Advertisement

Pattern Recognition by B Cells: The Role of Antigen Repetitiveness Versus Toll-Like Receptors

  • H. J. Hinton
  • A. Jegerlehner
  • M. F. Bachmann
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 319)

Abstract

Viruses induce excellent antibody responses due to several intrinsic features. Their repetitive, organised structure is optimal for the activation of the B cell receptor (BCR), leading to an increased humoral response and a decreased dependence on T cell help. Viruses also trigger Toll-like receptors (TLRs), which in addition to increasing overall Ig levels, drive the switch to the IgG2a isotype. This isotype is more efficient in viral and bacterial clearance and will activate complement, which in turn lowers the threshold of BCR activation. Exploiting these characteristics in vaccine design may help us to create vaccines which are as safe as a recombinant vaccine yet still as effective as a virus in inducing B cell responses.

Keywords

Vesicular Stomatitis Virus Epitope Density Antigen Organisation Antigen Repetitiveness High Epitope Density 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

APC

Antigen-presenting cell

BCR

B cell receptor

Ig

Immunoglobulin

IL

Interleukin

IFN

Interferon

LPS

Lipopolysaccharide

RBC

Red blood cell

RNA

Ribonucleic acid

STAT

Signal transducers and activators of transcription

TD

T cell-dependent

TI

T cell-independent

TLR

Toll-like receptor

VLP

Virus-like particle

VSV

Vesicular stomatitis virus

VSV-G

Glycoprotein of vesicular stomatitis virus

XID

X-linked immunodeficiency

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahearn JM, Fischer MB, Croix D, Goerg S, Ma M, Xia J, Zhou X, Howard RG, Rothstein TL, Carroll MC (1996) Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen Immunity 4:251–262.Google Scholar
  2. Ambuhl PM, Tissot AC, Fulurija A, Maurer P, Nussberger J, Sabat R, Nief V, Schellekens C, Sladko K, Roubicek K, Pfister T, Rettenbacher M, Volk HD, Wagner F, Muller P, Jennings GT, Bachmann MF (2007) A vaccine for hypertension based on virus-like particles: preclinical efficacy and phase I safety and immunogenicity J Hypertens 25:63–72.PubMedCrossRefGoogle Scholar
  3. Bacharier LB, Geha RS (2000) Molecular mechanisms of IgE regulation J Allergy Clin Immunol 105: S547–S558.PubMedCrossRefGoogle Scholar
  4. Bachmann MF, Rohrer UH, Kundig TM, Burki K, Hengartner H, Zinkernagel RM (1993) The influence of antigen organization on B cell responsiveness Science 262:1448–1451.PubMedCrossRefGoogle Scholar
  5. Bachmann MF, Kundig TM, Odermatt B, Hengartner H, Zinkernagel RM (1994) Free recirculation of memory B cells versus antigen-dependent differentiation to antibody-forming cells. J Immunol 153:3386–3397.PubMedGoogle Scholar
  6. Bachmann MF, Hengartner H, Zinkernagel RM (1995) T helper cell-independent neutralizing B cell response against vesicular stomatitis virus: role of antigen patterns in B cell induction? Eur J Immunol 25:3445–3451.PubMedCrossRefGoogle Scholar
  7. Bachmann MF, Zinkernagel RM (1996) The influence of virus structure on antibody responses and virus serotype formation. Immunol Today 17:553–558.PubMedCrossRefGoogle Scholar
  8. Bachmann MF, McKall-Faienza K, Schmits R, Bouchard D, Beach J, Speiser DE, Mak TW, Ohashi PS (1997) Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation. Immunity 7:549–557.PubMedCrossRefGoogle Scholar
