Autoimmunity Due to Defective NUR77, Fas, and TNF-RI Apoptosis

  • John D. Mountz
  • Carl K. EdwardsIII
  • Jianhua Cheng
  • Pingar Yang
  • Zheng Wang
  • Changdan Liu
  • Xiao Su
  • Horst Bluethmann
  • Tong Zhou
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 406)


Several molecules and pathways known to be of importance in apoptosis have been described in the thymus; however, their contribution to clonal deletion and tolerance induction remains controversial1–4. Although knockout of p53 leads to decreased sensitivity of murine thymocytes to radiation-induced apoptosis, negative selection remains intact5–7. Fas is a cell surface receptor that mediates apoptosis by interaction with a specific ligand and is expressed on most murine thymocytes8–11. Although mutant Fas antigen and Fas ligand cause autoimmune disease in 1pr/lpr and gld/gld mice, respectively10–12 no major negative selection defects have been found in Ipr/lpr mice13–17. Therefore, it is unlikely that Fas antigen is directly involved in negative selection in the thymus, but may be involved in apoptosis during early T cell development in the thymus. We have previously proposed that Fas expression duirng early thymocyte development plays a role in positive selection or pre-positive selection of thymocytes (Figure 1).


Negative Selection Double Positive Thymocyte Apoptosis Double Positive Thymocyte Transgenic Male Mouse 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G.J.V. Nossal, Negative selection of lymphocytes. Cell 76: 229 (1994).PubMedCrossRefGoogle Scholar
  2. 2.
    P. Golstein, D.M. Ojcius, and J.D. Young, Cell death mechanisms and the immune system. Immunol. Rev. 121: 29 (1991).PubMedCrossRefGoogle Scholar
  3. 3.
    B. Lucas, F. Vasseur, and C. Penit, Production, selection, and maturation of thymocytes with high surface density of TCR. J. Immunol. 153: 53 (1994).PubMedGoogle Scholar
  4. 4.
    J.A. Punt, B.A. Osborne, Y. Takahama, S.O. Sharrow, and A. Singer, Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28. J. Exp. Med. 179: 709 (1994).PubMedCrossRefGoogle Scholar
  5. 5.
    A.R. Clarke, C.A. Purdie, D.J. Harrison, R.G. Morris, C.C. Bird, M.L. Hooper, and A.H. Wyllie, Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 362: 849 (1993).PubMedCrossRefGoogle Scholar
  6. 6.
    S.W. Lowe, E.M. Schmitt, S.W. Smith, B.A. Osborne, and T. Jacks,p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847 (1993).Google Scholar
  7. 7.
    J.M. Lee and A. Bernstein, p53 mutations increase resistance to ionizing radiation. Proc. Natl. Acad. Sci. USA. 90: 5742 (1993).PubMedCrossRefGoogle Scholar
  8. 8.
    T. Suda, T. Takahashi, P. Golstein, and S. Nagata, Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 75: 1169 (1993).PubMedCrossRefGoogle Scholar
  9. 9.
    S. Nagata and P. Golstein. The Fas death factor. Science. 267: 1449 (1995).PubMedCrossRefGoogle Scholar
  10. 10.
    R. Watanabe-Fukunaga, C.I. Brannan, N.G. Copeland, N.A. Jenkins, and S. Nagata, Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 356: 314 (1992).PubMedCrossRefGoogle Scholar
  11. 11.
    D. Lynch, M. Watson, M.R. Alderson, P.R. Baum, R.E. Miller, T. Tough, M. Gibson, T. Davis-Smith, C.A. Smith, K. Hunter, D. Bhat, W. Din, R.G. Goodwin, and M.F Seldin, The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity. 1: 131 (1994).PubMedCrossRefGoogle Scholar
  12. 12.
    T. Takahashi, M. Tanaka, C.I. Brannan, N.A. Jenkins, N.G. Copeland, T. Suda, and S. Nagata, Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 76: 969 (1994).PubMedCrossRefGoogle Scholar
  13. 13.
