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IgA production without μ or δ chain expression in developing B cells

Nature Immunology volume 2, pages 625–631 (2001)Cite this article

Abstract

Surface, membrane-bound, immunoglobulin M (IgM) or IgD expression early in B cell ontogeny is considered essential for the differentiation of antibody-producing cells in mammals; only in IgM+ B cells is the heavy chain locus rearranged to express antibodies of other classes. We show here that IgA is selectively expressed in μMT mice, which lack IgM or IgD expression and have a pro-B cell developmental block. μMT IgA binds proteins of commensal intestinal bacteria and is weakly induced by Salmonella infection, although not through conventional immunization. This μMT IgA pathway requires extrasplenic peripheral lymphoid tissues and may be an evolutionarily primitive system in which immature B cells switch to IgA production at peripheral sites.

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Figure 1: Selective expression of IgA in μMT mice.
Figure 2: Ig expression in μMT lymphocytes.
Figure 3: IgA-producing cells can be detected in μMT mice histologically in the lamina propria and Peyer's patches of the ileum and in the spleen.
Figure 4: Reconstitution of wild-type and μMT IgA production.

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References

  1. Melchers, F. et al. Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells. Immunol. Rev. 175, 33–46 (2000).

    Article  CAS  Google Scholar 

  2. Hardy, R. R. et al. B-cell commitment, development and selection. Immunol. Rev. 175, 23–32 (2000).

    Article  CAS  Google Scholar 

  3. Pillai, S. The chosen few? Positive selection and the generation of naive B lymphocytes. Immunity 10, 493–502 (1999).

    Article  CAS  Google Scholar 

  4. Rolink, A., Grawunder, U., Winkler, T. H., Karasuyama, H. & Melchers, F. IL-2 receptor-α chain (Cd25,Tac) expression defines a crucial stage in pre-B-cell Development. Int. Immunol. 6, 1257–1264 (1994).

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Yuan, D., Witte, P. L., Tan, J., Hawley, J. & Dang, T. Regulation of IgM and IgD heavy chain gene expression: effect of abrogation of intergenic transcriptional termination. J. Immunol. 157, 2073–2081 (1996).

    CAS  PubMed  Google Scholar 

  7. Yuan, D. & Witte, P. L. Transcriptional regulation of μ and δ gene expression in bone marrow pre-B and B lymphocytes. J. Immunol. 140, 2808–2814 (1988).

    CAS  PubMed  Google Scholar 

  8. Kim, M., Qiu, P., Abuodeh, R., Chen, J. & Yuan, D. Differential regulation of transcription termination occurring at two different sites on the microdelta gene complex. Int. Immunol. 11, 813–824 (1999).

    Article  CAS  Google Scholar 

  9. Roes, J. & Rajewsky, K. Cell autonomous expression of IgD is not essential for the maturation of conventional B-cells. Int. Immunol. 3, 1367–1371 (1991).

    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. Tarlinton, D. M., Corcoran, L. M. & Strasser, A. Continued differentiation during B lymphopoiesis requires signals in addition to cell survival. Int. Immunol. 9, 1481–1494 (1997).

    Article  CAS  Google Scholar 

  12. Melamed, D., Miri, E., Leider, N. & Nemazee, D. Unexpected autoantibody production in membrane Igμ-deficient/lpr mice. J. Immunol. 165, 4353–4358 (2000).

    Article  CAS  Google Scholar 

  13. Alt, F. W., Rosenberg, N., Casanova, R. J., Thomas, E. & Baltimore, D. Immunoglobulin heavy-chain expression and class switching in a murine leukaemia cell line. Nature 296, 325–331 (1982).

    Article  CAS  Google Scholar 

  14. Burrows, P. D., Beck-Engeser, G. B. & Wabl, M. R. Immunoglobulin heavy-chain class switching in a pre-B cell line is accompanied by DNA rearrangement. Nature 306, 243–246 (1983).

    Article  CAS  Google Scholar 

  15. Vogler, L. B. et al. Diversity of immunoglobulin expression in leukaemic cells resembling B-lymphocyte precursors. Nature 290, 339–341 (1981).

    Article  CAS  Google Scholar 

  16. Harriman, G. R. et al. Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other immunoglobulin isotypes. J. Immunol. 162, 2521–2529 (1999).

    CAS  PubMed  Google Scholar 

  17. Chen, J. Z. et al. B-cell development in mice that lack one or both immunoglobulin κ-light chain genes. EMBO J. 12, 821–830 (1993).

    Article  CAS  Google Scholar 

  18. Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).

    Article  CAS  Google Scholar 

  19. Golovkina, T. V., Shlomchik, M., Hannum, L. & Chervonsky, A. Organogenic role of B lymphocytes in mucosal immunity. Science 286, 1965–1968 (1999).

    Article  CAS  Google Scholar 

  20. Mackie, R., Sghir, A. & Gaskins, H. R. Developmental microbial ecology of the neonatal gastrointestinal tract. Am. J. Clin. Nutr. 69, 1035–1045 (1999).