  9. Bachmann MF, Zinkernagel RM, Oxenius A (1998) Immune responses in the absence of costimulation: viruses know the trick. J Immunol 161:5791–5794.PubMedGoogle Scholar
  10. Barrington RA, Pozdnyakova O, Zafari MR, Benjamin CD, Carroll MC (2002) B lymphocyte memory: role of stromal cell complement and Fc{gamma}RIIB receptors. J Exp Med 196:1189–1200.PubMedCrossRefGoogle Scholar
  11. Bottger EC, Metzger S, Bitter-Suermann D, Stevenson G, Kleindienst S, Burger R (1986) Impaired humoral immune response in complement C3-deficient guinea pigs: absence of secondary antibody response. Eur J Immunol 16:1231–1235.PubMedCrossRefGoogle Scholar
  12. Carter RH, Fearon DT (1992) CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105–107.PubMedCrossRefGoogle Scholar
  13. Carter RH, Spycher MO, Ng YC, Hoffman R, Fearon DT (1988) Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J Immunol 141:457–463.PubMedGoogle Scholar
  14. Chackerian B, Lowy DR, Schiller JT (1999) Induction of autoantibodies to mouse CCR5 with recombinant papillomavirus particles. Proc Natl Acad Sci U S A 96:2373–2378.PubMedCrossRefGoogle Scholar
  15. Chackerian B, Lowy DR, Schiller JT (2001) Conjugation of a self-antigen to papillomavirus-like particles allows for efficient induction of protective autoantibodies. J Clin Invest 108:415–423.PubMedGoogle Scholar
  16. Chackerian B, Lenz P, Lowy DR, Schiller JT (2002) Determinants of autoantibody induction by conjugated papillomavirus virus-like particles. J Immunol 169:6120–6126.PubMedGoogle Scholar
  17. Coffman RL, Seymour BW, Lebman DA, Hiraki DD, Christiansen JA, Shrader B, Cherwinski HM, Savelkoul HF, Finkelman FD, Bond MW et al (1988) The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol Rev 102:5–28.PubMedCrossRefGoogle Scholar
  18. Cooke MP, Heath AW, Shokat KM, Zeng Y, Finkelman FD, Linsley PS, Howard M, Goodnow CC (1994) Immunoglobulin signal transduction guides the specificity of B cell–T cell interactions and is blocked in tolerant self-reactive B cells. J Exp Med 179:425–438.PubMedCrossRefGoogle Scholar
  19. Coutelier JP, van der Logt JT, Heessen FW, Warnier G, Van Snick J (1987) IgG2a restriction of murine antibodies elicited by viral infections. J Exp Med 165:64–69.PubMedCrossRefGoogle Scholar
  20. Dintzis HM, Dintzis RZ, Vogelstein B (1976) Molecular determinants of immunogenicity: the immunon model of immune response. Proc Natl Acad Sci U S A 73:3671–3675.PubMedCrossRefGoogle Scholar
  21. Dyer MR, Renner WA, Bachmann MF (2006) A second vaccine revolution for the new epidemics of the 21st century. Drug Discov Today 11:1028–1033.PubMedCrossRefGoogle Scholar
  22. Ellman L, Green I, Judge F, Frank MM (1971) In vivo studies in C4-deficient guinea pigs. J Exp Med 134:162–175.PubMedCrossRefGoogle Scholar
  23. Fearon DT, Wong WW (1983) Complement ligand-receptor interactions that mediate biological responses. Annu Rev Immunol 1:243–271.PubMedCrossRefGoogle Scholar
  24. Feldmann M, Basten A (1971) The relationship between antigenic structure and the requirement for thymus-derived cells in the immune response. J Exp Med 134:103–119.PubMedCrossRefGoogle Scholar
