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

Nature Immunologyvolume 10, pages889–898 (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.

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Figure 1: B cells of the upper respiratory mucosa generate IgD+IgM− plasmablasts by undergoing Cμ-to-Cδ CSRin 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 cellsin vivo.
Figure 4: IgD binds to basophilic and mast cell linesin 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.

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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
  2. Weifeng Xu
  3. Melanie Wilson
  4. Bing He
  5. Norman W Miller
  6. Eva Bengtén
  7. Eva-Stina Edholm
  8. Paul A Santini
  9. Poonam Rath
  10. April Chiu
  11. Marco Cattalini
  12. Jiri Litzman
  13. James B Bussel
  14. Bihui Huang
  15. Antonella Meini
  16. Kristian Riesbeck
  17. Charlotte Cunningham-Rundles
  18. Alessandro Plebani
  19. Andrea Cerutti

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 toAndrea Cerutti.

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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 Immunol10, 889–898 (2009). https://doi.org/10.1038/ni.1748

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