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:

IgE+ memory B cells and plasma cells generated through a germinal-center pathway

An Addendum to this article was published on 15 November 2013

Abstract

Immunoglobulin E (IgE) antibodies are pathogenic in asthma and allergic diseases, but the in vivo biology of IgE-producing (IgE+) cells is poorly understood. A model of the differentiation of IgE+ B cells proposes that IgE+ cells develop through a germinal-center IgG1+ intermediate and that IgE memory resides in the compartment of IgG1+ memory B cells. Here we have used a reporter mouse expressing green fluorescent protein associated with membrane IgE transcripts (IgE-GFP) to assess in vivo IgE responses. In contrast to the IgG1-centered model of IgE switching and memory, we found that IgE+ cells developed through a germinal-center IgE+ intermediate to form IgE+ memory B cells and plasma cells. Our studies delineate a new model for the in vivo biology of IgE switching and memory.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: An IgE-GFP reporter marks IgE-switched B cells in ex vivo IgE-switch cultures of splenic B cells from IgE-GFP reporter mice.
Figure 2: In vivo generation of IgG1-switched B cells after infection of IgE-GFP reporter mice with N. brasiliensis.
Figure 3: In vivo generation of IgE-switched B cells after infection of IgE-GFP reporter mice with N. brasiliensis.
Figure 4: In vivo generation of IgE+ plasma cells after infection of IgE-GFP reporter mice with N. brasiliensis.
Figure 5: Immunofluorescence confocal microscopy of IgE+ germinal-center cells, plasma cells and memory B cells in the lymph nodes of IgE-GFP reporter mice left uninfected or infected with N. brasiliensis.
Figure 6: In vivo generation of IgE-switched B cells after immunization of IgE-GFP reporter mice with TNP-ovalbumin.
Figure 7: In vivo generation of IgE-switched B cells after a second infection of IgE-GFP reporter mice with N. brasiliensis.
Figure 8: Purified IgE+ memory B cells produce IgE after adoptive transfer and infection with N. brasiliensis.

Similar content being viewed by others

References

  1. Gould, H.J. & Sutton, B.J. IgE in allergy and asthma today. Nat. Rev. Immunol. 8, 205–217 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Gould, H.J. et al. The biology of IGE and the basis of allergic disease. Annu. Rev. Immunol. 21, 579–628 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Galli, S.J., Tsai, M. & Piliponsky, A.M. The development of allergic inflammation. Nature 454, 445–454 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Oettgen, H.C. & Geha, R.S. IgE regulation and roles in asthma pathogenesis. J. Allergy Clin. Immunol. 107, 429–440 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Katona, I.M., Urban, J.F. Jr., Scher, I., Kanellopoulos-Langevin, C. & Finkelman, F.D. Induction of an IgE response in mice by Nippostrongylus brasiliensis: characterization of lymphoid cells with intracytoplasmic or surface IgE. J. Immunol. 130, 350–356 (1983).

    CAS  PubMed  Google Scholar 

  6. Katona, I.M., Urban, J.F. Jr. & Finkelman, F.D. B cells that simultaneously express surface IgM and IgE in Nippostrongylus brasiliensis–infected SJA/9 mice do not provide evidence for isotype switching without gene deletion. Proc. Natl. Acad. Sci. USA 82, 511–515 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Elgueta, R., de Vries, V.C. & Noelle, R.J. The immortality of humoral immunity. Immunol. Rev. 236, 139–150 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Gatto, D. & Brink, R. The germinal center reaction. J. Allergy Clin. Immunol. 126, 898–907 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Good-Jacobson, K.L. & Shlomchik, M.J. Plasticity and heterogeneity in the generation of memory B cells and long-lived plasma cells: the influence of germinal center interactions and dynamics. J. Immunol. 185, 3117–3125 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Kurosaki, T., Aiba, Y., Kometani, K., Moriyama, S. & Takahashi, Y. Unique properties of memory B cells of different isotypes. Immunol. Rev. 237, 104–116 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Vinuesa, C.G., Sanz, I. & Cook, M.C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845–857 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Yoshida, T. et al. Memory B and memory plasma cells. Immunol. Rev. 237, 117–139 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Achatz-Straussberger, G. et al. Limited humoral immunoglobulin E memory influences serum immunoglobulin E levels in blood. Clin. Exp. Allergy 39, 1307–1313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Erazo, A. et al. Unique maturation program of the IgE response in vivo. Immunity 26, 191–203 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brightbill, H.D. et al. Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice. J. Clin. Invest. 120, 2218–2229 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Batista, F.D., Efremov, D.G. & Burrone, O.R. Characterization and expression of alternatively spliced IgE heavy chain transcripts produced by peripheral blood lymphocytes. J. Immunol. 154, 209–218 (1995).