  25. Fischer MB, Ma M, Goerg S, Zhou X, Xia J, Finco O, Han S, Kelsoe G, Howard RG, Rothstein TL, Kremmer E, Rosen FS, Carroll MC (1996) Regulation of the B cell response to T-dependent antigens by classical pathway complement. J Immunol 157:549–556.PubMedGoogle Scholar
  26. Fischer MB, Goerg S, Shen L, Prodeus AP, Goodnow CC, Kelsoe G, Carroll MC (1998) Dependence of germinal center B cells on expression of CD21/CD35 for survival. Science 280:582–585.PubMedCrossRefGoogle Scholar
  27. Gatto D, Ruedl C, Odermatt B, Bachmann MF (2004) Rapid response of marginal zone B cells to viral particles J Immunol 173:4308–4316.PubMedGoogle Scholar
  28. Gatto D, Pfister T, Jegerlehner A, Martin SW, Kopf M, Bachmann MF (2005) Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1. J Exp Med 201:993–1005.PubMedCrossRefGoogle Scholar
  29. Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314:1936–1938.PubMedCrossRefGoogle Scholar
  30. Gustavsson S, Kinoshita T, Heyman B (1995) Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction. J Immunol 154:6524–6528.PubMedGoogle Scholar
  31. Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC (1991) Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens Nature 353:765–769.PubMedCrossRefGoogle Scholar
  32. Hebell T, Ahearn JM, Fearon DT (1991) Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 254:102–105.PubMedCrossRefGoogle Scholar
  33. Heyman B, Wiersma EJ, Kinoshita T (1990) In vivo inhibition of the antibody response by a complement receptor-specific monoclonal antibody. J Exp Med 172:665–668.PubMedCrossRefGoogle Scholar
  34. Jackson CG, Ochs HD, Wedgwood RJ (1979) Immune response of a patient with deficiency of the fourth component of complement and systemic lupus erythematosus. N Engl J Med 300:1124–1129.PubMedCrossRefGoogle Scholar
  35. Jacob J, Kelsoe G (1992) In situ studies of the primary immune response to (4-hydroxy-3- nitrophenyl) acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med 176:679–687.PubMedCrossRefGoogle Scholar
  36. Jegerlehner A, Storni T, Lipowsky G, Schmid M, Pumpens P, Bachmann MF (2002a) Regulation of IgG antibody responses by epitope density and CD21-mediated costimulation. Eur J Immunol 32:3305–3314.PubMedCrossRefGoogle Scholar
  37. Jegerlehner A, Tissot A, Lechner F, Sebbel P, Erdmann I, Kundig T, Bachi T, Storni T, Jennings G, Pumpens P, Renner WA, Bachmann MF (2002b) A molecular assembly system that renders antigens of choice highly repetitive for induction of protective B cell responses. Vaccine 20:3104–3112.PubMedCrossRefGoogle Scholar
  38. Jegerlehner A, Maurer P, Bessa J, Hinton HJ, Kopf M, Bachmann MF (2007) TLR9 signaling in B cells determines class switch recombination to IgG2a. J Immunol 178:2415–2420.PubMedGoogle Scholar
  39. Jeurissen A, Ceuppens JL, Bossuyt X (2004) T lymphocyte dependence of the antibody response to ‘T lymphocyte independent type 2’ antigens. Immunology 111:1–7.PubMedCrossRefGoogle Scholar
  40. Johnson DC, Schlesinger MJ, Elson EL (1981) Fluorescence photobleaching recovery measurements reveal differences in envelopment of Sindbis and vesicular stomatitis viruses. Cell 23:423–431.PubMedCrossRefGoogle Scholar
  41. Justewicz DM, Doherty PC, Webster RG (1995) The B-cell response in lymphoid tissue of mice immunized with various antigenic forms of the influenza virus hemagglutinin. J Virol 69:5414–5421.PubMedGoogle Scholar
