The Biology of IgE: Molecular Mechanism Restraining Potentially Dangerous High Serum IgE Titres In Vivo

  • Gernot AchatzEmail author
  • Gertrude Achatz-Straussberger
  • Stefan Feichtner
  • Sebastian Koenigsberger
  • Stefan Lenz
  • Doris Peckl-Schmid
  • Nadja Zaborsky
  • Marinus Lamers


Our knowledge about the regulation of the expression of IgE and its biological function is at best limited. We do, however, know that the production of IgE is tightly regulated which is reflected by the fact that the steady-state serum levels of IgE in mice and humans are 3–4 orders of magnitude lower if compared to IgG1, which is an immunoglobulin isotype expressed in response to the same cytokine milieu. What are the rate-limiting steps responsible for this discrepancy? In the following chapter six molecular mechanisms restraining IgE levels will be discussed in detail. The understanding of these mechanisms, combined with the analysis of the biological function of the IgE molecule during an immune response, is the prerequisite for the establishment of new systemic IgE-targeted therapeutic strategies in the future.


Cytoplasmic Tail Antigen Receptor Class Switch Recombination Systemic Anaphylactic Reaction Constant Exon 
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.



Experimental work and publication charges were supported by the Austrian Science Foundation (P19017-B13), the Austrian National Bank (OENB grant: 11710) and the Christian Doppler Laboratory for Allergy Diagnosis and Therapy.


  1. 1.
    Vernersson M, Aveskogh M, Hellman L (2004) Cloning of IgE from the echidna (Tachyglossus aculeatus) and a comparative analysis of epsilon chains from all three extant mammalian lineages. Dev Comp Immunol 28:61–75PubMedGoogle Scholar
  2. 2.
    Kumar S, Hedges SB (1998) A molecular timescale for vertebrate evolution. Nature 392:917–920PubMedGoogle Scholar
  3. 3.
    Warr GW, Magor KE, Higgins DA (1995) IgY: Clues to the origins of modern antibodies. Immunol Today 16:392–398PubMedGoogle Scholar
  4. 4.
    Gould HJ, Sutton BJ, Beavil AJ, Beavil RL, McCloskey N, Coker HA, Fear D, Smurthwaite L (2003) The biology of IGE and the basis of allergic disease. Annu Rev Immunol 21: 579–628PubMedGoogle Scholar
  5. 5.
    Siebenkotten G, Esser C, Wabl M, Radbruch A (1992) The murine IgG1/IgE class switch program. Eur J Immunol 22:1827–1834PubMedGoogle Scholar
  6. 6.
    Vieira P, Rajewsky K (1988) The half-lives of serum immunoglobulins in adult mice. Eur J Immunol 18:313–316PubMedGoogle Scholar
  7. 7.
    Yu P, Kosco-Vilbois M, Richards M, Kohler G, Lamers MC (1994) Negative feedback regulation of IgE synthesis by murine CD23. Nature 369:753–756PubMedGoogle Scholar
  8. 8.
    Achatz G, Luger E, Geisberger R, Achatz-Straussberger G, Breitenbach M, Lamers M (2001) The IgE antigen receptor: a key regulator for the production of IgE antibodies. Int Arch Allergy Immunol 124:31–34PubMedGoogle Scholar
  9. 9.
    Achatz G, Nitschke L, Lamers MC (1997) Effect of transmembrane and cytoplasmic domains of IgE on the IgE response. Science 276:409–411PubMedGoogle Scholar
  10. 10.
    Karnowski A, Achatz-Straussberger G, Klockenbusch C, Achatz G, Lamers MC (2006) Inefficient processing of mRNA for the membrane form of IgE is a genetic mechanism to limit recruitment of IgE-secreting cells. Eur J Immunol 36:1917–1925PubMedGoogle Scholar
  11. 11.
    Luger E, Lamers M, Achatz-Straussberger G, Geisberger R, Infuhr D, Breitenbach M, Crameri R, Achatz G (2001) Somatic diversity of the immunoglobulin repertoire is controlled in an isotype-specific manner. Eur J Immunol 31:2319–2330PubMedGoogle Scholar
  12. 12.
    Achatz-Straußberger G, Königsberger S, Karnowsky A, Lamers M, Achatz G (2007). Elevated histamine release in chimeric IgE/IgG1 antigen receptor knock-in mice. Allergy Clin Immunol Int Hogrefe & Huber Supp 2:121–123Google Scholar
  13. 13.
    Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, Davidson NO, Honjo T (1999) Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem 274: 18470–18476PubMedGoogle Scholar
  14. 14.
    Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563PubMedGoogle Scholar
  15. 15.
    Petersen-Mahrt SK, Harris RS, Neuberger MS (2002) AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418:99–103PubMedGoogle Scholar
  16. 16.
    Di Noia J, Neuberger MS (2002) Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419:43–48PubMedGoogle Scholar
  17. 17.
    Kenter AL (2005) Class switch recombination: an emerging mechanism. Curr Top Microbiol Immunol 290:171–199PubMedGoogle Scholar
  18. 18.
    Durandy A, Taubenheim N, Peron S, Fischer A (2007) Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv Immunol 94:275–306PubMedGoogle Scholar
  19. 19.
    Linehan LA, Warren WD, Thompson PA, Grusby MJ, Berton MT (1998) STAT6 is required for IL-4-induced germline Ig gene transcription and switch recombination. J Immunol 161:302–310PubMedGoogle Scholar
  20. 20.
