Advertisement

Autoimmunity, Self-Tolerance and Immune Homeostasis: From Whole Animal Phenotypes to Molecular Pathways

  • Christopher C. Goodnow
  • Richard Glynne
  • Srini Akkaraju
  • Jane Rayner
  • David Mack
  • James I. Healy
  • Shirine Chaudhry
  • Lisa Miosge
  • Lauren Wilson
  • Peter Papathanasiou
  • Adele Loy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 490)

Abstract

Current therapy for autoimmune disease is based on broad-spectrum immune suppression, rather than specific correction of defective tolerance mechanisms. On the preventive front, we are not yet able to identify individuals at risk of autoimmune disease or predict clinical course. To develop more specific therapeutic and diagnostic tools, we will need a map of the cellular and molecular pathways and genes that underpin immunological self-tolerance, illuminating the points where the process goes wrong and where it can be corrected.

Keywords

Autoantibody Production Immune Homeostasis Autoimmune Lymphoproliferative Syndrome Animal Phenotype Anergic Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    C. C. Goodnow, J. G. Cyster, S. B. Hartley, S. E. Bell, M. P. Cooke, J. I. Healy, S. Akkaraju, J. C. Rathmell, S. L. Pogue, K. P. Shokat, Self-tolerance checkpoints in B lymphocyte development, Adv Immunol 59, 279–368(1995).PubMedCrossRefGoogle Scholar
  2. 2.
    S. B. Hartley, M. P. Cooke, D. A. Fulcher, A. W. Harris, S. Cory, A. Basten, C. C. Goodnow, Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death, Cell 72, 325–335(1993).PubMedCrossRefGoogle Scholar
  3. 3.
    K. M. Murphy, A. B. Heimberger, D. Y. Loh, Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRIo thymocytes in vivo, Science 250, 1720–1723 (1990).PubMedCrossRefGoogle Scholar
  4. 4.
    J. G. Cyster, S. B. Hartley, C. C. Goodnow, Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire [see comments], Nature 371, 389–395(1994).PubMedCrossRefGoogle Scholar
  5. 5.
    J. C. Rathmell, M. P. Cooke, W. Y. Ho, J. Grein, S. E. Townsend, M. M. Davis, C. C. Goodnow, CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells, Nature 376, 181–184(1995).PubMedCrossRefGoogle Scholar
  6. 6.
    L. Van Parijs, D. A. Peterson, A. K. Abbas, The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens, Immunity 8, 265–274(1998).PubMedCrossRefGoogle Scholar
  7. 7.
    L. Zheng, G. Fisher, R. E. Miller, J. Peschon, D. H. Lynch, M. J. Lenardo, Induction of apoptosis in mature T cells by tumour necrosis factor, Nature 377, 348–351(1995).CrossRefGoogle Scholar
  8. 8.
    K. M. Shokat, C. C. Goodnow, Antigen-induced B-cell death and elimination during germinal-centre immune responses, Nature 375, 334–338(1995).PubMedCrossRefGoogle Scholar
  9. 9.
    E. R. Kearney, K. A. Pape, D. Y. Loh, M. K. Jenkins, Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo, Immunity 1, 327–339(1994).PubMedCrossRefGoogle Scholar
  10. 10.
    M. P. Cooke, A. W. Heath, K. M. Shokat, Y. Zeng, F. D. Finkelman, P. S. Linsley, M. Howard, C. C. Goodnow, Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells, J. Exp. Med. 179, 425–438(1994).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Schwartz, T cell clonal anergy, xCurr. Opin. Immunol. 9, 351–357(1997).Google Scholar
  12. 12.
    S. Akkaraju, W. Y. Ho, D. Leong, K. Canaan, M. M. Davis, C. C. Goodnow, A range of CD4 T cell tolerance: partial inactivation to organ-specific antigen allows nondestructive thyroiditis or insulitis, Immunity 7, 255–271(1997).PubMedCrossRefGoogle Scholar