    B.L. Kotzin, S.K. Babcock, and L.R. Herron, Deletion of potentially self-reactive T cell receptor specificities in L3T4-, Lyt2- T cells of 1pr mice. J. Exp. Med. 168: 2221 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    P.A. Singer, R.S. Balderas, R.J. McEvilly, M. Bobardt, and A.N. Theofilopoulos, Tolerance-related Vß clonal deletions in normal CD4–CD8-, TCR-a/ß+ and abnormal 1pr and gld cell populations. J. Exp. Med. 170: 1869 (1989).PubMedCrossRefGoogle Scholar
  15. 15.
    J.D. Mountz, T.M. Smith, and K.S. Toth, Altered expression of self-reactive T cell receptor V(3 regions in autoimmune mice. J. Immunol. 144: 2159 (1990).PubMedGoogle Scholar
  16. 16.
    T. Zhou, H. Bluethmann, J. Eldridge, K. Berry, and J.D. Mountz, Abnormal thymocyte development and production of autoreactive T cells in TCR transgenic autoimmune mice. J. Immunol. 147: 466 (1991).PubMedGoogle Scholar
  17. 17.
    T. Zhou, J.D. Mountz, C.K. Edwards, III, K. Berry, and H. Bluethmann, Defective maintenance of T cell tolerance to a superantigen in MRL-1pr/lpr. J. Exp. Med. 176: 1063 (1992).CrossRefGoogle Scholar
  18. 18.
    R.P. Bissonnette, F. Echeverri, A. Mahboubi, and D.R Green, Apoptotic cell death induced by c-myc is inhibited by bc1–2. Nature. 359: 552 (1992).CrossRefGoogle Scholar
  19. 19.
    A. Fanidi, E.A. Harrington, and G.I. Evan, Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 359: 554 (1992).PubMedCrossRefGoogle Scholar
  20. 20.
    A. Strasser, A.W. Harris, and S. Cory, Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 67: 889 (1991).Google Scholar
  21. 21.
    N.C. Moore, G. Anderson, G.T. Williams, and J.J Owen, Developmental regulation of bc1–2 expression in the thymus. Immunology. 81: 115 (1994).PubMedGoogle Scholar
  22. 22.
    D. Veis, C.M. Sorenson, J.R. Shutter, and S.J. Korsmeyer, Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 75: 229 (1993).PubMedCrossRefGoogle Scholar
  23. 23.
    M. Katsumata, R.M. Siegel, D.C. Louie, T. Miyashita, Y. Tsujimoto, P.C. Nowell, M.I. Greene, and J.C. Reed, Differential effects of bc1–2 on T and B cells in transgenic mice. Proc. Natl. Acad. Sci. USA. 89: 11376 (1992).PubMedCrossRefGoogle Scholar
  24. 24.
    R.M. Siegel, M. Katsumata, T. Miyashita, D.C. Louie, M.I. Greene, and J.C. Reed, Inhibition of thymocyte apoptosis and negative antigenic selection in bcl-2 transgenic mice. Proc. Natl. Acad. Sci., USA. 89: 7003 (1992).CrossRefGoogle Scholar
  25. 25.
    C.L. Sentman, J.R. Shutter, D. Hockenbery, O. Kanagawa, and S. Korsmeyer, Bc1–2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 67: 879 (1991).Google Scholar
  26. 26.
    A. Strasser, A.W. Harris, H. von Boehmer, and S. Cory, Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a Bcl-2 transgene. Proc. Natl. Acad. Sci. USA. 91: 1376 (1994).PubMedCrossRefGoogle Scholar
  27. 27.
    K. Lundberg and K. Shortman, Small cortical thymocytes are subject to positive selection. J. Exp. Med. 179: 1475 (1994).PubMedCrossRefGoogle Scholar
  28. 28.
    W. Tao, S.J. Teh, I. Melhado, F. Jirik, S.J. Korsmeyer, and H.S. Teh, The T cell receptor repertoire of CD4–8+ thymocytes is altered by overexpression of the bcl-2 protooncogene in the thymus. J. Exp. Med. 179: 145 (1994).PubMedCrossRefGoogle Scholar
  29. 29.
    J. Milbrandt, Nerve growth factor induces a gene homologous to the glucocorcoid receptor gene. Neuron. 1: 183 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    T.G. Hazel, D. Nathans, and L.F. Lau, A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc. Natl. Acad. Sci. USA. 85: 8444 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    G.T. Williams and L.F. Lau, Activation of the inducible orphan receptor gene Nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol. Cell Biol. 13: 6124 (1993).PubMedGoogle Scholar
  32. 32.
