Article | Published:

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

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 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).

  2. 2

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

  3. 3

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

  4. 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).

  5. 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).

  6. 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).

  7. 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).

  8. 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).

  9. 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).

  10. 10

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

  11. 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).

  12. 12

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

  13. 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).

  14. 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).

  15. 15

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

  16. 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).

  17. 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).

  18. 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).

  19. 19

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

  20. 20

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

  21. 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).

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 26

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

  27. 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).

  28. 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).

  29. 29

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

  30. 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).

  31. 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).

  32. 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).

  33. 33

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

  34. 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).

  35. 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).

  36. 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).

Download references

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.).

Author information

Correspondence to Andrew J. S. Macpherson.

Rights and permissions

Reprints and Permissions

About this article

Further reading

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.