Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell–stimulating programs in basophils

Nature Immunology volume 10, pages 889–898 (2009)Cite this article

Abstract

Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells express together with IgM through alternative RNA splicing. Here we report active T cell–dependent and T cell–independent IgM-to-IgD class switching in B cells of the human upper respiratory mucosa. This process required activation-induced cytidine deaminase (AID) and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell–stimulating factors, including cathelicidin, interleukin 1 (IL-1), IL-4 and B cell–activating factor (BAFF), after IgD crosslinking. By showing dysregulation of IgD class–switched B cells and 'IgD-armed' basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: B cells of the upper respiratory mucosa generate IgD+IgM− plasmablasts by undergoing Cμ-to-Cδ CSR in situ.
Figure 2: Cμ-to-Cδ CSR occurs through both T cell–dependent and T cell–independent pathways, requires AID, and leads to the production of IgD antibodies that bind to respiratory bacteria.
Figure 3: IgD binds to basophils and mast cells in vivo.
Figure 4: IgD binds to basophilic and mast cell lines in vitro.
Figure 5: Basophils release immunostimulating and proinflammatory factors after IgD crosslinking.
Figure 6: Basophils release antimicrobial factors after IgD crosslinking.
Figure 7: More IgD class–switched plasmablasts and 'IgD-armed' basophils in inflamed tissues from patients with periodic fever syndromes.

Similar content being viewed by others

References

  1. Rowe, D.S. & Fahey, J.L. A new class of human immunoglobulins. J. Exp. Med. 121, 171–199 (1965).

    Article  CAS  Google Scholar 

  2. Butler, J.E., Sun, J. & Navarro, P. The swine Ig heavy chain locus has a single JH and no identifiable IgD. Int. Immunol. 8, 1897–1904 (1996).

    Article  CAS  Google Scholar 

  3. Ohta, Y. & Flajnik, M. IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc. Natl. Acad. Sci. USA 103, 10723–10728 (2006).

    Article  CAS  Google Scholar 

  4. Preud'homme, J.L. et al. Structural and functional properties of membrane and secreted IgD. Mol. Immunol. 37, 871–887 (2000).

    Article  CAS  Google Scholar 

  5. Bengten, E. et al. The IgH locus of the channel catfish, Ictalurus punctatus, contains multiple constant region gene sequences: different genes encode heavy chains of membrane and secreted IgD. J. Immunol. 169, 2488–2497 (2002).

    Article  CAS  Google Scholar 

  6. Schlissel, M.S. Regulating antigen-receptor gene assembly. Nat. Rev. Immunol. 3, 890–899 (2003).

    Article  CAS  Google Scholar 

  7. Maki, R. et al. The role of DNA rearrangement and alternative RNA processing in the expression of immunoglobulin δ genes. Cell 24, 353–365 (1981).

    Article  CAS  Google Scholar 

  8. Nitschke, L., Kosco, M.H., Kohler, G. & Lamers, M.C. Immunoglobulin D-deficient mice can mount normal immune responses to thymus-independent and -dependent antigens. Proc. Natl. Acad. Sci. USA 90, 1887–1891 (1993).

    Article  CAS  Google Scholar 

  9. Roes, J. & Rajewsky, K. Immunoglobulin D (IgD)-deficient mice reveal an auxiliary receptor function for IgD in antigen-mediated recruitment of B cells. J. Exp. Med. 177, 45–55 (1993).

    Article  CAS  Google Scholar 

  10. Lutz, C. et al. IgD can largely substitute for loss of IgM function in B cells. Nature 393, 797–801 (1998).

    Article  CAS  Google Scholar 

  11. Monroe, J.G., Havran, W.L. & Cambier, J.C. B lymphocyte activation: entry into cell cycle is accompanied by decreased expression of IgD but not IgM. Eur. J. Immunol. 13, 208–213 (1983).

    Article  CAS  Google Scholar 

  12. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  Google Scholar 

  13. Odegard, V.H. & Schatz, D.G. Targeting of somatic hypermutation. Nat. Rev. Immunol. 6, 573–583 (2006).

    Article  CAS  Google Scholar 

  14. Chaudhuri, J. & Alt, F.W. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat. Rev. Immunol. 4, 541–552 (2004).

    Article  CAS  Google Scholar 

  15. Aruffo, A. et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 72, 291–300 (1993).

    Article  CAS  Google Scholar 

  16. Litinskiy, M.B. et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 3, 822–829 (2002).

    Article  CAS  Google Scholar 

  17. Castigli, E. et al. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201, 35–39 (2005).

    Article  CAS  Google Scholar 

  18. Xu, W. et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat. Immunol. 8, 294–303 (2007).

    Article  CAS  Google Scholar 

  19. He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

    Article  CAS  Google Scholar 

  20. Cerutti, A. The regulation of IgA class switching. Nat. Rev. Immunol. 8, 421–434 (2008).

    Article  CAS  Google Scholar 

  21. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat. Genet. 37, 829–834 (2005).