  42. Kelley JM, Emerson SU, Wagner RR (1972) The glycoprotein of vesicular stomatitis virus is the antigen that gives rise to and reacts with neutralizing antibody. J Virol 10:1231–1235.PubMedGoogle Scholar
  43. Klaus GG, Pepys MB, Kitajima K, Askonas BA (1979) Activation of mouse complement by different classes of mouse antibody. Immunology 38:687–695.PubMedGoogle Scholar
  44. Kopf M, Abel B, Gallimore A, Carroll M, Bachmann MF (2002) Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection. Nat Med 8:373–378.PubMedCrossRefGoogle Scholar
  45. Kundig TM, Senti G, Schnetzler G, Wolf C, Prinz Vavricka BM, Fulurija A, Hennecke F, Sladko K, Jennings GT, Bachmann MF (2006) Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J Allergy Clin Immunol 117:1470–1476.PubMedCrossRefGoogle Scholar
  46. Leclerc C, Charbit A, Martineau P, Deriaud E, Hofnung M (1991) The cellular location of a foreign B cell epitope expressed by recombinant bacteria determines its T cell-independent or T cell-dependent characteristics. J Immunol 147:3545–3552.PubMedGoogle Scholar
  47. Lin L, Gerth AJ, Peng SL (2004) CpG DNA redirects class-switching towards “Th1-like” Ig isotype production via TLR9 and MyD88. Eur J Immunol 34:1483–1487.PubMedCrossRefGoogle Scholar
  48. Liu N, Ohnishi N, Ni L, Akira S, Bacon KB (2003) CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. Nat Immunol 4:687–693.PubMedCrossRefGoogle Scholar
  49. Liu YJ, Zhang J, Lane PJ, Chan EY, MacLennan IC (1991) Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur J Immunol 21:2951–2962.PubMedCrossRefGoogle Scholar
  50. Markine-Goriaynoff D, van der Logt JT, Truyens C, Nguyen TD, Heessen FW, Bigaignon G, Carlier Y, Coutelier JP (2000) IFN-gamma-independent IgG2a production in mice infected with viruses and parasites. Int Immunol 12:223–230.PubMedCrossRefGoogle Scholar
  51. Martin F, Oliver AM, Kearney JF (2001) Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14:617–629.PubMedCrossRefGoogle Scholar
  52. Maurer P, Jennings GT, Willers J, Rohner F, Lindman Y, Roubicek K, Renner WA, Muller P, Bachmann MF (2005) A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity. Eur J Immunol 35:2031–2040.PubMedCrossRefGoogle Scholar
  53. McHeyzer-Williams LJ, McHeyzer-Williams MG (2005) Antigen-specific memory B cell development. Annu Rev Immunol 23:487–513.PubMedCrossRefGoogle Scholar
  54. Melnick JL (1996) Current status of poliovirus infections. Clin Microbiol Rev 9:293–300.PubMedGoogle Scholar
  55. MMWR (1986) Update: influenza activity–United States. MMWR Morb Mortal Wkly Rep 35:249–251.Google Scholar
  56. Mond JJ, Lees A, Snapper CM (1995) T cell-independent antigens type 2. Annu Rev Immunol 13:655–692.PubMedCrossRefGoogle Scholar
  57. Mond JJ, Stein KE, Subbarao B, Paul WE (1979) Analysis of B cell activation requirements with TNP-conjugated polyacrylamide beads. J Immunol 123:239–245.PubMedGoogle Scholar
  58. Nemazee D, Gavin A, Hoebe K, Beutler B (2006) Immunology: Toll-like receptors and antibody responses. Nature 441:E4; discussion E4.Google Scholar
  59. Nimmerjahn F, Ravetch JV (2005) Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science 310:1510–1512.PubMedCrossRefGoogle Scholar
  60. O’Neil KM, Ochs HD, Heller SR, Cork LC, Morris JM, Winkelstein JA (1988) Role of C3 in humoral immunity. Defective antibody production in C3-deficient dogs. J Immunol 140:1939–1945.PubMedGoogle Scholar