    Xu L, Gorham B, Li SC, Bottaro A, Alt FW, Rothman P (1993) Replacement of germ-line epsilon promoter by gene targeting alters control of immunoglobulin heavy chain class switching. Proc Natl Acad Sci USA 90:3705–3709PubMedGoogle Scholar
  21. 21.
    Yoshikawa K, Okazaki IM, Eto T, Kinoshita K, Muramatsu M, Nagaoka H, Honjo T (2002) AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296:2033–2036PubMedGoogle Scholar
  22. 22.
    Di Noia JM, Neuberger MS (2007) Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 76:1–22PubMedGoogle Scholar
  23. 23.
    Rothman P, Li SC, Gorham B, Glimcher L, Alt F, Boothby M (1991) Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. Mol Cell Biol 11:5551–5561PubMedGoogle Scholar
  24. 24.
    Grewal IS, Foellmer HG, Grewal KD, Xu J, Hardardottir F, Baron JL, Janeway CA, Jr., Flavell RA (1996) Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273:1864–1867PubMedGoogle Scholar
  25. 25.
    Claudio E, Brown K, Park S, Wang H, Siebenlist U (2002) BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 3:958–965PubMedGoogle Scholar
  26. 26.
    de Vries JE, Punnonen J, Cocks BG, de Waal Malefyt R, Aversa G (1993) Regulation of the human IgE response by IL4 and IL13. Res Immunol 144:597–601PubMedGoogle Scholar
  27. 27.
    Thienes CP, De Monte L, Monticelli S, Busslinger M, Gould HJ, Vercelli D (1997) The transcription factor B cell-specific activator protein (BSAP) enhances both IL-4- and CD40-mediated activation of the human epsilon germline promoter. J Immunol 158:5874–5882PubMedGoogle Scholar
  28. 28.
    Agresti A, Vercelli D (2002) c-Rel is a selective activator of a novel IL-4/CD40 responsive element in the human Ig gamma4 germline promoter. Mol Immunol 38:849–859PubMedGoogle Scholar
  29. 29.
    Shen CH, Stavnezer J (2001) Activation of the mouse Ig germline epsilon promoter by IL-4 is dependent on AP-1 transcription factors. J Immunol 166:411–423PubMedGoogle Scholar
  30. 30.
    Harris MB, Chang CC, Berton MT, Danial NN, Zhang J, Kuehner D, Ye BH, Kvatyuk M, Pandolfi PP, Cattoretti G, Dalla-Favera R, Rothman PB (1999) Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching. Mol Cell Biol 19:7264–7275PubMedGoogle Scholar
  31. 31.
    Sugai M, Gonda H, Kusunoki T, Katakai T, Yokota Y, Shimizu A (2003) Essential role of Id2 in negative regulation of IgE class switching. Nat Immunol 4:25–30PubMedGoogle Scholar
  32. 32.
    Schoetz U, Cervelli M, Wang YD, Fiedler P, Buerstedde JM (2006) E2A expression stimulates Ig hypermutation. J Immunol 177:395–400PubMedGoogle Scholar
  33. 33.
    Nambu Y, Sugai M, Gonda H, Lee CG, Katakai T, Agata Y, Yokota Y, Shimizu A (2003) Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302:2137–2140PubMedGoogle Scholar
  34. 34.
    Strom L, Lundgren M, Severinson E (2003) Binding of Ikaros to germline Ig heavy chain gamma1 and epsilon promoters. Mol Immunol 39:771–782PubMedGoogle Scholar
  35. 35.
    Schaffer A, Kim EC, Wu X, Zan H, Testoni L, Salamon S, Cerutti A, Casali P (2003) Selective inhibition of class switching to IgG and IgE by recruitment of the HoxC4 and Oct-1 homeodomain proteins and Ku70/Ku86 to newly identified ATTT cis-elements. J Biol Chem 278:23141–23150PubMedGoogle Scholar
  36. 36.
    Kim EC, Edmonston CR, Wu X, Schaffer A, Casali P (2004) The HoxC4 homeodomain protein mediates activation of the immunoglobulin heavy chain 3' hs1,2 enhancer in human B cells. Relevance to class switch DNA recombination. J Biol Chem 279:42258–42269PubMedGoogle Scholar
  37. 37.
    Laurencikiene J, Deveikaite V, Severinson E (2001) HS1,2 enhancer regulation of germline epsilon and gamma2b promoters in murine B lymphocytes: evidence for specific promoter-enhancer interactions. J Immunol 167:3257–3265PubMedGoogle Scholar
  38. 38.
    Laurencikiene J, Tamosiunas V, Severinson E (2007) Regulation of epsilon germline transcription and switch region mutations by IgH locus 3' enhancers in transgenic mice. Blood 109:159–167PubMedGoogle Scholar
  39. 39.
    Manis JP, van der Stoep N, Tian M, Ferrini R, Davidson L, Bottaro A, Alt FW (1998) Class switching in B cells lacking 3ʹ immunoglobulin heavy chain enhancers. J Exp Med 188:1421-1431PubMedGoogle Scholar
  40. 40.
    Hein K, Lorenz MG, Siebenkotten G, Petry K, Christine R, Radbruch A (1998) Processing of switch transcripts is required for targeting of antibody class switch recombination. J Exp Med 188:2369–2374PubMedGoogle Scholar
  41. 41.
    Mao CS, Stavnezer J (2001) Differential regulation of mouse germline Ig gamma 1 and epsilon promoters by IL-4 and CD40. J Immunol 167:1522–1534PubMedGoogle Scholar
  42. 42.