    S.R. Abu-Shakra, A.J. Cole, and D.B. Drachman, Nerve stimulation and denervation induce differential patterns of immediate early gene mRNA expression in skeletal muscle. Brain Res. Mol. Brain Res. 18: 216 (1993).PubMedCrossRefGoogle Scholar
  33. 33.
    S.W. Law, O.M. Conneely, F.J. DeMayo, and B.W. O’Malley, Identification of a new brain-specific transcription factor, NurRl. Mol. Endocrinol. 6: 2129 (1992).PubMedCrossRefGoogle Scholar
  34. 34.
    I.J. Davis, T.G. Hazel, R.H. Chen, J. Blenis, and L.F. Lau, Functional domains and phosphorylation of the orphan receptor Nur77. Mol. Endocrinol. 7: 953 (1993).PubMedCrossRefGoogle Scholar
  35. 35.
    J.K. Yoon and L.F. Lau, Transcriptional activation of the inducible nuclear receptor gene Nur77 by nerve growth factor and membrane depolarization in PC 12 cells. J. Biol. Chem. 268: 9148 (1993).PubMedGoogle Scholar
  36. 36.
    T.E. Wilson, T.J. Fahrner, M. Johnston, and J. Milbrandt, Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science. 252: 1296 (1991).PubMedCrossRefGoogle Scholar
  37. 37.
    T.E. Wilson, R.E. Paulsen, K.A. Padgett, and J. Milbrandt, Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Science. 256: 107 (1992).PubMedCrossRefGoogle Scholar
  38. 38.
    Z-G. Liu, S.W. Smith, K.A. McLaughlin, L.M. Schwartz, and B.A. Osborne, Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene Nur77. Nature. 367: 281 (1994).PubMedCrossRefGoogle Scholar
  39. 39.
    J.D. Woronica, B. Cainan, V. Ngo, and A. Winoto, Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature. 367: 277 (1994).CrossRefGoogle Scholar
  40. 40.
    T. Okabe, R. Takayanagi, K. Imasaki, H. Masafumi, H. Nawata, and T. Watanabe, cDNA cloning of a NGF1-B/Nur77-related transcription factor from an apoptotic human T cell line. J. Immunol. 154: 3871 (1995).PubMedGoogle Scholar
  41. 41.
    Y. Yang, M. Mercep, C.F. Ware, and J.D. Ashwell, Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids. J. Exp. Med. 181: 1673 (1995).PubMedCrossRefGoogle Scholar
  42. 42.
    M.S. Vacchio, V. Papadopoulos, J.D. Ashwell, Steroid production in the thymus: implications for thymocyte selection. J. Exp. Med. 179: 1835 (1994).PubMedCrossRefGoogle Scholar
  43. 43.
    S.L. Lee, R.L. Wesselschmidt, G.P. Linette, O. Kanagawa, J.H. Russell, and J. Milbrandt, Unimpared thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B Nur77. Science. 269: 532 (1995).PubMedCrossRefGoogle Scholar
  44. 44.
    J. Kaye, M.-L. Hsu, M.-E. Sauron, S.C. Jameson, N.R.J. Gascoigne, and S.M. Hedrick, Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 341: 746 (1989).PubMedCrossRefGoogle Scholar
  45. 45.
    J. Kaye and S.M. Hedrick, Analysis of specificity for antigen, Mls, and allogeneic MHC by transfer of T-cell receptor a-and 3-chain genes. Nature. 336: 580 (1988).PubMedCrossRefGoogle Scholar
  46. 46.
    P. Kisielow, H. Bluethmann, U.D. Staerz„ M. Steinmetz, and H. von Boehmer, Tolerance in T-cell receptor transgenic mice involves deletion of immature CD4+8+ thymocytes. Nature. 333: 742 (1988).PubMedCrossRefGoogle Scholar
  47. 47.
    P. Kisielow, H.S. Teh, H. Bluethmann, and H. von Boehmer, Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature. 335: 730 (1988).PubMedCrossRefGoogle Scholar
  48. 48.
    H. von Boehmer, Developmental biology of T cells in T cell receptor transgenic mice. Annu. Rev. Immunol. 8: 531 (1990).PubMedCrossRefGoogle Scholar
  49. 49.
    H-S. Teh, H. Kishi, B. Scott, and H. von Boehmer, Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules. J. Exp. Med. 169: 795 (1989).PubMedCrossRefGoogle Scholar
  50. 50.
    T. Zhou, H. Bluethmann, J. Eldridge, K. Berry, and J.D. Mountz, Origin of CD4–CD8-B220+ T cells in MRL-1pr/lpr mice. Clues from a T cell receptor (3 transgenic mouse. J. Immunol. 150: 3651 (1993).PubMedGoogle Scholar
  51. 51.
    M.C. Kiefer, M.J. Brauer, V.C. Powers, J.J. Wu, S.R. Umansky, L.D. Tomei, and P.J. Barr, Modulation of apoptosis by the widely distributed bc1–2 homologue Bak. Nature. 374: 736 (1995).PubMedCrossRefGoogle Scholar
  52. 52.
    E. Yang, J. Zha, J. Jockel, L.H. Boise, C.B Thompson, and S.J. Korsmeyer, Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 80: 285 (1995).PubMedCrossRefGoogle Scholar
  53. 53.
    X.M. Yin, Z.N. Oltval, and S.J. Korsmeyer, BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 369: 321 (1994).PubMedCrossRefGoogle Scholar
  54. 54.
    Z.N. Oltvai, C.L. Milliman, and S.J. Korsmeyer, Bc1–2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74: 609 (1993).PubMedCrossRefGoogle Scholar
  55. 55.
    S.T. Ju, D.J. Panka, H. Cui, R. Ettinger, M. el-Khatib, D.H. Sherr, B.Z. Stanger, and A. Marshak-Rothstein, Fas (CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 373: 444 (1995).PubMedCrossRefGoogle Scholar
  56. 56.
    T. Brunner, R.J. Mogil, D. LaFace, N.J. Yoo, A. Mahboubi, F. Echeverri, S.J. Martin, W.R. Force, D.H. Lynch, and C.F. Ware, Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 373: 441 (1995).PubMedCrossRefGoogle Scholar
  57. 57.
    J. Dhein, H. Walczak, C. Baumler, K.M. Debatin, and P.H. Krammer, Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature. 373: 438 (1995).PubMedCrossRefGoogle Scholar
  58. 58.
    M.R. Alderson, T.W. Tough, T. Davis-Smith, S. Braddy, B. Falk, K.A. Schooley, R.G. Goodwin, C.A. Smith, F. Ramsdell, and D.H. Lynch, Fas ligand mediates activation-induced cell death in human T lymphocytes. J. Exp. Med. 181: 71 (1995).CrossRefGoogle Scholar
  59. 59.
    D. Kabelitz, T. Pohl, and K. Pechhold, Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes. Immunol. Today. 14: 339 (1993).CrossRefGoogle Scholar
  60. 60.
    D.R. Green and D.W. Scott, Activation-induced apoptosis in lymphocytes. Curr. Opin. Immunol. 6: 476 (1994).PubMedCrossRefGoogle Scholar
  61. 61.
    W.F. Davidson, C. Calkins, A. Hugins, T. Giese, and K.L. Holmes, Cytokine secretion by C3H-lpr and -gld T cells. Hypersecretion of IFN-y and tumor necrosis factor-a by stimulated CD4+ T cells. J. Immunol. 146: 4138 (1991).PubMedGoogle Scholar
  62. 62.
    J.D. Mountz, T.J. Baker, D.R. Borcherding, H. Bluethmann, T. Zhou, and C.K. Edwards, III, Increased susceptability of fas mutant MRL-1pr/lpr mice to staphylococcal enterotoxin B-induced septic shock. J. Immunol. 155: 4829 (1995).PubMedGoogle Scholar
  63. 63.
    T. Zhou, J.D. Mountz, C.K. Edwards, III, K. Berry, and H. Bluethmann, Defective maintenance of T cell tolerance to a superantigen in MRL-1pr/Ipr. J. Exp. Med. 176: 1063 (1992).CrossRefGoogle Scholar
  64. 64.