    Article  CAS  Google Scholar 

  22. McHeyzer-Williams, M.G. & Ahmed, R. B cell memory and the long-lived plasma cell. Curr. Opin. Immunol. 11, 172–179 (1999).

    Article  CAS  Google Scholar 

  23. Stavnezer, J. Antibody class switching. Adv. Immunol. 61, 79–146 (1996).

    Article  CAS  Google Scholar 

  24. Arpin, C. et al. The normal counterpart of IgD myeloma cells in germinal center displays extensively mutated IgVH gene, Cμ-Cδ switch, and λ light chain expression. J. Exp. Med. 187, 1169–1178 (1998).

    Article  CAS  Google Scholar 

  25. Plebani, A. et al. IgM and IgD concentrations in the serum and secretions of children with selective IgA deficiency. Clin. Exp. Immunol. 53, 689–696 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu, Y.J. et al. Normal human IgD+ IgM− germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. Immunity 4, 603–613 (1996).

    Article  CAS  Google Scholar 

  27. Brandtzaeg, P. et al. The B-cell system of human mucosae and exocrine glands. Immunol. Rev. 171, 45–87 (1999).

    Article  CAS  Google Scholar 

  28. Koelsch, K. et al. Mature B cells class switched to IgD are autoreactive in healthy individuals. J. Clin. Invest. 117, 1558–1565 (2007).

    Article  CAS  Google Scholar 

  29. Conrad, D.H., Ben-Sasson, S.Z., Le Gros, G., Finkelman, F.D. & Paul, W.E. Infection with Nippostrongylus brasiliensis or injection of anti-IgD antibodies markedly enhances Fc-receptor-mediated interleukin 4 production by non-B, non-T cells. J. Exp. Med. 171, 1497–1508 (1990).

    Article  CAS  Google Scholar 

  30. Seder, R.A. et al. Mouse splenic and bone marrow cell populations that express high-affinity Fcε receptors and produce interleukin 4 are highly enriched in basophils. Proc. Natl. Acad. Sci. USA 88, 2835–2839 (1991).

    Article  CAS  Google Scholar 

  31. Yoshimoto, T., Bendelac, A., Watson, C., Hu-Li, J. & Paul, W.E. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science 270, 1845–1847 (1995).

    Article  CAS  Google Scholar 

  32. Gauchat, J.F. et al. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365, 340–343 (1993).

    Article  CAS  Google Scholar 

  33. Min, B. et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med. 200, 507–517 (2004).

    Article  CAS  Google Scholar 

  34. Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 9, 310–318 (2008).

    Article  CAS  Google Scholar 

  35. Denzel, A. et al. Basophils enhance immunological memory responses. Nat. Immunol. 9, 733–742 (2008).

    Article  CAS  Google Scholar 

  36. Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).

    Article  CAS  Google Scholar 

  37. Bekeredjian-Ding, I. et al. TLR9-activating DNA up-regulates ZAP70 via sustained PKB induction in IgM+ B cells. J. Immunol. 181, 8267–8277 (2008).

    Article  CAS  Google Scholar 

  38. Klein, U., Rajewsky, K. & Kuppers, R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188, 1679–1689 (1998).

    Article  CAS  Google Scholar 

  39. Zhao, Y. et al. Artiodactyl IgD: the missing link. J. Immunol. 169, 4408–4416 (2002).

    Article  CAS  Google Scholar 

  40. Kluin, P.M. et al. IgD class switching: identification of a novel recombination site in neoplastic and normal B cells. Eur. J. Immunol. 25, 3504–3508 (1995).

    Article  CAS  Google Scholar 

  41. Granucci, F. et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat. Immunol. 2, 882–888 (2001).

    Article  CAS  Google Scholar 

  42. Leonard, W.J. & Spolski, R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat. Rev. Immunol. 5, 688–698 (2005).

    Article  CAS  Google Scholar 

  43. Cunningham-Rundles, C. & Ponda, P.P. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat. Rev. Immunol. 5, 880–892 (2005).

    Article  CAS  Google Scholar 

  44. Garibyan, L. et al. Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID). J. Clin. Invest. 117, 1550–1557 (2007).

    Article  CAS  Google Scholar 

  45. Zhang, L. et al. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes. J. Allergy Clin. Immunol. 120, 1178–1185 (2007).

    Article  CAS  Google Scholar 

  46. Riesbeck, K. & Nordstrom, T. Structure and immunological action of the human pathogen Moraxella catarrhalis IgD-binding protein. Crit. Rev. Immunol. 26, 353–376 (2006).

    Article  CAS  Google Scholar 

  47. Vladutiu, A.O. Immunoglobulin D: properties, measurement, and clinical relevance. Clin. Diagn. Lab. Immunol. 7, 131–140 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Dawicki, W. & Marshall, J.S. New and emerging roles for mast cells in host defence. Curr. Opin. Immunol. 19, 31–38 (2007).

    Article  CAS  Google Scholar 

  49. Karasuyama, H., Mukai, K., Tsujimura, Y. & Obata, K. Newly discovered roles for basophils: a neglected minority gains new respect. Nat. Rev. Immunol. 9, 9–13 (2008).