    Fear DJ, McCloskey N, OʹConnor B, Felsenfeld G, Gould HJ (2004) Transcription of Ig germline genes in single human B cells and the role of cytokines in isotype determination. J Immunol 173:4529–4538PubMedGoogle Scholar
  43. 43.
    Selsing E (2006) Ig class switching: targeting the recombinational mechanism. Curr Opin Immunol 18:249–254PubMedGoogle Scholar
  44. 44.
    Zarrin AA, Alt FW, Chaudhuri J, Stokes N, Kaushal D, Du Pasquier L, Tian M (2004) An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nat Immunol 5:1275–1281PubMedGoogle Scholar
  45. 45.
    Larson ED, Duquette ML, Cummings WJ, Streiff RJ, Maizels N (2005) MutSalpha binds to and promotes synapsis of transcriptionally activated immunoglobulin switch regions. Curr Biol 15:470–474PubMedGoogle Scholar
  46. 46.
    Kaminski DA, Stavnezer J (2007) Stimuli that enhance IgA class switching increase histone 3 acetylation at S alpha, but poorly stimulate sequential switching from IgG2b. Eur J Immunol 37:240–251PubMedGoogle Scholar
  47. 47.
    Wang L, Whang N, Wuerffel R, Kenter AL (2006) AID-dependent histone acetylation is detected in immunoglobulin S regions. J Exp Med 203:215–226PubMedGoogle Scholar
  48. 48.
    Bradley SP, Kaminski DA, Peters AH, Jenuwein T, Stavnezer J (2006) The histone methyltransferase Suv39h1 increases class switch recombination specifically to IgA. J Immunol 177:1179–1188PubMedGoogle Scholar
  49. 49.
    Zarrin AA, Tian M, Wang J, Borjeson T, Alt FW (2005) Influence of switch region length on immunoglobulin class switch recombination. Proc Natl Acad Sci USA 102:2466–2470PubMedGoogle Scholar
  50. 50.
    Shinkura R, Ito S, Begum NA, Nagaoka H, Muramatsu M, Kinoshita K, Sakakibara Y, Hijikata H, Honjo T (2004) Separate domains of AID are required for somatic hypermutation and class-switch recombination. Nat Immunol 5:707–712PubMedGoogle Scholar
  51. 51.
    Chaudhuri J, Khuong C, Alt FW (2004) Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430:992–998PubMedGoogle Scholar
  52. 52.
    Basu U, Chaudhuri J, Alpert C, Dutt S, Ranganath S, Li G, Schrum JP, Manis JP, Alt FW (2005) The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438:508–511PubMedGoogle Scholar
  53. 53.
    Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, Ikebe D, Yamamoto M, Igarashi K (2004) The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429:566–571PubMedGoogle Scholar
  54. 54.
    Borggrefe T, Keshavarzi S, Gross B, Wabl M, Jessberger R (2001) Impaired IgE response in SWAP-70-deficient mice. Eur J Immunol 31:2467–2475PubMedGoogle Scholar
  55. 55.
    Buckley RH, Wray BB, Belmaker EZ (1972) Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics 49:59–70PubMedGoogle Scholar
  56. 56.
    Davis SD, Schaller J, Wedgwood RJ (1966) Jobʹs Syndrome. Recurrent, “cold”, staphylococcal abscesses. Lancet 1:1013–1015PubMedGoogle Scholar
  57. 57.
    Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O’Connell AC, Puck JM (1999) Hyper-IgE syndrome with recurrent infections – an autosomal dominant multisystem disorder. N Engl J Med 340:692–702PubMedGoogle Scholar
  58. 58.
    Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schaffer AA, Puck JM, Grimbacher B (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357:1608–1619PubMedGoogle Scholar
  59. 59.
    Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H (2007) Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448:1058–1062PubMedGoogle Scholar
  60. 60.
    de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, von Bernuth H, Samarina A, Janniere L, Fieschi C, Stephan JL, Boileau C, Lyonnet S, Jondeau G, Cormier-Daire V, Le Merrer M, Hoarau C, Lebranchu Y, Lortholary O, Chandesris MO, Tron F, Gambineri E, Bianchi L, Rodriguez-Gallego C, Zitnik SE, Vasconcelos J, Guedes M, Vitor AB, Marodi L, Chapel H, Reid B, Roifman C, Nadal D, Reichenbach J, Caragol I, Garty BZ, Dogu F, Camcioglu Y, Gulle S, Sanal O, Fischer A, Abel L, Stockinger B, Picard C, Casanova JL (2008) Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med 205:1543–1550PubMedGoogle Scholar
  61. 61.
    Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O’Shea J, Holland SM, Paul WE, Douek DC (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773–776PubMedGoogle Scholar
  62. 62.
    Schindler C, Plumlee C (2008) Inteferons pen the JAK-STAT pathway. Semin Cell Dev Biol 122:401–408Google Scholar
  63. 63.
    Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse HC, 3rd, Liu C, Schwartzberg PL, Leonard WJ (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298:1630–1634PubMedGoogle Scholar
  64. 64.
    Kishida T, Hiromura Y, Shin-Ya M, Asada H, Kuriyama H, Sugai M, Shimizu A, Yokota Y, Hama T, Imanishi J, Hisa Y, Mazda O (2007) IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice. J Immunol 179:8554–8561PubMedGoogle Scholar
  65. 65.
    Haba S, Ovary Z, Nisonoff A (1985) Clearance of IgE from serum of normal and hybridoma-bearing mice. J Immunol 134:3291–3297PubMedGoogle Scholar
  66. 66.
    Hirano T, Hom C, Ovary Z (1983) Half-life of murine IgE antibodies in the mouse. Int Arch Allergy Appl Immunol 71:182–184PubMedGoogle Scholar
  67. 67.
    Hanashiro K, Tokeshi Y, Nakasone T, Sunagawa M, Nakamura M, Kosugi T (2001) Analysis of IgE turnover in non-sensitized and sensitized rats. Mediators Inflamm 10:217–221PubMedGoogle Scholar
  68. 68.
    Waldmann TA, Iio A, Ogawa M, McIntyre OR, Strober W (1976) The metabolism of IgE. Studies in normal individuals and in a patient with IgE myeloma. J Immunol 117: 1139–1144PubMedGoogle Scholar
  69. 69.
    Brambell FW (1966) The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet 2:1087–1093PubMedGoogle Scholar
  70. 70.
    Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, Petkova S, Avanessian L, Choi EY, Shaffer DJ, Eden PA, Anderson CL (2003) The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol 170:3528–3533PubMedGoogle Scholar
  71. 71.
    Lu W, Zhao Z, Zhao Y, Yu S, Zhao Y, Fan B, Kacskovics I, Hammarstrom L, Li N (2007) Over-expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice. Immunology 19:311–318Google Scholar
  72. 72.
    Simister NE, Mostov KE (1989) An Fc receptor structurally related to MHC class I antigens. Nature 337:184–187PubMedGoogle Scholar
  73. 73.
    Ahouse JJ, Hagerman CL, Mittal P, Gilbert DJ, Copeland NG, Jenkins NA, Simister NE (1993) Mouse MHC class I-like Fc receptor encoded outside the MHC. J Immunol 151:6076–6088PubMedGoogle Scholar
  74. 74.
    Sutton BJ, Gould HJ (1993) The human IgE network. Nature 366:421–428PubMedGoogle Scholar
  75. 75.
    Yokota A, Kikutani H, Tanaka T, Sato R, Barsumian EL, Suemura M, Kishimoto T (1988) Two species of human Fc epsilon receptor II (Fc epsilon RII/CD23): tissue-specific and IL-4-specific regulation of gene expression. Cell 55:611–618PubMedGoogle Scholar
  76. 76.
    Delespesse G, Sarfati M, Wu CY, Fournier S, Letellier M (1992) The low-affinity receptor for IgE. Immunol Rev 125:77–97PubMedGoogle Scholar
  77. 77.
    Delespesse G, Suter U, Mossalayi D, Bettler B, Sarfati M, Hofstetter H, Kilcherr E, Debre P, Dalloul A (1991) Expression, structure, and function of the CD23 antigen. Adv Immunol 49:149–191PubMedGoogle Scholar
  78. 78.
    Maeda K, Burton GF, Padgett DA, Conrad DH, Huff TF, Masuda A, Szakal AK, Tew JG (1992) Murine follicular dendritic cells and low affinity Fc receptors for IgE (Fc epsilon RII). J Immunol 148:2340–2347PubMedGoogle Scholar
  79. 79.
    Rao M, Lee WT, Conrad DH (1987) Characterization of a monoclonal antibody directed against the murine B lymphocyte receptor for IgE. J Immunol 138:1845–1851PubMedGoogle Scholar
  80. 80.
    Sukumar S, Conrad DH, Szakal AK, Tew JG (2006) Differential T cell-mediated regulation of CD23 (Fc epsilonRII) in B cells and follicular dendritic cells. J Immunol 176:4811–4817PubMedGoogle Scholar
  81. 81.
    Conrad DH (1990) Fc epsilon RII/CD23: the low affinity receptor for IgE. Annu Rev Immunol 8:623–645PubMedGoogle Scholar
  82. 82.
    Gould H, Sutton B, Edmeades R, Beavil A (1991) CD23/Fc epsilon RII: C-type lectin membrane protein with a split personality? Monogr Allergy 29:28–49PubMedGoogle Scholar
  83. 83.
    Chretien I, Helm BA, Marsh PJ, Padlan EA, Wijdenes J, Banchereau J (1988) A monoclonal anti-IgE antibody against an epitope (amino acids 367–376) in the CH3 domain inhibits IgE binding to the low affinity IgE receptor (CD23). J Immunol 141:3128–3134PubMedGoogle Scholar
  84. 84.
    Richards ML, Katz DH (1990) The binding of IgE to murine Fc epsilon RII is calcium-dependent but not inhibited by carbohydrate. J Immunol 144:2638–2646PubMedGoogle Scholar
  85. 85.
    Kilmon MA, Shelburne AE, Chan-Li Y, Holmes KL, Conrad DH (2004) CD23 trimers are preassociated on the cell surface even in the absence of its ligand, IgE. J Immunol 172: 1065–1073PubMedGoogle Scholar
  86. 86.
    Dierks SE, Bartlett WC, Edmeades RL, Gould HJ, Rao M, Conrad DH (1993) The oligomeric nature of the murine Fc epsilon RII/CD23. Implications for function. J Immunol 150:2372–2382PubMedGoogle Scholar
  87. 87.
    Weskamp G, Ford JW, Sturgill J, Martin S, Docherty AJ, Swendeman S, Broadway N, Hartmann D, Saftig P, Umland S, Sehara-Fujisawa A, Black RA, Ludwig A, Becherer JD, Conrad DH, Blobel CP (2006) ADAM10 is a principal ‘sheddase’ of the low-affinity immunoglobulin E receptor CD23. Nat Immunol 7:1293–1298PubMedGoogle Scholar
  88. 88.