    Article  Google Scholar 

  21. Londono, L. P. et al. Immunisation of mice using Salmonella typhimurium expressing human papillomavirus inserted into hepatitis B virus core antigen. Vaccine 14, 545–552 (1996).

    Article  CAS  Google Scholar 

  22. Kroese, F. G. M. et al. Many of the IgA producing plasma cells in the murine gut are derived from self-replenishing precursors in the peritoneal cavity. Int. Immunol. 1, 75–84 (1988).

    Article  Google Scholar 

  23. Shinkura, R. et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding NF-κB-inducing kinase. Nature Genet. 22, 74–77 (1999).

    Article  CAS  Google Scholar 

  24. Nanno, M. et al. Development of intestinal intraepithelial T lymphocytes is independent of Peyer's patches and lymph nodes in aly mutant mice. J. Immunol. 153, 2014–2020 (1994).

    CAS  Google Scholar 

  25. Matsumoto, M. et al. Involvement of distinct cellular compartments in the abnormal lymphoid organogenesis in lymphotoxin-α-deficient mice and alymphoplasia (aly) mice defined by the chimeric analysis. J. Immunol. 163, 1584–1591 (1999).

    CAS  PubMed  Google Scholar 

  26. Warr, G. W., Magor, K. E. & Higgins, D. A. IgY: clues to the origins of modern antibodies. Immunol. Today 16, 392–398 (1995).

    Article  CAS  Google Scholar 

  27. Brandzaeg, P., Krajci, P., Lamm, M. E. & Kaetzel, C. S. in Handbook of Mucosal Immunology (ed. Ogra, P. L.) 113–126 (Academic Press, San Diego, 1994).

    Book  Google Scholar 

  28. Bos, N. A. et al. Monoclonal immunoglobulin A derived from peritoneal B cells is encoded by both germ line and somatically mutated VH genes and is reactive with commensal bacteria. Infect. Immun. 64, 616–623 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bhat, N. M. et al. The ontogeny and functional characteristics of human B-1 (CD5+ B) cells. Int. Immunol. 4, 243–252 (1992).

    Article  CAS  Google Scholar 

  30. Reynaud, C. A., Mackay, C. R., Muller, R. G. & Weill, J. C. Somatic generation of diversity in a mammalian primary lymphoid organ: the sheep ileal Peyer's patches. Cell 64, 995–1005 (1991).

    Article  CAS  Google Scholar 

  31. Reynaud, C. A., Garcia, C., Hein, W. R. & Weill, J. C. Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 80, 115–125 (1995).

    Article  CAS  Google Scholar 

  32. Chen, J. Z. et al. Immunoglobulin gene rearrangement in B-cell deficient mice generated by targeted deletion of the J(H) locus. Int. Immunol. 5, 647–656 (1993).

    Article  CAS  Google Scholar 

  33. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    Article  CAS  Google Scholar 

  34. Clarke, B. E., Brown, A. L. & Grace, K. G. Presentation and immunogenicity of viral epitopes on the surface of hybrid hepatitis B core particles produced in bacteria. J. Gen. Virol. 71, 1109–1117 (1990).

    Article  CAS  Google Scholar 

  35. Henderson, P. J. & Macpherson, A. J. Assay, genetics, proteins, and reconstitution of proton-linked galactose, arabinose, and xylose transport systems of Escherichia coli. Methods Enzymol. 125, 387–429 (1986).

    Article  CAS  Google Scholar 

  36. Krebber, A. et al. Reliable cloning of functional antibody variable domains from hybridomas and spleen cell repertoires employing a reengineered phage display system. J. Immunol. Methods 201, 35–55 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank T. Uhr and the staff of the Labortierkunde, Universität Zürich, for technical assistance and E. Wagner of the Basel Institute and F. Ronchese of the Malaghan Institute of Medical Research for serum samples from their μMT colonies. Supported by the Swiss Nationalfonds (grant numbers 31-50900.97 and 31-50884.97), the Kanton of Zürich and the Medical Research Council of Canada (A. L.).

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Authors and Affiliations

  1. Institute of Experimental Immunology, Universitätsspital, Schmelzbergstrasse 12, Zürich, CH8091, Switzerland

    Andrew J. S. Macpherson, Alain Lamarre, Kathy McCoy, Bernard Odermatt, Hans Hengartner & Rolf M. Zinkernagel

  2. Centocor, 200 Great Valley Parkway, Malvern, 19355, PA, USA

    Gregory R. Harriman

  3. Biochemistry Department, Centre for Molecular Microbiology and Immunology, Imperial College of Science, Technology and Medicine, Exhibition Road, London, SW7 2AZ, UK

    Gordon Dougan

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  1. Andrew J. S. Macpherson
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Correspondence to Andrew J. S. Macpherson.

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Macpherson, A., Lamarre, A., McCoy, K. et al. IgA production without μ or δ chain expression in developing B cells. Nat Immunol 2, 625–631 (2001). https://doi.org/10.1038/89775

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