  13. 13.
    C. C. Goodnow, R. Brink, E. Adams, Breakdown of self-tolerance in anergic B lymphocytes, Nature 352, 532–536(1991).PubMedCrossRefGoogle Scholar
  14. 14.
    A. O’Garra, L. Steinman, K. Gijbels, CD4+ T-cell subsets in autoimmunity, Curr Opin Immunol 9, 872–883(1997).PubMedCrossRefGoogle Scholar
  15. 15.
    S. Cobbold, H. Waldmann, Infectious tolerance, Curr Opin Immunol 10, 518–524(1998).PubMedCrossRefGoogle Scholar
  16. 16.
    P. L. Cohen, R. A. EisenbergLprand gld: single gene models of systemic autoimmunity and lymphoproliferative disease, Ann. Rev. Immunol. 9, 243–269(1991).CrossRefGoogle Scholar
  17. 17.
    J. C. Rathmell, C. C. Goodnow, Effects of theIprmutation on elimination and inactivation of self-reactive B cells, J. Immunol. 153, 2831–2842(1994).Google Scholar
  18. 18.
    R. Watanabe-Fukunaga, C. I. Branna, N. G. Copeland, N. A. Jenkins, S. Nagata, Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis, Nature 356, 314–317(1992).PubMedCrossRefGoogle Scholar
  19. 19.
    G. Fisher, F. Rosenberg, S. Straus, J. Dale, L. Middelton, A. Lin, W. Strober, M. Lenardo, J. Puck, Dominant Interfering Fas Gene Mutations Impair Apoptosis in a Human Autoimmune Lymphoproliferative Syndrome, Cell 81, 935–946(1995).CrossRefGoogle Scholar
  20. 20.
    F. Rieux-Laucat, F. Le Deist, C. Hivroz, A. Roberts, K. Debatin, A. Fischer, J. de Villartay, Mutations in Fas Associated with Human Lymphoproliferative Syndrome and Autoimmunity, Science 268, 1347–1349(1995).PubMedCrossRefGoogle Scholar
  21. 21.
    E. S. Sobel, T. Katagiri, K. Katagiri, S. C. Morris, P. L. Cohen, R. A. Eisenberg, An intrinsic B cell defect is required for the production of autoantibodies in theIprmodel of murine systemic autoimmunity, J. Exp. Med. 173, 1441–1449(1991).PubMedCrossRefGoogle Scholar
  22. 22.
    H. Fukuyama, M. Adachi, S. Suematsu, K. Miwa, T. Suda, N. Yoshida, S. Nagata, Transgenic expression of Fas in T cells blocks lymphoproliferation but not autoimmune disease in MRL-lpr mice, J Immunol 160, 3805–3811(1998).PubMedGoogle Scholar
  23. 23.
    H. Komano, Y. Ikegami, M. Yokoyama, R. Suzuki, S. Yonehara, Y. Yamasaki, N. Shinohara, Severe impairment of B cell function inIpr/lprmice expressing transgenic Fas selectively on B cells, Int Immunol 11, 1035–1042(1999).PubMedCrossRefGoogle Scholar
  24. 24.
    S. E. Townsend, C. C. Goodnow, Abortive proliferation of rare T cells induced by direct or indirect antigen presentation by rare B cells in vivo, J. Exp Med 187, 1611–1621(1998).PubMedCrossRefGoogle Scholar
  25. 25.
    E. S. Sobel, P. L. Cohen, R. A. EisenbergIprT cells are necessary for autoantibody production in Iprmice, J. Immunol. 150, 4160–4167(1993).PubMedGoogle Scholar
  26. 26.
    J. Wu, T. Zhou, J. Zhang, J. He, W. Gause, J. Mountz, Correction of accelerated autoimmune disease by early replacement of the mutatedIprgene with the normal Fas apoptosis gene in the T cells of transgenicMRL-Ipr/lprmice, Proc Natl Acad Sci U S A 15, 2344–2348(1994).CrossRefGoogle Scholar
  27. 27.
    D. Y. Mason, M. Jones, C. C. Goodnow, Development and follicular localization of tolerant B lymphocytes in lysozyme/anti-lysozyme IgM/IgD transgenic mice, International Immunol. 4, 163–175(1992).CrossRefGoogle Scholar
  28. 28.
    J. C. Rathmell, S. E. Townsend, J. C. Xu, R. A. Flavell, C. C. Goodnow, Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor, Cell 87, 319–329(1996).PubMedCrossRefGoogle Scholar