  61. Ochs HD, Wedgwood RJ, Frank MM, Heller SR, Hosea SW (1983) The role of complement in the induction of antibody responses. Clin Exp Immunol 53:208–216.PubMedGoogle Scholar
  62. Ochsenbein AF, Pinschewer DD, Odermatt B, Carroll MC, Hengartner H, Zinkernagel RM (1999) Protective T cell-independent antiviral antibody responses are dependent on complement. J Exp Med 190:1165–1174.PubMedCrossRefGoogle Scholar
  63. Parker DC (1993) T cell-dependent B cell activation. Annu Rev Immunol 11:331–360.PubMedGoogle Scholar
  64. Pasare C, Medzhitov R (2005) Control of B-cell responses by Toll-like receptors Nature 438:364–368.PubMedCrossRefGoogle Scholar
  65. Peng SL, Li J, Lin L, Gerth A (2003) The role of T-bet in B cells. Nat Immunol 4:1041; author reply 1041.Google Scholar
  66. Peng SL, Szabo SJ, Glimcher LH (2002) T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci U S A 99:5545–5550.PubMedCrossRefGoogle Scholar
  67. Petri WA Jr, Wagner RR (1979) Reconstitution into liposomes of the glycoprotein of vesicular stomatitis virus by detergent dialysis. J Biol Chem 254:4313–4316.PubMedGoogle Scholar
  68. Rohn TA, Jennings GT, Hernandez M, Grest P, Beck M, Zou Y, Kopf M, Bachmann MF (2006) Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis. Eur J Immunol 36:2857–2867.PubMedCrossRefGoogle Scholar
  69. Roost HP, Bachmann MF, Haag A, Kalinke U, Pliska V, Hengartner H, Zinkernagel RM (1995) Early high-affinity neutralizing anti-viral IgG responses without further overall improvements of affinity. Proc Natl Acad Sci U S A 92:1257–1261.PubMedCrossRefGoogle Scholar
  70. Russell DM, Dembic Z, Morahan G, Miller JF, Burki K, Nemazee D (1991) Peripheral deletion of self-reactive B cells. Nature 354:308–311.PubMedCrossRefGoogle Scholar
  71. Simons K, Helenius A, Leonard K, Sarvas M, Gething MJ (1978) Formation of protein micelles from amphiphilic membrane proteins. Proc Natl Acad Sci U S A 75:5306–5310.PubMedCrossRefGoogle Scholar
  72. Spohn G, Schwarz K, Maurer P, Illges H, Rajasekaran N, Choi Y, Jennings GT, Bachmann MF (2005) Protection against osteoporosis by active immunization with TRANCE/RANKL displayed on virus-like particles. J Immunol 175:6211–6218.PubMedGoogle Scholar
  73. Sung JJ, Lik-Yuen H (2006) HBV-ISS (Dynavax). Curr Opin Mol Ther 8:150–155.PubMedGoogle Scholar
  74. Van den Eertwegh AJ, Noelle RJ, Roy M, Shepherd DM, Aruffo A, Ledbetter JA, Boersma WJ, Claassen E (1993) In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions. J Exp Med 178:1555–1565.PubMedCrossRefGoogle Scholar
  75. Viola A, Lanzavecchia A (1996) T cell activation determined by T cell receptor number and tunable thresholds Science 273:104–106.PubMedCrossRefGoogle Scholar
  76. Vos Q, Lees A, Wu ZQ, Snapper CM, Mond JJ (2000) B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunol Rev 176:154–170.PubMedCrossRefGoogle Scholar
  77. Wickelgren I (2006) Immunology. Mouse studies question importance of toll-like receptors to vaccines. Science 314:1859–1860.PubMedCrossRefGoogle Scholar
  78. Wurster AL, Tanaka T, Grusby MJ (2000) The biology of Stat4 and Stat6. Oncogene 19:2577–2584.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • H. J. Hinton
  • A. Jegerlehner
  • M. F. Bachmann
    • 1
  1. 1.Cytos Biotechnology AGZürich-SchlierenSwitzerland

Personalised recommendations