The Journal of Allergy and Clinical Immunology
Volume 122, Issue 4 , Pages 811-819.e2 , October 2008

Genetic or pharmaceutical blockade of p110δ phosphoinositide 3-kinase enhances IgE production

  • Ting-ting Zhang, MSc

      Affiliations

    • CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada
    • Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
    • ,
  • Klaus Okkenhaug, PhD

      Affiliations

    • Laboratory of Lymphocyte Signalling and Development, the Babraham Institute, Cambridge, United Kingdom
    • ,
  • Baher F. Nashed, MD, PhD

      Affiliations

    • CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada
    • Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
    • ,
  • Kamal D. Puri, PhD

      Affiliations

    • Calistoga Pharmaceuticals, Seattle, Wash
    • ,
  • Zachary A. Knight, PhD

      Affiliations

    • Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Calif
    • ,
  • Kevan M. Shokat, PhD

      Affiliations

    • Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, Calif
    • ,
  • Bart Vanhaesebroeck, PhD

      Affiliations

    • Institute of Cancer, Queen Mary's School of Medicine and Dentistry, University of London, London, United Kingdom
    • ,
  • Aaron J. Marshall, PhD

      Affiliations

    • CIHR National Training Program in Allergy and Asthma Research, University of Manitoba, Winnipeg, Manitoba, Canada
    • Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
    • Corresponding Author InformationReprint requests: Aaron J. Marshall, PhD, Department of Immunology, University of Manitoba, 730 William Ave, Winnipeg, MB, Canada.

Received 28 March 2008 ,Revised 2 July 2008 ,Accepted 11 August 2008.