  29. 29.
    D. J. Lenschow, A. I. Sperling, M. P. Cooke, G. Freeman, L. Rhee, D. C. Decker, G. Gray, L. M. Nadler, C. C. Goodnow, J. A. Bluestone, Differential up-regulation of the B7–1 and B7–2 costimulatory molecules after Ig receptor engagement by antigen, J Immunol 153, 1990–1997(1994).Google Scholar
  30. 30.
    W. Y. Ho, M. P. Cooke, C. C. Goodnow, M. M. Davis, Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells, J. Exp. Med. 179, 1539–1549(1994).PubMedCrossRefGoogle Scholar
  31. 31.
    J. C. Rathmell, S. Fournier, B. Weintraub, J. Allison, C. Goodnow, Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4(+) T cells, J Exp Med 188, 651–659(1998).PubMedCrossRefGoogle Scholar
  32. 32.
    L. Foote, A. Marshak-Rothstein, T. Rothstein, Tolerant B lymphocytes acquire resistance to Fas-mediated apoptosis after treatment with interleukin 4 but not after treatment with specific antigen unless a surface immunoglobulin threshold is exceeded, J Exp Med 187, 847–853(1998).PubMedCrossRefGoogle Scholar
  33. 33.
    K. Erb, B. Ruger, M. von Brevern, B. Ryffel, A. Schimpl, K. Riven, Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in mice, J Exp Med 185, 329–339(1997).PubMedCrossRefGoogle Scholar
  34. 34.
    T. Schneider, G. Fischer, T. Donohoe, T. Colarusso, R. TL, A novel gene coding for a Fas apoptosis inhibitory molecule (FAIM) isolated from inducibly Fas-resistant B lymphocytes, J Exp Med 189, 949–956(1999).Google Scholar
  35. 35.
    T. Schneider, D. Grillot, L. Foote, G. Nunez, T. Rothstein, Bcl-x protects primary B cells against Fas-mediated apoptosis, J Immunol 159, 4834–4839(1997).PubMedGoogle Scholar
  36. 36.
    R. J. Grumont, I. J. Rourke, S. Gerondakis, Rel-dependent induction of Al transcription is required to protect B cells from antigen receptor ligation-induced apoptosis, Genes Dev 13, 400–411(1999).PubMedCrossRefGoogle Scholar
  37. 37.
    J. I. Healy, R. E. Dolmetsch, R. S. Lewis, C. C. Goodnow, Quantitative and qualitative control of antigen receptor signalling in tolerant B lymphocytes, Novartis Found Symp 215, 137–144(1998).PubMedGoogle Scholar
  38. 38.
    R. Glynne, S. Akkaraju, J. I. Healy, J. Rayner, C. C. Goodnow, D. H. Mack, How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis, Nature 403, 672–676(2000).PubMedCrossRefGoogle Scholar
  39. 39.
    J. I. Healy, R. E. Dolmetsch, L. A. Timmerman, J. G. Cyster, M. L. Thomas, G. R. Crabtree, R. S. Lewis, C. C. Goodnow, Different nuclear signals are activated by the B cell receptor during positive versus negative signaling, Immunity 6, 419–428(1997).PubMedCrossRefGoogle Scholar
  40. 40.
    S. Hitotsumachi, D. A. Carpenter, W. L. Russell, Dose-repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia, Proc natl Acad Sci USA 82, 6619–6621(1985).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Christopher C. Goodnow
    • 1
  • Richard Glynne
    • 2
  • Srini Akkaraju
    • 2
  • Jane Rayner
    • 1
  • David Mack
    • 3
  • James I. Healy
    • 2
  • Shirine Chaudhry
    • 1
  • Lisa Miosge
    • 1
  • Lauren Wilson
    • 1
  • Peter Papathanasiou
    • 1
  • Adele Loy
    • 1
  1. 1.ACRF Genetics Laboratory, Medical Genome Centre, John Curtin School of Medical ResearchAustralian National UniversityCanberraAustralia
  2. 2.Dept of Microbiology and ImmunologyStanford University School of MedicineStanfordUSA
  3. 3.AffymetrixSanta ClaraUSA

Personalised recommendations