies. FASEB J. 1995;9:133–9.PubMedCrossRefPubMedCentralGoogle Scholar
  87. Parnes O. From interception to incorporation: degeneracy and promiscuous recognition as precursors of a paradigm shift in immunology. Mol Immunol. 2004;40:985–91.Google Scholar
  88. Pellequer JL, Westhof E, Van Regenmortel MHV. Predicting the location of continuous epitopes in proteins from their primary structures. Methods Enzymol. 1991;203:176–201.PubMedPubMedCentralGoogle Scholar
  89. Ponomarenko JV, Van Regenmortel MHV. B cell epitope prediction. In: Gu J, Bourne PE, editors. Structural bioinformatics. 2nd ed. Hoboken, NJ: John Wiley; 2009. p. 849–79.Google Scholar
  90. Raghunathan G, Smart J, Williams J, Almagro JC. Antigen-binding site anatomy and somatic mutations in antibodies that recognize different types of antigens. J Mol Recognit. 2012;25:103–13.PubMedCrossRefPubMedCentralGoogle Scholar
  91. Rajewsky K. Clonal selection and learning in the antibody system. Nature. 1996;381:751–8.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Richards FF, Konigsberg WH, Rosenstein RW, Varga JM. On the specificity of antibodies. Science. 1975;187:130–7.Google Scholar
  93. Rubinstein ND, Mayrose I, Halperin D, Yekutieli D, Gershoni JM, Pupko T. Computational characterization of B-cell epitopes. Mol Immunol. 2008;45:3477–89.PubMedPubMedCentralGoogle Scholar
  94. Sällberg M, Sherefa K, Zhang ZX. The antigen/antibody specificity exchanger: a new peptide based tool for re-directing antibodies of other specificities to recognize the V3 domain of HIV-1 gp120. Biochem Biophys Res Commun. 1994;205:1386–90.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Schroer JA, Bender T, Feldmann T, Kim KJ. Mapping epitopes on the insulin molecule using monoclonal antibodies. Eur J Immunol. 1983;13:693–700.Google Scholar
  96. Schubert W. Systematic, spatial imaging of large multimolecular assemblies and the emerging principles of supramolecular order in biological systems. J Mol Recognit. 2014;27:3–18.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Schubert W, Bonnekoh B, Pommer AJ, Philipsen L, Böckelmann R, Malykh Y, Gollnick H, Friedenberger M, Bode M, Dress AWM. Analyzing proteome topology and function by automated multi-dimensional fluorescence microscopy. Nat Biotechnol. 2006;24:1270–8.PubMedCrossRefPubMedCentralGoogle Scholar
  98. Sela-Culang I, Kunik V, Ofran Y. The structural basis of antibody-antigen recognition. Front Immunol. 2013;4:302. Scholar
  99. Sela-Culang I, Benhnia MR, Matho MH, Kaever T, Maybeno M, Schlossman A, Nimrod G, Li S, Xiang Y, Zajonc D, Crotty S, Ofran Y, Peters B. Using a combined computational-experimental approach to predict antibody-specific B cell epitopes. Structure. 2014;22(4):646–57. Scholar
  100. Sercarz EE, Maverakis E. Recognition and function in a degenerate immune system. Mol Immunol. 2004;40:1003–108.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Sethi DK, Agarwal A, Manivel V, Rao KV, Salunke DM. Differential epitope positioning within the germline antibody enhances promiscuity in the primary immune response. Immunity. 2006;24:429–8.PubMedCrossRefPubMedCentralGoogle Scholar
  102. Silverstein AM. History of immunology: development of the concept of immunologic specificity: II. Cell Immunol. 1982;71:183–95.PubMedCrossRefGoogle Scholar
  103. Sivalingam GN, Sheperd AJ. An analysis of B-cell epitope discontinuity. Mol Immunol. 2012;51:304–9.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Soga S, Kuroda D, Shirai H, Kobori M, Hirayama N. Use of amino acid composition to predict epitope residues of individual antibodies. Protein Eng Des Sel. 2010;23:441–8.PubMedCrossRefPubMedCentralGoogle Scholar
