Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice

Abstract

STUDIES on transgenic mice expressing immunoglobulins against self-antigens1–6 have shown that self-tolerance is maintained by active elimination (clonal deletion)1–3,7, functional inactivation (clonal anergy)4,5,8 of self-reactive B cells, or a combination of both6. We have established and characterized a transgenic mouse line expressing an anti-erythrocyte autoantibody6. In contrast to other autoantibody transgenic lines, about 50% of the animals of this transgenic line suffer from autoimmune disease, indicating a loss of self-tolerance. Here we show that peritoneal Ly-1 B cells (also known as B-l cells9) are responsible for this autoimmune disease in our transgenic mice. A few self-reactive Ly-1 B cells that have somehow escaped the deletion mechanism expand in the peritoneum because of the absence of self-antigen. These Ly-1 B cells are eliminated in vivo by apoptosis once exposed to self-antigen. On the basis of these results we propose a novel autoantibody production mechanism whereby self-reactive B cellssequestered in compartments free of self-antigens may survive, proliferate and be activated for generation of pathogenic auto-antibodies in autoimmune diseases.

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References

  1. 1

    Nemazee, D. A. & Bürki, K. Nature 337, 562–566 (1989).

  2. 2

    Nemazee, D. & Bürki, K. Proc. natn. Acad. Sci. U.S.A. 86, 8039–8043 (1989).

  3. 3

    Hartley, S. B. et al. Nature 353, 765–769 (1991).

  4. 4

    Goodnow, C. C. et al. Nature 334, 676–682 (1988).

  5. 5

    Erikson, J. et al. Nature 349, 331–334 (1991).

  6. 6

    Okamoto, M. et al. J. exp. Med. 175, 71–79 (1992).

  7. 7

    Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (Vanderbilt Univ. Press, Nashville, 1959).

  8. 8

    Pike, B. L., Boyd, A. W. & Nossal, G. J. V. Proc. natn. Acad. Sci. U.S.A. 79, 2013–2017 (1982).

  9. 9

    Kantor, A. B. Immun. Today 12, 388 (1991).

  10. 10

    Herzenberg, L. A. et al. Immunol. Rev. 93, 81–102 (1986).

  11. 11

    Hardy, R. R. & Hayakawa, K. Immunol. Rev. 93, 53–102 (1986).

  12. 12

    Hayakawa, K. et al. Eur. J. Immun. 16, 1313–1316 (1986).

  13. 13

    Marcos, M. A. R. et al. Eur. J. Immun. 19, 2031–2035 (1989).

  14. 14

    Williams, J. R., Litte, J. B. & Shiplesy, W. U. Nature 252, 754–755 (1974).

  15. 15

    Goldstein, P., Ojcius, D. M. & Young, D. E. Immunol. Rev. 121, 30–65 (1991).

  16. 16

    Sedgwick, J. D. & Holt, P. G. J. immunol. Meth. 57, 301–309 (1983).

  17. 17

    Czerkinsky, C. et al. J. immunol. Meth. 65, 109–121 (1983).

  18. 18

    Bosma, G. C., Custer, R. P. & Bosma, M. J. Nature 301, 527–530 (1983).

  19. 19

    Shlomchik, M. J. et al. Nature 328, 805–811 (1987).

  20. 20

    Shlomchik, M. J., Aucoin, A. H., Pisetsky, D. S. & Weigert, M. G. Proc. natn. Acad. Sci. U.S.A. 84, 9150–9154 (1987).

  21. 21

    Shlomchik, M. et al. J. exp. Med. 171, 265–297 (1990).

  22. 22

    Hayakawa, K. et al. Proc. natn. Acad. Sci. U.S.A. 81, 2494–2498 (1984).

  23. 23

    Casali, P. et al. Science 236, 77–80 (1987).

  24. 24

    Hardy, R. R. et al. Science 236, 81–83 (1987).

  25. 25

    Smith, H. R. & Steinberg, A. D. A. Rev. Immun. 1, 175–210 (1983).

  26. 26

    Schwarts, R. S. & Datta, S. K. Fundamental Immunology 2nd edn (ed. Paul, W. E.) 819–866 (Raven, New York, 1989).

  27. 27

    Casali, P. et al. J. Immun. 143, 3476–3483 (1989).

  28. 28

    Benhamou, L. E., Cazenave, P. A. & Sarthou, P. Eur. J. Immun. 20, 1405–1407 (1990).

  29. 29

    Hasbold, J. & Klaus, G. G. B. Eur. J. Immun. 20, 1685–1690 (1990).

  30. 30

    Russell, D. M. et al. Nature 354, 308–311 (1991).

  31. 31

    Dianond, B. & Sharff, M. D. Proc. natn. Acad. Sci. U.S.A. 81, 5841–5844 (1984).

  32. 32

    Giusti, A. M., Chien, N. C., Zack, D. J., Shin, S. U. & Scharff, M. D. Proc. natn. Acad. Sci. U.S.A. 84, 2926–2930 (1987).

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Murakami, M., Tsubata, T., Okamoto, M. et al. Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature 357, 77–80 (1992). https://doi.org/10.1038/357077a0

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