References 

  1. Corry DB, Kheradmand F. Induction and regulation of the IgE response. Nature. 1999;402:B18–B23
  2. Vercelli D. The regulation of IgE synthesis. Clin Allergy Immunol. 2002;16:179–196
  3. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102:553–563
  4. Stavnezer J. Immunoglobulin class switching. Curr Opin Immunol. 1996;8:199–205
  5. Finkelman FD, Holmes J, Katona IM, Urban JF, Beckmann MP, Park LS, et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333
  6. Jabara HH, Fu SM, Geha RS, Vercelli D. CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells. J Exp Med. 1990;172:1861–1864
  7. Iciek LA, Delphin SA, Stavnezer J. CD40 cross-linking induces Ig epsilon germline transcripts in B cells via activation of NF-kappaB: synergy with IL-4 induction. J Immunol. 1997;158:4769–4779
  8. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996;380:630–633
  9. Rommel C, Camps M, Ji H. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?. Nat Rev Immunol. 2007;7:191–201
  10. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3:317–330
  11. Fruman DA. Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr Opin Immunol. 2004;16:314–320
  12. Aagaard-Tillery KM, Jelinek DF. Phosphatidylinositol 3-kinase activation in normal human B lymphocytes. J Immunol. 1996;156:4543–4554
  13. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006;125:733–747
  14. Kashiwada M, Lu P, Rothman PB. PIP3 pathway in regulatory T cells and autoimmunity. Immunol Res. 2007;39:194–224
  15. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, et al. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature. 2004;431:1007–1011
  16. Nashed BF, Zhang T, Al-Alwan M, Srinivasan G, Halayko AJ, Okkenhaug K, et al. Role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation. Eur J Immunol. 2007;37:416–424
  17. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297:1031–1034
  18. Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, et al. Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood. 2006;107:642–650
  19. Rush JS, Hasbold J, Hodgkin PD. Cross-linking surface Ig delays CD40 ligand- and IL-4-induced B cell Ig class switching and reveals evidence for independent regulation of B cell proliferation and differentiation. J Immunol. 2002;168:2676–2682
  20. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE. Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J Immunol. 2003;170:2647–2654
  21. Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med. 2005;11:507–514
  22. Lewkowich IP, HayGlass KT. Endogenous IFN-gamma and IL-18 production directly limit induction of type 2 immunity in vivo. Eur J Immunol. 2002;32:3536–3545
  23. Frasca D, Van der Put E, Riley RL, Blomberg BB. Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J Immunol. 2004;172:2155–2162
  24. Katona IM, Urban JF, Scher I, Kanellopoulos-Langevin C, Finkelman FD. Induction of an IgE response in mice by Nippostrongylus brasiliensis: characterization of lymphoid cells with intracytoplasmic or surface IgE. J Immunol. 1983;130:350–356
  25. Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, et al. Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood. 2005;106:1432–1440
  26. Mandler R, Finkelman FD, Levine AD, Snapper CM. IL-4 induction of IgE class switching by lipopolysaccharide-activated murine B cells occurs predominantly through sequential switching. J Immunol. 1993;150:407–418
  27. Sudowe S, Arps V, Vogel T, Kolsch E. The role of interleukin-4 in the regulation of sequential isotype switch from immunoglobulin G1 to immunoglobulin E antibody production. Scand J Immunol. 2000;51:461–471
  28. Hasbold J, Lyons AB, Kehry MR, Hodgkin PD. Cell division number regulates IgG1 and IgE switching of B cells following stimulation by CD40 ligand and IL-4. Eur J Immunol. 1998;28:1040–1051
  29. Snapper CM, Finkelman FD, Stefany D, Conrad DH, Paul WE. IL-4 induces co-expression of intrinsic membrane IgG1 and IgE by murine B cells stimulated with lipopolysaccharide. J Immunol. 1988;141:489–498
  30. Kinoshita K, Honjo T. Unique and unprecedented recombination mechanisms in class switching. Curr Opin Immunol. 2000;12:195–198
  31. Donahue AC, Fruman DA. Distinct signaling mechanisms activate the target of rapamycin in response to different B-cell stimuli. Eur J Immunol. 2007;37:2923–2936
  32. Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol. 2006;177:5122–5128
  33. Dedeoglu F, Horwitz B, Chaudhuri J, Alt FW, Geha RS. Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB. Int Immunol. 2004;16:395–404
  34. Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, Calame K, et al. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity. 2006;25:545–557
  35. Blaeser F, Bryce PJ, Ho N, Raman V, Dedeoglu F, Donaldson DD, et al. Targeted inactivation of the IL-4 receptor alpha chain I4R motif promotes allergic airway inflammation. J Exp Med. 2003;198:1189–1200
  36. Cameron L, Gounni AS, Frenkiel S, Lavigne F, Vercelli D, Hamid Q. S epsilon S mu and S epsilon S gamma switch circles in human nasal mucosa following ex vivo allergen challenge: evidence for direct as well as sequential class switch recombination. J Immunol. 2003;171:3816–3822
  37. Erazo A, Kutchukhidze N, Leung M, Christ AP, Urban JF, Curotto de Lafaille MA, et al. Unique maturation program of the IgE response in vivo. Immunity. 2007;26:191–203
  38. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298:1630–1634
  39. Aalberse RC, Platts-Mills TA. How do we avoid developing allergy: modifications of the TH2 response from a B-cell perspective. J Allergy Clin Immunol. 2004;113:983–986
  40. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet. 1997;16:161–170
  41. Harris MB, Chang CC, Berton MT, Danial NN, Zhang J, Kuehner D, et al. Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching. Mol Cell Biol. 1999;19:7264–7275

 Supported by the Canadian Institutes of Health Research (MOP-42382), the CIHR National Training Program in Allergy and Asthma Research, the SickKids Foundation (Toronto), and the Manitoba Institute of Child Health. T.Z. was supported by studentships from the Manitoba Institute of Child Health and the CIHR National Training Program in Allergy and Asthma Research. A.J.M. was supported by a Canada Research Chair.

 Disclosure of potential conflict of interest: K. Okkenhaug has served as a consultant for Piramed and has received grants from the BBSRC and the British Heart Foundation. B. Vanhaesebroeck has served as a consultant for Piramed and AstraZeneca and has received research support from Piramed, UCB–CellTech and AstraZeneca. A. J. Marshall received operating grants from the Canadian Institutes of Health Research and the SickKids Foundation (Toronto). The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(08)01500-5

doi: 10.1016/j.jaci.2008.08.008

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 4 , Pages 811-819.e2 , October 2008

Article Tools

* Image Usage & Resolution