  105. Sperling R, Francus T, Siskind GW. Degeneracy of antibody specificity. J Immunol. 1983;131:882–5.PubMedPubMedCentralGoogle Scholar
  106. Stewart J. Immunoglobulins did not arise in evolution to fight infection. Immunol Today. 1992;13:396–9.PubMedCrossRefPubMedCentralGoogle Scholar
  107. Sundberg EJ, Mariuzza RA. Molecular recognition in antibody-antigen complexes. Adv Protein Chem. 2002;61:119–60.PubMedPubMedCentralGoogle Scholar
  108. Talmage DW. Immunological specificity, unique combinations of selected natural globulins provide an alternative to the classical concept. Science. 1959;129:1643–8.PubMedPubMedCentralGoogle Scholar
  109. Tarlinton DM, Smith KG. Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre. Immunol Today. 2000;21:436–41.PubMedCrossRefGoogle Scholar
  110. Thornton JM, Edwards MS, Taylor WR, Barlow DJ. Location of “continuous” antigenic determinants in the protruding regions of proteins. EMBO J. 1986;5:409–13.PubMedPubMedCentralGoogle Scholar
  111. Thorpe IF, Brooks CL III. Molecular evolution of affinity and flexibility in the immune system. Proc Natl Acad Sci U S A. 2007;104:8821–6.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Timmerman P, Puijk WC, Meloen RH. Functional reconstruction and synthetic mimicry of a conformational epitope using CLIPS technology. J Mol Recognit. 2007;20:283–99.Google Scholar
  113. Tropsha A, Kizer JS, Chaiken IM. Making sense from antisense: a review of experimental data and developing ideas on sense-antisense peptide recognition. J Mol Recognit. 1992;5:43–54.PubMedPubMedCentralGoogle Scholar
  114. Underwood PA. Theoretical considerations of the ability of monoclonal antibodies to detect antigenic differences between closely related variants, with particular reference to heterospecific reactions. J Immunol Methods. 1985;85:295–307.PubMedPubMedCentralGoogle Scholar
  115. Urbain-Vansanten G. Concomitant synthesis, in separate cells, of non-reactive immunoglobulins and specific antibodies after immunization with tobacco mosaic virus. Immunology. 1970;19:783–97.PubMedPubMedCentralGoogle Scholar
  116. Van Regenmortel MHV. Serological studies on naturally occurring strains and chemically induced mutants of tobacco mosaic virus. Virology. 1967;31:467–80.PubMedCrossRefPubMedCentralGoogle Scholar
  117. Van Regenmortel MHV. Serology and immunochemistry of plant viruses. New-York: Academic; 1982. p. 268.Google Scholar
  118. Van Regenmortel MHV. The concept and operational definition of protein epitopes. Philos Trans R Soc Lond B. 1989b;323:451–66.CrossRefGoogle Scholar
  119. Van Regenmortel MHV. From absolute to exquisite specificity. Reflections on the fuzzy nature of species, specificity and antigenic sites. J Immunol Methods. 1998;216:37–48.PubMedPubMedCentralGoogle Scholar
  120. Van Regenmortel MHV. Immunoinformatics may lead to a reappraisal of the nature of B cell epitopes and of the feasibility of synthetic peptide vaccines. J Mol Recognit. 2006;19:183–7.Google Scholar
  121. Van Regenmortel MHV. Synthetic peptide vaccines and the search for neutralization of B cell epitopes. Open Vaccine J. 2009a;2:33–44. Scholar
  122. Van Regenmortel MHV. Requirements for empirical immunogenicity trials, rather than structure-based design, for developing an effective HIV vaccine. Arch Virol. 2012a;157:1–20.CrossRefGoogle Scholar
  123. Van Regenmortel MHV. Basic research in HIV vaccinology is hampered by reductionist thinking. Front Immunol. 2012b;3:194. Scholar