    Lemieux GA, Blumenkron F, Yeung N, Zhou P, Williams J, Grammer AC, Petrovich R, Lipsky PE, Moss ML, Werb Z (2007) The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10. J Biol Chem 282:14836–14844PubMedGoogle Scholar
  89. 89.
    Bartlett WC, Kelly AE, Johnson CM, Conrad DH (1995) Analysis of murine soluble Fc epsilon RII sites of cleavage and requirements for dual-affinity interaction with IgE. J Immunol 154:4240–4246PubMedGoogle Scholar
  90. 90.
    Stief A, Texido G, Sansig G, Eibel H, Le Gros G, van der Putten H (1994) Mice deficient in CD23 reveal its modulatory role in IgE production but no role in T and B cell development. J Immunol 152:3378–3390PubMedGoogle Scholar
  91. 91.
    Getahun A, Hjelm F, Heyman B (2005) IgE enhances antibody and T cell responses in vivo via CD23+ B cells. J Immunol 175:1473–1482PubMedGoogle Scholar
  92. 92.
    Texido G, Eibel H, Le Gros G, van der Putten H (1994) Transgene CD23 expression on lymphoid cells modulates IgE and IgG1 responses. J Immunol 153:3028–3042PubMedGoogle Scholar
  93. 93.
    Payet M, Conrad DH (1999) IgE regulation in CD23 knockout and transgenic mice. Allergy 54:1125–1129PubMedGoogle Scholar
  94. 94.
    Cho SW, Kilmon MA, Studer EJ, van der Putten H, Conrad DH (1997) B cell activation and Ig, especially IgE, production is inhibited by high CD23 levels in vivo and in vitro. Cell Immunol 180:36–46PubMedGoogle Scholar
  95. 95.
    Carlsson F, Hjelm F, Conrad DH, Heyman B (2007) IgE enhances specific antibody and T-cell responses in mice overexpressing CD23. Scand J Immunol 66:261–270PubMedGoogle Scholar
  96. 96.
    Lewis G, Rapsomaniki E, Bouriez T, Crockford T, Ferry H, Rigby R, Vyse T, Lambe T, Cornall R (2004) Hyper IgE in New Zealand black mice due to a dominant-negative CD23 mutation. Immunogenetics 56:564–571PubMedGoogle Scholar
  97. 97.
    Flores-Romo L, Shields J, Humbert Y, Graber P, Aubry JP, Gauchat JF, Ayala G, Allet B, Chavez M, Bazin H (1993) Inhibition of an in vivo antigen-specific IgE response by antibodies to CD23. Science 261:1038–1041PubMedGoogle Scholar
  98. 98.
    Kilmon MA, Ghirlando R, Strub MP, Beavil RL, Gould HJ, Conrad DH (2001) Regulation of IgE production requires oligomerization of CD23. J Immunol 167:3139–3145PubMedGoogle Scholar
  99. 99.
    Nakamura T, Kloetzer WS, Brams P, Hariharan K, Chamat S, Cao X, LaBarre MJ, Chinn PC, Morena RA, Shestowsky WS, Li YP, Chen A, Reff ME (2000) In vitro IgE inhibition in B cells by anti-CD23 monoclonal antibodies is functionally dependent on the immunoglobulin Fc domain. Int J Immunopharmacol 22:131–141PubMedGoogle Scholar
  100. 100.
    Sherr E, Macy E, Kimata H, Gilly M, Saxon A (1989) Binding the low affinity Fc epsilon R on B cells suppresses ongoing human IgE synthesis. J Immunol 142:481–489PubMedGoogle Scholar
  101. 101.
    Munoz O, Brignone C, Grenier-Brossette N, Bonnefoy JY, Cousin JL (1998) Binding of anti-CD23 monoclonal antibody to the leucine zipper motif of FcepsilonRII/CD23 on B cell membrane promotes its proteolytic cleavage. Evidence for an effect on the oligomer/monomer equilibrium. J Biol Chem 273:31795–31800PubMedGoogle Scholar
  102. 102.
    Wakai M, Pasley P, Sthoeger ZM, Posnett DN, Brooks R, Hashimoto S, Chiorazzi N (1993) Anti-CD23 monoclonal antibodies: comparisons of epitope specificities and modulating capacities for IgE binding and production. Hybridoma 12:25–43PubMedGoogle Scholar
  103. 103.
    Ford JW, Kilmon MA, Haas KM, Shelburne AE, Chan-Li Y, Conrad DH (2006) In vivo murine CD23 destabilization enhances CD23 shedding and IgE synthesis. Cell Immunol 243:107–117PubMedGoogle Scholar
  104. 104.
    Aubry JP, Pochon S, Graber P, Jansen KU, Bonnefoy JY (1992) CD21 is a ligand for CD23 and regulates IgE production. Nature 358:505–507PubMedGoogle Scholar
  105. 105.
    Christie G, Barton A, Bolognese B, Buckle DR, Cook RM, Hansbury MJ, Harper GP, Marshall LA, McCord ME, Moulder K, Murdock PR, Seal SM, Spackman VM, Weston BJ, Mayer RJ (1997) IgE secretion is attenuated by an inhibitor of proteolytic processing of CD23 (Fc epsilonRII). Eur J Immunol 27:3228–3235PubMedGoogle Scholar
  106. 106.