    J.D. Mountz, T. Zhou, R.E. Long, H. Bluethmann, W.J. Koopman, and C.K. Edwards, III, T cell influence on superantigen-induced arthritis in MRL-1pr/lpr mice. Arthritis Rheum. 37: 113 (1994).PubMedCrossRefGoogle Scholar
  65. 65.
    L. Zheng, G. Fisher, R.E. Miller, J. Peschon, D. Lynch, and M.J. Lenardo, Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 377: 348 (1995).PubMedCrossRefGoogle Scholar
  66. 66.
    L.A. Tartaglia, T.M. Ayres, G.H. Wong, and D.V. Goeddel, A novel domain within the 55 kd TNF receptor signals cell death. Cell. 74: 845 (1993).PubMedCrossRefGoogle Scholar
  67. 67.
    N. Itoh, and S. Nagata, A novel protein domain required for apoptosis, Mutational analysis of human Fas antigen. J. Biol. Chem. 268: 10932 (1993).PubMedGoogle Scholar
  68. 68.
    B.Z. Stanger, P. Leder, T.H. Lee, E. Kim, and B. Seed, RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 81: 513 (1995).PubMedCrossRefGoogle Scholar
  69. 69.
    A.M. Chinnaiyan, K. O’Rourke, M. Tewari, and V.M. Dixit, FADD, a novel death domain-containing protein, interacts with /he death domain of Fas and initiates apoptosis. Cell. 81: 505 (1995).PubMedCrossRefGoogle Scholar
  70. 70.
    M.P. Boldin, E.E. Varf6lomeev, Z. Pancer, I.L. Mett, J.H. Camonis, and D.Wallach. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270: 7795 (1995).PubMedCrossRefGoogle Scholar
  71. 71.
    M.P. Boldin, I.L. Mett, E.E. Varfolomeev, I. Chumakov, Y. Shemer-Avni, J.H. Camonis, and D. Wallach, Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APOI prompts signaling for TNF and Fas/APO1 effects. J. Biol. Chem. 270: 387 (1995).PubMedCrossRefGoogle Scholar
  72. 72.
    H. Hsu, J. Xiong, and D.V. Goeddel, The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 81: 495 (1995).PubMedCrossRefGoogle Scholar
  73. 73.
    G.H.W. Wong, and D. Goeddel, Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. J. Immunol. 152: 1751, (1994).Google Scholar
  74. 74.
    K. Schulze-Osthoff, P.H. Krammer, and W. Droge, Divergent signalling via APO-1/Fas and the TNF receptor, two homologous molecules involved in physiological cell death. EMBO J. 13: 4587 (1994).PubMedGoogle Scholar
  75. 75.
    L.A. Tartaglia, M. Rothe, Y-F. Hu, and D.V. Goeddel, Tumor necrosis factor’s cytotoxic activity is signaled by the p55 TNF receptor. Cell 73: 213 (1993).PubMedCrossRefGoogle Scholar
  76. 76.
    A. Sarin, M. Conan-Cibotti, and P.A. Henkart, Cytotoxic effect of TNF and lymphotoxin on T lymphoblasts. J. Immunol. 155: 3716 (1995).PubMedGoogle Scholar
  77. 77.
    R.A. Heller, K. Song, and N. Fan. Cytotoxicity by tumor necrosis factor is mediated by both p55 and p70 receptors. Cell 73: 213 (1993).CrossRefGoogle Scholar
  78. 78.
    K.C.F. Sheehan, J.K. Pinckard, C.D. Arthur, L.P. Dehner, D.V. Goeddel, and R.D. Schreiber, Monoclonal antibodies specific for murine p55 and p75 tumor necrosis factor receptors: identification of a novel in vivo role for p75. J. Exp. Med. 181: 607 (1995).PubMedCrossRefGoogle Scholar
  79. 79.
    J. Rothe, W. Lesslauer, H. Loetscher, Y. Lang, P. Koebel, F. Kontgen, A. Althage, R. Zinkernagel, M. Steinmetz, and H. Bluethmann, Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature (Lond) 364: 798 (1993).CrossRefGoogle Scholar
  80. 80.