  124. Van Regenmortel MHV. An outdated notion of antibody specificity is one of the major detrimental assumptions of the structure-based reverse vaccinology paradigm, which prevented it from developing an effective HIV-1 vaccine. Front Immunol. 2014b;5:593. Scholar
  125. Van Regenmortel MHV, Hardie G. Immunochemical studies of tobacco mosaic virus--II. Univalent and monogamous bivalent binding of IgG antibody. Immunochemistry. 1976;13:503–7.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Van Regenmortel MHV, Pellequer J-L. Predicting antigenic determinants in proteins: looking for unidimensional solutions to a three-dimensional problem? Pept Res. 1994;7:224–8.Google Scholar
  127. Von Sengbusch P, Wittman HG. Serological and physicochemical properties of the wild strain and two mutants of tobacco mosaic virus with the same amino acid exchange in different positions of the protein chain. Biochem Biophys Res Commun. 1965;18:780–7.Google Scholar
  128. Vyas JM, Van der Veen AG, Ploegh HL. The known unknowns of antigen processing and presentation. Nat Rev Immunol. 2008;8:607–18.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Wabl M, Cascalho M, Steinberg C. Hypermutation in antibody affinity maturation. Curr Opin Immunol. 1999;11:186–9.PubMedCrossRefPubMedCentralGoogle Scholar
  130. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science. 2003;301:1374–7.Google Scholar
  131. Wedemayer GJ, Patten PA, Wang LH, Schultz PG, Stevens R. Structural insights into the evolution of an antibody combining site. Science. 1997;276:1665–9.PubMedCrossRefPubMedCentralGoogle Scholar
  132. Wu TT, Kabat EA. An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J Exp Med. 1970;132:211–50.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Wucherpfennig KW, Allen PM, Celada F, Cohen IR, De Boer R, Garcia KC, Goldstein B, Greenspan R, Hafler D, Hodgkin P, et al. Polyspecificity of T cell and B cell receptor recognition. Semin Immunol. 2007;19:216–24.CrossRefPubMedPubMedCentralGoogle Scholar
  134. Yao B, Zhang L, Liang S, Zhang C. SVMTriP: a method to predict antigenic epitopes using support vector machine to integrate tri-peptide similarity and propensity. PLoS One. 2012;7:e45152.PubMedPubMedCentralCrossRefGoogle Scholar
  135. Yin J, Beuscher AE IV, Andryski SE, Stevens RC, Schultz PG. Structural plasticity and the evolution of antibody affinity and specificity. J Mol Biol. 2003;330:651–6.PubMedPubMedCentralGoogle Scholar
  136. Zhang W, Xiong Y, Zhao M, Zou H, Ye X, Liu J. Prediction of conformational B-cell epitopes from 3D structure by random forests with a distant-based feature. BMC Bioinf. 2011;12:341.CrossRefGoogle Scholar
  137. Zhou ZH, Tzioufas AG, Notkins AL. Properties and function of polyreactive antibodies and polyreactive antigen-binding B cells. J Autoimmun. 2007a;29:219–28.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Zhou ZH, Zhang Y, Hu YF, Wahl LM, Cisar JO, Notkins AL. The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies. Cell Host Microbe. 2007b;1:51–61.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Zhou T, Xu L, Dey B, Hessell AJ, VanRyk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature. 2007c;445:732–7.PubMedPubMedCentralGoogle Scholar
  140. Zhu P, Liu J, Bess J Jr, Chertova E, Lifson JD, Grisé H, Ofek GA, Taylor KA, Roux KH. Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature. 2006;441:847–52.PubMedCrossRefPubMedCentralGoogle Scholar
  141. Zotos D, Tarlington DM. Determining germinal centre B cell fate. Trends Immunol. 2012;33:281–8.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Marc H V Van Regenmortel
    • 1
  1. 1.School of BiotechnologyUniversity of StrasbourgIllkirchFrance

Personalised recommendations