    McCloskey N, Hunt J, Beavil RL, Jutton MR, Grundy GJ, Girardi E, Fabiane SM, Fear DJ, Conrad DH, Sutton BJ, Gould HJ (2007) Soluble CD23 Monomers Inhibit and Oligomers Stimulate IGE Synthesis in Human B Cells. J Biol Chem 282:24083–24091PubMedGoogle Scholar
  107. 107.
    Hibbert RG, Teriete P, Grundy GJ, Beavil RL, Reljic R, Holers VM, Hannan JP, Sutton BJ, Gould HJ, McDonnell JM (2005) The structure of human CD23 and its interactions with IgE and CD21. J Exp Med 202:751–760PubMedGoogle Scholar
  108. 108.
    Gauld SB, Benschop RJ, Merrell KT, Cambier JC (2005) Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat Immunol 6:1160–1167PubMedGoogle Scholar
  109. 109.
    McHeyzer-Williams LJ, Malherbe LP, McHeyzer-Williams MG (2006) Checkpoints in memory B-cell evolution. Immunol Rev 211:255–268PubMedGoogle Scholar
  110. 110.
    Grupp SA, Campbell K, Mitchell RN, Cambier JC, Abbas AK (1993) Signaling-defective mutants of the B lymphocyte antigen receptor fail to associate with Ig-alpha and Ig-beta/gamma. J Biol Chem 268:25776–25779PubMedGoogle Scholar
  111. 111.
    Shaw AC, Mitchell RN, Weaver YK, Campos-Torres J, Abbas AK, Leder P (1990) Mutations of immunoglobulin transmembrane and cytoplasmic domains: effects on intracellular signaling and antigen presentation. Cell 63:381–392PubMedGoogle Scholar
  112. 112.
    Batista FD, Efremov DG, Burrone OR (1995) Characterization and expression of alternatively spliced IgE heavy chain transcripts produced by peripheral blood lymphocytes. J Immunol 154:209–218PubMedGoogle Scholar
  113. 113.
    Peng C, Davis FM, Sun LK, Liou RS, Kim YW, Chang TW (1992) A new isoform of human membrane-bound IgE. J Immunol 148:129–136PubMedGoogle Scholar
  114. 114.
    Zhang K, Saxon A, Max EE (1992) Two unusual forms of human immunoglobulin E encoded by alternative RNA splicing of epsilon heavy chain membrane exons. J Exp Med 176:233–243PubMedGoogle Scholar
  115. 115.
    Poggianella M, Bestagno M, Burrone OR (2006) The extracellular membrane-proximal domain of human membrane IgE controls apoptotic signaling of the B cell receptor in the mature B cell line A20. J Immunol 177:3597–3605PubMedGoogle Scholar
  116. 116.
    Batista FD, Anand S, Presani G, Efremov DG, Burrone OR (1996) The two membrane isoforms of human IgE assemble into functionally distinct B cell antigen receptors. J Exp Med 184:2197–2205PubMedGoogle Scholar
  117. 117.
    Venkitaraman AR, Williams GT, Dariavach P, Neuberger MS (1991) The B-cell antigen receptor of the five immunoglobulin classes. Nature 352:777–781PubMedGoogle Scholar
  118. 118.
    Lam KP, Kuhn R, Rajewsky K (1997) In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90:1073–1083PubMedGoogle Scholar
  119. 119.
    Patel KJ, Neuberger MS (1993) Antigen presentation by the B cell antigen receptor is driven by the alpha/beta sheath and occurs independently of its cytoplasmic tyrosines. Cell 74: 939–946PubMedGoogle Scholar
  120. 120.
    Kaisho T, Schwenk F, Rajewsky K (1997) The roles of gamma 1 heavy chain membrane expression and cytoplasmic tail in IgG1 responses. Science 276:412–415PubMedGoogle Scholar
  121. 121.
    Sato M, Adachi T, Tsubata T (2007) Augmentation of signaling through BCR containing IgE but not that containing IgA due to lack of CD22-mediated signal regulation. J Immunol 178:2901–2907PubMedGoogle Scholar
  122. 122.
    Wakabayashi C, Adachi T, Wienands J, Tsubata T (2002) A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 298:2392–2395PubMedGoogle Scholar
  123. 123.
    Ravetch JV, Lanier LL (2000) Immune inhibitory receptors. Science 290:84–89PubMedGoogle Scholar
  124. 124.
    Oberndorfer I, Schmid D, Geisberger R, Achatz-Straussberger G, Crameri R, Lamers M, Achatz G (2006) HS1-associated protein X-1 interacts with membrane-bound IgE: impact on receptor-mediated internalization. J Immunol 177:1139–1145PubMedGoogle Scholar
  125. 125.
    Erazo A, Kutchukhidze N, Leung M, Christ AP, Urban JF, Jr., Curotto de Lafaille MA, Lafaille JJ (2007) Unique maturation program of the IgE response in vivo. Immunity 26:191–203PubMedGoogle Scholar
  126. 126.
    Shapiro-Shelef M, Lin KI, McHeyzer-Williams LJ, Liao J, McHeyzer-Williams MG, Calame K (2003) Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19:607–620PubMedGoogle Scholar
  127. 127.
    Kelly KA, Butch AW (2007) Antigen-specific immunoglobulin E+ B cells are preferentially localized within germinal centres. Immunology 120:345–353PubMedGoogle Scholar
  128. 128.
    Auci DL, Chice SM, Heusser C, Athanassiades TJ, Durkin HG (1992) Origin and fate of IgE-bearing lymphocytes. II. Gut-associated lymphoid tissue as sites of first appearance of IgE-bearing B lymphocytes and hapten-specific IgE antibody-forming cells in mice immunized with benzylpenicilloyl-keyhole limpet hemocyanin by various routes: relation to asialo GM1 ganglioside+ cells and IgE/CD23 immune complexes. J Immunol 149:2241–2248PubMedGoogle Scholar
  129. 129.
    Wang CH, Richards EM, Block RD, Lezcano EM, Gutierrez R (1998) Early induction and augmentation of parasitic antigen-specific antibody-producing B lymphocytes in the non-Peyerʹs patch region of the small intestine. Front Biosci 3:A58–65PubMedGoogle Scholar
  130. 130.
    Galli G, Guise J, Tucker PW, Nevins JR (1988) Poly(A) site choice rather than splice site choice governs the regulated production of IgM heavy-chain RNAs. Proc Natl Acad Sci USA 85:2439–2443PubMedGoogle Scholar
  131. 131.
    Gerster T, Picard D, Schaffner W (1986) During B-cell differentiation enhancer activity and transcription rate of immunoglobulin heavy chain genes are high before mRNA accumulation. Cell 45:45–52PubMedGoogle Scholar
  132. 132.
    Phillips C, Jung S, Gunderson SI (2001) Regulation of nuclear poly(A) addition controls the expression of immunoglobulin M secretory mRNA. EMBO J 20:6443–6452PubMedGoogle Scholar
  133. 133.
    Christofori G, Keller W (1988) 3ʹ cleavage and polyadenylation of mRNA precursors in vitro requires a poly(A) polymerase, a cleavage factor, and a snRNP. Cell 54:875–889PubMedGoogle Scholar
  134. 134.
    Gilmartin GM, Nevins JR (1989) An ordered pathway of assembly of components required for polyadenylation site recognition and processing. Genes Dev 3:2180–2190PubMedGoogle Scholar
  135. 135.
    Takagaki Y, Ryner LC, Manley JL (1989) Four factors are required for 3ʹ-end cleavage of pre-mRNAs. Genes Dev 3:1711–1724PubMedGoogle Scholar
  136. 136.
    Takagaki Y, Manley JL, MacDonald CC, Wilusz J, Shenk T (1990) A multisubunit factor, CstF, is required for polyadenylation of mammalian pre-mRNAs. Genes Dev 4:2112–2120PubMedGoogle Scholar
  137. 137.
    Murthy KG, Manley JL (1995) The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3ʹ-end formation. Genes Dev 9:2672–2683PubMedGoogle Scholar
  138. 138.
    Murthy KG, Manley JL (1992) Characterization of the multisubunit cleavage-polyadenylation specificity factor from calf thymus. J Biol Chem 267:14804–14811PubMedGoogle Scholar
  139. 139.
    Keller W, Bienroth S, Lang KM, Christofori G (1991) Cleavage and polyadenylation factor CPF specifically interacts with the pre-mRNA 3ʹ processing signal AAUAAA. Embo J 10:4241–4249PubMedGoogle Scholar
  140. 140.
    Beyer K, Dandekar T, Keller W (1997) RNA ligands selected by cleavage stimulation factor contain distinct sequence motifs that function as downstream elements in 3'-end processing of pre-mRNA. J Biol Chem 272:26769–26779PubMedGoogle Scholar
  141. 141.
    Takagaki Y, Manley JL (1997) RNA recognition by the human polyadenylation factor CstF. Mol Cell Biol 17:3907–3914PubMedGoogle Scholar
  142. 142.
    MacDonald CC, Wilusz J, Shenk T (1994) The 64-kilodalton subunit of the CstF polyadenylation factor binds to pre-mRNAs downstream of the cleavage site and influences cleavage site location. Mol Cell Biol 14:6647–6654PubMedGoogle Scholar
  143. 143.
    Wahle E, Lustig A, Jeno P, Maurer P (1993) Mammalian poly(A)-binding protein II. Physical properties and binding to polynucleotides. J Biol Chem 268:2937–2945PubMedGoogle Scholar
  144. 144.
    Wahle E, Keller W (1996) The biochemistry of polyadenylation. Trends Biochem Sci 21:247–250PubMedGoogle Scholar
  145. 145.
    Raabe T, Bollum FJ, Manley JL (1991) Primary structure and expression of bovine poly(A) polymerase. Nature 353:229–234PubMedGoogle Scholar
  146. 146.
    Moreira A, Takagaki Y, Brackenridge S, Wollerton M, Manley JL, Proudfoot NJ (1998) The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3' end formation by two distinct mechanisms. Genes Dev 12:2522–2534PubMedGoogle Scholar
  147. 147.
    Takagaki Y, Seipelt RL, Peterson ML, Manley JL (1996) The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell 87:941–952PubMedGoogle Scholar
  148. 148.
    Galli G, Guise JW, McDevitt MA, Tucker PW, Nevins JR (1987) Relative position and strengths of poly(A) sites as well as transcription termination are critical to membrane versus secreted mu-chain expression during B-cell development. Genes Dev 1:471–481PubMedGoogle Scholar
  149. 149.
    Guise JW, Lim PL, Yuan D, Tucker PW (1988) Alternative expression of secreted and membrane forms of immunoglobulin mu-chain is regulated by transcriptional termination in stable plasmacytoma transfectants. J Immunol 140:3988–3994PubMedGoogle Scholar
  150. 150.