    K. Pfeffer, T. Matsuyama, T.M. Kündig, A. Wakeham, K. Kishihara, A. Shahinian, K. Wiegmann, P.S. Ohashi, M. Krönke, and T.W. Mak, Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73: 457 (1993).PubMedCrossRefGoogle Scholar
  81. 81.
    S.L. Erickson, F.J. de Sauvage, K. Kikly, K. Carver-Moore, S. Pitts-Meek, N. Gillett, K.C.F. Sheehan, R.D. Schreiber, D.V. Goeddel, and M.W. Moore, Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature 372: 560 (1994).PubMedCrossRefGoogle Scholar
  82. 82.
    P. Vassalli, The pathophysiology of tumor necrosis factors. Annu. Rev. Immunol. 10: 411 (1992).PubMedCrossRefGoogle Scholar
  83. 83.
    C.O. Jacob and H.O. McDevitt, Tumour necrosis factor-alpha in murine autoimmune `lupus’ nephritis. Nature 331: 356 (1988).CrossRefGoogle Scholar
  84. 84.
    X.D. Yang, R. Tisch, S.M. Singer, Z.A. Cao, R.S. Liblau, R.D. Schreiber, H.O. McDevitt, Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J. Exp. Med. 180: 995 (1994).PubMedCrossRefGoogle Scholar
  85. 85.
    S. Gerder, D.E. Picarella, P.S. Linsley, R.A. Flavell, Costimulator B7–1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice. Proc. Natl. Acad. Sci., USA 91: 5138 (1994).CrossRefGoogle Scholar
  86. 86.
    A. Schattner, Lymphokines in autoimmunity-a critical review. Clin. Immunol. Immunopathol. 70: 177 (1994).PubMedCrossRefGoogle Scholar
  87. 87.
    H. Ishida, T. Muchamuel, S. Sakaguchi, S. Andrade, S. Menon, and M. Howard, Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J. Exp. Med. 179: 305 (1994).PubMedCrossRefGoogle Scholar
  88. 88.
    C.O. Jacob, Studies on the role of tumor necrosis factor in mutine and human autoimmunity. J. Autoimmun. 5: 133 (1992).PubMedCrossRefGoogle Scholar
  89. 89.
    P.W. Gray, K. Barrett, D. Chantry, M. Turner, and M. Feldmann, Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein. Proc. Natl. Acad. Sci., USA 87: 7380 (1990).CrossRefGoogle Scholar
  90. 90.
    F.M. Brennan, D.L. Gibbons, A.P. Cope, P. Katsikis, R.N. Maini, M. Feldmann, TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand. J. Immunol. 42: 158, (1995).PubMedCrossRefGoogle Scholar
  91. 91.
    A. Ashkenazi, S.A. Marsters, D.J. Capon, S.M. Chamow, I.S. Figari, D. Pennica, D.V. Goeddel, M.A. Palladino, and D.H. Smith, Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. Proc. Natl. Acad. Sci., USA 88: 10535, (1991).CrossRefGoogle Scholar
  92. 92.
    M. Feldmann, F.M. Brennan, R.O. Williams, A.P. Cope, D.L. Gibbons, P.D. Katsikis, R.N. Maini, Evaluation of the role of cytokines in autoimmune disease: the importance of TNF alpha in rheumatoid arthritis. Prog. Growth Factor Res. 4: 247, (1992).PubMedCrossRefGoogle Scholar
  93. 93.
    C.O. Jacob, Tumor necrosis factor alpha in autoimmunity: pretty girl or old witch? Immunol Today 13: 122 (1992).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • John D. Mountz
    • 1
    • 2
  • Carl K. EdwardsIII
    • 3
  • Jianhua Cheng
    • 1
    • 2
  • Pingar Yang
    • 1
  • Zheng Wang
    • 1
  • Changdan Liu
    • 1
  • Xiao Su
    • 1
  • Horst Bluethmann
    • 4
  • Tong Zhou
    • 1
  1. 1.Department of Medicine Division of Clinical Immunology and RheumatologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.The Birmingham Veterans Administration Medical CenterBirminghamUSA
  3. 3.Department of InflammationAmgen Boulder, Inc.BoulderUSA
  4. 4.Pharmaceutical Research Gene TechnologiesF. Hoffmann-LaRoche, Ltd.BaselSwitzerland

Personalised recommendations