    CAS  PubMed  Google Scholar 

  17. Davis, F.M., Gossett, L.A. & Chang, T.W. An epitope on membrane-bound but not secreted IgE: implications in isotype-specific regulation. Bio/Technology 9, 53–56 (1991).

    CAS  Google Scholar 

  18. Ishida, N., Ueda, S., Hayashida, H., Miyata, T. & Honjo, T. The nucleotide sequence of the mouse immunoglobulin ɛ gene: comparison with the human ɛ gene sequence. EMBO J. 1, 1117–1123 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, K., Saxon, A. & Max, E.E. Two unusual forms of human immunoglobulin E encoded by alternative RNA splicing of ɛ heavy chain membrane exons. J. Exp. Med. 176, 233–243 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Lebrun, P. & Spiegelberg, H.L. Concomitant immunoglobulin E and immunoglobulin G1 formation in Nippostrongylus brasiliensis-infected mice. J. Immunol. 139, 1459–1465 (1987).

    CAS  PubMed  Google Scholar 

  21. Finkelman, F.D. et al. Suppression of in vivo polyclonal IgE responses by monoclonal antibody to the lymphokine B-cell stimulatory factor 1. Proc. Natl. Acad. Sci. USA 83, 9675–9678 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K.A. B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene. Nature 350, 423–426 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Oracki, S.A., Walker, J.A., Hibbs, M.L., Corcoran, L.M. & Tarlinton, D.M. Plasma cell development and survival. Immunol. Rev. 237, 140–159 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Haba, S., Ovary, Z. & Nisonoff, A. Clearance of IgE from serum of normal and hybridoma-bearing mice. J. Immunol. 134, 3291–3297 (1985).

    CAS  PubMed  Google Scholar 

  26. Hirano, T., Hom, C. & Ovary, Z. Half-life of murine IgE antibodies in the mouse. Int. Arch. Allergy Appl. Immunol. 71, 182–184 (1983).

    Article  CAS  PubMed  Google Scholar 

  27. Jung, S., Siebenkotten, G. & Radbruch, A. Frequency of immunoglobulin E class switching is autonomously determined and independent of prior switching to other classes. J. Exp. Med. 179, 2023–2026 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Pape, K.A., Taylor, J.J., Maul, R.W., Gearhart, P.J. & Jenkins, M.K. Different B cell populations mediate early and late memory during an endogenous immune response. Science 331, 1203–1207 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Aiba, Y. et al. Preferential localization of IgG memory B cells adjacent to contracted germinal centers. Proc. Natl. Acad. Sci. USA 107, 12192–12197 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pochanke, V., Hatak, S., Hengartner, H., Zinkernagel, R.M. & McCoy, K.D. Induction of IgE and allergic-type responses in fur mite-infested mice. Eur. J. Immunol. 36, 2434–2445 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R. Locksley (University of California, San Francisco) for larvae of N. brasiliensis; J. Cupp, R. Weimer, J.-W. Tsai, R. Noubade, J. Dunyanen, R. Ferrando and M. Larson for technical assistance; H. Qi for advice on germinal-center imaging; and F. Martin, M.Balazs, and A. Zarrin for discussions and advice.

Author information

Authors and Affiliations

Authors

Contributions

O.T., H.D.B., E.L. and J.G.E. designed and did experiments, and wrote the manuscript; D.Y., E.E.M.S. and M.Z. did experiments; C.D.A. designed experiments and wrote the manuscript; W.P.L. and M.X. designed experiments; and L.C.W. designed experiments, wrote the manuscript, and super vised the project.

Corresponding author

Correspondence to Lawren C Wu.

Ethics declarations

Competing interests

All authors are employed by Genentech, and D.Y., H.D.B., E.E.M.S., M.Z., E.L., W.P.L., J.G.E., C.D.A., M.X. and L.C.W. hold equity in the Roche Group.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 5754 kb)

Supplementary Video 1

GFP+ cells show rapid migration dynamics in the lymph node follicles of N. brasiliensis-infected IgE-GFP reporter mice. GFP+ cells (green) were visualized in an intact mesenteric lymph node by 2-photon microscopy at 13 days post-infection. The second harmonic signal (blue) identifies the collagen-rich lymph node capsule. Time shown in Hrs:Mins:Secs. Scale bar, 30μm. (MOV 1275 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Talay, O., Yan, D., Brightbill, H. et al. IgE+ memory B cells and plasma cells generated through a germinal-center pathway. Nat Immunol 13, 396–404 (2012). https://doi.org/10.1038/ni.2256

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2256

This article is cited by

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