    Yan DH, Weiss EA, Nevins JR (1995) Identification of an activity in B-cell extracts that selectively impairs the formation of an immunoglobulin mu s poly(A) site processing complex. Mol Cell Biol 15:1901–1906PubMedGoogle Scholar
  151. 151.
    Flaspohler JA, Milcarek C (1990) Myelomas and lymphomas expressing the Ig gamma 2a H chain gene have similar transcription termination regions. J Immunol 144:2802–2810PubMedGoogle Scholar
  152. 152.
    Flaspohler JA, Boczkowski D, Hall BL, Milcarek C (1995) The 3ʹ-untranslated region of membrane exon 2 from the gamma 2a immunoglobulin gene contributes to efficient transcription termination. J Biol Chem 270:11903–11911PubMedGoogle Scholar
  153. 153.
    Lebman DA, Park MJ, Fatica R, Zhang Z (1992) Regulation of usage of membrane and secreted 3ʹ termini of alpha mRNA differs from mu mRNA. J Immunol 148: 3282–3289PubMedGoogle Scholar
  154. 154.
    Edwalds-Gilbert G, Veraldi KL, Milcarek C (1997) Alternative poly(A) site selection in complex transcription units: means to an end? Nucleic Acids Res 25:2547–2561PubMedGoogle Scholar
  155. 155.
    Coyle JH, Lebman DA (2000) Correct immunoglobulin alpha mRNA processing depends on specific sequence in the C alpha 3-alpha M intron. J Immunol 164:3659–3665PubMedGoogle Scholar
  156. 156.
    Anand S, Batista FD, Tkach T, Efremov DG, Burrone OR (1997) Multiple transcripts of the murine immunoglobulin epsilon membrane locus are generated by alternative splicing and differential usage of two polyadenylation sites. Mol Immunol 34:175–183PubMedGoogle Scholar
  157. 157.
    Batista FD, Efremov DG, Burrone OR (1996) Characterization of a second secreted IgE isoform and identification of an asymmetric pathway of IgE assembly. Proc Natl Acad Sci USA 93:3399–3404PubMedGoogle Scholar
  158. 158.
    Manz RA, Hauser AE, Hiepe F, Radbruch A (2005) Maintenance of serum antibody levels. Annu Rev Immunol 23:367–386PubMedGoogle Scholar
  159. 159.
    Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A (1998) Survival of long-lived plasma cells is independent of antigen. Int Immunol 10:1703–1711PubMedGoogle Scholar
  160. 160.
    Manz RA, Thiel A, Radbruch A (1997) Lifetime of plasma cells in the bone marrow. Nature 388:133–134PubMedGoogle Scholar
  161. 161.
    Holt PG, Sedgwick JD, O’Leary C, Krska K, Leivers S (1984) Long-lived IgE- and IgG-secreting cells in rodents manifesting persistent antibody responses. Cell Immunol 89: 281–289PubMedGoogle Scholar
  162. 162.
    Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, Radbruch A, Hiepe F, Manz RA (2004) Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med 199:1577–1584PubMedGoogle Scholar
  163. 163.
    Hauser AE, Debes GF, Arce S, Cassese G, Hamann A, Radbruch A, Manz RA (2002) Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol 169:1277–1282PubMedGoogle Scholar
  164. 164.
    Hauser AE, Muehlinghaus G, Manz RA, Cassese G, Arce S, Debes GF, Hamann A, Berek C, Lindenau S, Doerner T, Hiepe F, Odendahl M, Riemekasten G, Krenn V, Radbruch A (2003) Long-lived plasma cells in immunity and inflammation. Ann N Y Acad Sci 987:266–269PubMedGoogle Scholar
  165. 165.
    Hargreaves DC, Hyman PL, Lu TT, Ngo VN, Bidgol A, Suzuki G, Zou YR, Littman DR, Cyster JG (2001) A coordinated change in chemokine responsiveness guides plasma cell movements. J Exp Med 194:45–56PubMedGoogle Scholar
  166. 166.
    Muehlinghaus G, Cigliano L, Huehn S, Peddinghaus A, Leyendeckers H, Hauser AE, Hiepe F, Radbruch A, Arce S, Manz RA (2005) Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells. Blood 105:3965–3971PubMedGoogle Scholar
  167. 167.
    Achatz-Straussberger G, Zaborsky N, Konigsberger S, Luger EO, Lamers M, Crameri R, Achatz G (2008) Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR. Eur J Immunol 38:3167–3177PubMedGoogle Scholar
  168. 168.
    Leffell MS, Donnenberg AD, Rose NR. Handbook of Human Immunology. 1 ed. Boca Raton FL: CRC Press, 1997Google Scholar
  169. 169.
    Peppard JV, Orlans E (1980) The biological half-lives of four rat immunoglobulin isotypes. Immunology 40:683–686PubMedGoogle Scholar
  170. 170.
    Medesan C, Cianga P, Mummert M, Stanescu D, Ghetie V, Ward ES (1998) Comparative studies of rat IgG to further delineate the Fc:FcRn interaction site. Eur J Immunol 28: 2092–2100PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Gernot Achatz
    • 1
    Email author
  • Gertrude Achatz-Straussberger
    • 1
  • Stefan Feichtner
    • 1
  • Sebastian Koenigsberger
    • 1
  • Stefan Lenz
    • 1
  • Doris Peckl-Schmid
    • 1
  • Nadja Zaborsky
    • 1
  • Marinus Lamers
    • 2
  1. 1.Department of Molecular BiologyUniversity of SalzburgSalzburgAustria
  2. 2.Max Planck Institute for ImmunobiologyFreiburgGermany

Personalised recommendations