    Article  Google Scholar 

  50. Gala, F.A. & Morrison, S.L. The role of constant region carbohydrate in the assembly and secretion of human IgD and IgA1. J. Biol. Chem. 277, 29005–29011 (2002).

    Article  CAS  Google Scholar 

  51. Yamaguchi, Y. et al. Identification of multiple novel epididymis-specific β-defensin isoforms in humans and mice. J. Immunol. 169, 2516–2523 (2002).

    Article  CAS  Google Scholar 

  52. Oppenheim, J.J. & Yang, D. Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. 17, 359–365 (2005).

    Article  CAS  Google Scholar 

  53. Garlanda, C., Bottazzi, B., Bastone, A. & Mantovani, A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu. Rev. Immunol. 23, 337–366 (2005).

    Article  CAS  Google Scholar 

  54. Ryan, J.G. & Kastner, D.L. Fevers, genes, and innate immunity. Curr. Top. Microbiol. Immunol. 321, 169–184 (2008).

    CAS  PubMed  Google Scholar 

  55. Drenth, J.P., Goertz, J., Daha, M.R. & van der Meer, J.W. Immunoglobulin D enhances the release of tumor necrosis factor-α, and interleukin-1β as well as interleukin-1 receptor antagonist from human mononuclear cells. Immunology 88, 355–362 (1996).

    Article  CAS  Google Scholar 

  56. Johansen, F.E. et al. Regional induction of adhesion molecules and chemokine receptors explains disparate homing of human B cells to systemic and mucosal effector sites: dispersion from tonsils. Blood 106, 593–600 (2005).

    Article  CAS  Google Scholar 

  57. Xue, B. et al. Physiology of IgD. IV. Enhancement of antibody production in mice bearing IgD-secreting plasmacytomas. J. Exp. Med. 159, 103–113 (1984).

    Article  CAS  Google Scholar 

  58. Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114 (2001).

    Article  CAS  Google Scholar 

  59. Miller, N.W. et al. Development and characterization of channel catfish long term B cell lines. J. Immunol. 152, 2180–2189 (1994).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Kirshenbaum and D. Metcalfe (US National Institutes of Health) for the mast cell line LAD2; F. Facchetti (Università di Brescia) for tissue samples; and R. Silver, R. Schreiner and F. Diaz (Weill Medical College of Cornell University) for primary lung mast cells and discussion of transcytosis assays. Supported by the US National Institutes of Health (R01 AI057653, R01 AI057653 supplement and R01 AI074378 to A.C.; and funds from T32 AI07621 to W.X.), the Cancer Research Institute (P.A.S.), The Irma T. Hirschl Charitable Trust (A.C.), the Ministerio de Ciencia e Innovación (Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica SAF 2008-02725 to A.C.) and Fondazione C. Golgi and Centro Immunodeficienze Mario Di Martino (A.P.).

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA

    Kang Chen, Weifeng Xu, Bing He, Paul A Santini, Poonam Rath, April Chiu & Andrea Cerutti

  2. Graduate Program of Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA

    Kang Chen, Paul A Santini, Poonam Rath, Bihui Huang & Andrea Cerutti

  3. Department of Microbiology, University of Mississippi Medical Center, Jackson, Mississippi, USA

    Melanie Wilson, Norman W Miller, Eva Bengtén & Eva-Stina Edholm

  4. Clinica Pediatrica e Istituto di Medicina Molecolare 'A. Nocivelli', Università di Brescia, Brescia, Italy

    Marco Cattalini, Antonella Meini & Alessandro Plebani

  5. Department of Clinical Immunology and Allergology, St. Anne's University Hospital, Masaryk University, Brno, Czech Republic

    Jiri Litzman

  6. Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA

    James B Bussel

  7. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA

    Bihui Huang

  8. Department of Laboratory Medicine, Medical Microbiology, Malmö University Hospital, Lund University, Malmö, Sweden

    Kristian Riesbeck

  9. Mount Sinai Medical Center, New York, New York, USA

    Charlotte Cunningham-Rundles

Authors
  1. Kang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weifeng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norman W Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eva Bengtén
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eva-Stina Edholm
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul A Santini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Poonam Rath
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. April Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marco Cattalini
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jiri Litzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. James B Bussel
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Bihui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Antonella Meini
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kristian Riesbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Charlotte Cunningham-Rundles
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alessandro Plebani
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Andrea Cerutti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.C. designed and did research and wrote the paper; W.X., M.W., B. He, E.B., E.-S.E., N.W.M. and P.R. did research and discussed data; P.A.S. discussed data; B.Hu. provided reagents and did research; A.Ch., A.M., M.C., J.L., K.R., C.C.-R., J.B.B. and A.P. provided blood and tissue samples and discussed data; and A.Ce. designed research, discussed data and wrote the paper.

Corresponding author

Correspondence to Andrea Cerutti.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 1–2 (PDF 2272 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, K., Xu, W., Wilson, M. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell–stimulating programs in basophils. Nat Immunol 10, 889–898 (2009). https://doi.org/10.1038/ni.1748

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1748

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing