The Journal of Allergy and Clinical Immunology
Volume 103, Issue 5 , Pages 729-738 , May 1999

The role of Fas and related death receptors in autoimmune and other disease states

Received 1 February 1999 ,Revised 2 March 1999 ,Accepted 2 March 1999.

References 

  1. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257
  2. Nicholson D, Thornberry N. Caspases: killer proteases. Trends Biochem Sci. 1997;22:299–306
  3. Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, et al.  Monoclonal antibody–mediated tumor regression by induction of apoptosis. Science. 1989;245:301–305
  4. Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, et al.  The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991;66:233–243
  5. Tartaglia LA, Ayres TM, Wong GH, Goeddel DV. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993;74:845–853
  6. Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75:1169–1178
  7. Tanaka M, Suda T, Takahashi T, Nagata S. Expression of the functional soluble form of human fas ligand in activated lymphocytes. EMBO J. 1995;14:1129–1135
  8. Screaton GR, Xu XN, Olsen AL, Cowper AE, Tan R, McMichael AJ, et al.  LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. Proc Natl Acad Sci U S A. 1997;94:4615–4619
  9. Chinnaiyan AM, O’Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, et al.  Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science. 1996;274:990–992
  10. Kitson J, Raven T, Jiang YP, Goeddel DV, Giles KM, Pun KT, et al.  A death-domain-containing receptor that mediates apoptosis. Nature. 1996;384:372–375
  11. Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J. Characterization of two receptors for TRAIL. FEBS Lett. 1997;416:329–334
  12. Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T, et al.  TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-κB. Immunity. 1997;7:831–836
  13. Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science. 1998;279:1954–1958
  14. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997;277:815–818
  15. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, et al.  TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J. 1997;16:5386–5397
  16. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, et al.  Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277:818–821
  17. Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF, et al.  Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med. 1997;186:1165–1170
  18. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, et al.  A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol. 1997;7:1003–1006
  19. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992;356:314–317
  20. Lynch DH, Watson ML, Alderson MR, Baum PR, Miller RE, Tough T, et al.  The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity. 1994;1:131–136
  21. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, et al.  Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995;14:5579–5588
  22. Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D. A novel protein that interacts with the death domain of Fas-Apo-1 contains a sequence motif related to the death domain. J Biol Chem. 1995;270:7795–7798
  23. Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995;81:505–512
  24. Eberstadt M, Huang B, Chen Z, Meadows RP, Ng SC, Zheng L, et al.  NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature. 1998;392:941–945
  25. Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, et al.  FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell. 1996;85:817–827
  26. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1995;85:803–815
  27. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, et al.  Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 1998;17:1675–1687
  28. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996;85:803–815
  29. Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. An induced proximity model for caspase-8 activation. J Biol Chem. 1998;273:2926–2930
  30. Martin DA, Siegel RM, Zheng L, Lenardo MJ. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal. J Biol Chem. 1998;273:4345–4349
  31. Zhang J, Cado D, Chen A, Kabra NH, Winoto A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature. 1998;392:296–300
  32. Wadsworth S, Yui K, Siegel RM, Tenenholz DE, Hirsch JA, Greene MI. Origin and selection of peripheral CD4-CD8- T cells bearing alpha/beta T cell antigen receptors in autoimmune gld mice. Eur J Immunol. 1990;20:723–730
  33. Herron LR, Eisenberg RA, Roper E, Kakkanaiah VN, Cohen PL, Kotzin BL. Selection of the T cell receptor repertoire in Lpr mice. J Immunol. 1993;151:3450–3459
  34. Miyawaki T, Uehara T, Nibu R, Tsuji T, Yachie A, Yonehara S, et al.  Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. J Immunol. 1992;149:3753–3758
  35. Peter ME, Kischkel FC, Scheuerpflug CG, Medema JP, Debatin KM, Krammer PH. Resistance of cultured peripheral T cells towards activation-induced cell death involves a lack of recruitment of FLICE (MACH/caspase 8) to the CD95 death-inducing signaling complex. Eur J Immunol. 1997;27:1207–1212
  36. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, et al.  Inhibition of death receptor signals by cellular FLIP. Nature. 1997;388:190–195
  37. Combadiere B, Freedman M, Chen L, Shores EW, Love P, Lenardo MJ. Qualitative and quantitative contributions of the T cell receptor zeta chain to mature T cell apoptosis. J Exp Med. 1996;183:2109–2117
  38. Combadiere B, e Sousa CR, Germain RN, Lenardo MJ. Selective induction of apoptosis in mature T lymphocytes by variant T cell receptor ligands. J Exp Med. 1998;187:349–355
  39. Hornung F, Zheng L, Lenardo MJ. Maintenance of clonotype specificity in CD95/Apo-1/Fas-mediated apoptosis of mature T lymphocytes. J Immunol. 1997;159:3816–3822
  40. Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995;377:348–351
  41. Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L, et al.  Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med. 1997;185:1837–1849
  42. Van Parijs L, Peterson DA, Abbas AK. The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens. Immunity. 1998;8:265–274
  43. Kuroda K, Yagi J, Imanishi K, Yan XJ, Li XY, Fujimaki W, et al.  Implantation of IL-2-containing osmotic pump prolongs the survival of superantigen-reactive T cells expanded in mice injected with bacterial superantigen. J Immunol. 1996;157:1422–1431
  44. Nemazee D, Guiet C, Buerki K, Marshak-Rothstein A. B lymphocytes from the autoimmune-prone mouse strain MLR/lpr manifest an intrinsic defect in tetraparental MRL/lpr in equilibrium DBA/2 chimeras. J Immunol. 1991;147:2536–2539
  45. Goodnow CC, Cyster JG, Hartley SB, Bell SE, Cooke MP, Healy JI, et al.  Self-tolerance checkpoints in B lymphocyte development. Adv Immunol. 1995;59:279–368
  46. Erikson J, Mandik L, Bui A, Eaton A, Noorchashm H, Nguyen KA, et al.  Self-reactive B cells in nonautoimmune and autoimmune mice. Immunol Res. 1998;17:49–61
  47. Rathmell JC, Townsend SE, Xu JC, Flavell RA, Goodnow CC. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell. 1996;87:319–329
  48. Rothstein TL, Wang JK, Panka DJ, Foote LC, Wang Z, Stanger B, et al.  Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells. Nature. 1995;374:163–165
  49. Foote LC, Schneider TJ, Fischer GM, Wang JK, Rasmussen B, Campbell KA, et al.  Intracellular signaling for inducible antigen receptor-mediated Fas resistance in B cells. J Immunol. 1996;157:1878–1885
  50. Kiener PA, Davis PM, Starling GC, Mehlin C, Klebanoff SJ, Ledbetter JA, et al.  Differential induction of apoptosis by Fas-Fas ligand interactions in human monocytes and macrophages. J Exp Med. 1997;185:1511–1516
  51. Kikuchi H, Iizuka R, Sugiyama S, Gon G, Mori H, Arai M, et al.  Monocytic differentiation modulates apoptotic response to cytotoxic anti-Fas antibody and tumor necrosis factor a in human monoblast U937 cells. J Leukoc Biol. 1996;60:778–783
  52. Koppi TA, Tough-Bement T, Lewinsohn DM, Lynch DH, Alderson MR. CD40 ligand inhibits Fas/CD95-mediated apoptosis of human blood-derived dendritic cells. Eur J Immunol. 1997;27:3161–3165
  53. Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DH, Thomson AW. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol. 1997;158:5676–5684
  54. Steinman RM, Pack M, Inaba K. Dendritic cells in the T-cell areas of lymphoid organs. Immunol Rev. 1997;156:25–37
  55. Suss G, Shortman K. A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis. J Exp Med. 1996;183:1789–1796
  56. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science. 1998;282:290–293
  57. Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S. Essential roles of the Fas ligand in the development of hepatitis. Nat Med. 1997;3:409–413
  58. Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, et al.  Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med. 1995;182:1223–1230
  59. Seino K, Kayagaki N, Takeda K, Fukao K, Okumura K, Yagita H. Contribution of Fas ligand to T cell-mediated hepatic injury in mice. Gastroenterology. 1997;113:1315–1322
  60. Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995;270:1189–1192
  61. Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC. A role for CD95 ligand in preventing graft rejection. Nature. 1995;377:630–632
  62. Lau HT, Yu M, Fontana A, Stoeckert CJ. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science. 1996;273:109–112
  63. Kang SM, Hoffmann A, Le D, Springer ML, Stock PG, Blau HM. Immune response and myoblasts that express Fas ligand. [letter] Science. 1997;278:1322–1324
  64. Kang SM, Schneider DB, Lin Z, Hanahan D, Dichek DA, Stock PG, et al.  Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med. 1997;3:738–743
  65. Allison J, Georgiou HM, Strasser A, Vaux DL. Transgenic expression of CD95 ligand on islet β cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc Natl Acad Sci U S A. 1997;94:3943–3947
  66. Chen JJ, Sun Y, Nabel GJ. Regulation of the proinflammatory effects of fas ligand (CD95L). Science. 1998;282:1714–1717
  67. Sneller MC, Straus SE, Jaffe ES, Jaffe JS, Fleisher TA, Stetler-Stevenson M, et al.  A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest. 1992;90:334–341
  68. Sneller MC, Wang J, Dale JK, Strober W, Middelton LA, Choi Y, et al.  Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood. 1997;89:1341–1348
  69. Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269
  70. Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, et al.  Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81:935–946
  71. Rieux-Laucat F, Diest FL, Roberts IA, Debatin KM, Fisher A, Villartay JP. Mutations in Fas-associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995;268:1347–1351
  72. Martin DA, Zheng L, Siegel RM, Huang B, Fisher GH, Wang J, et al.  Defective CD95 (Fas /APO-1) signal complex formation in the human autoimmune lymphoproliferative syndrome (ALPS). Proc Natl Acad Sci U S A. 1999; In press
  73. Lim MS, Straus SE, Dale JK, Fleisher TA, Stetler-Stevenson M, Strober W, et al.  Pathological findings in human autoimmune lymphoproliferative syndrome. Am J Pathol. 1998;153:1541–1550
  74. Infante A, Britton H, DiNapoli T, Middleton MJ, Lenardo M, Jackson C, et al.  The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. J Pediatr. 1998;133:629–633
  75. Jackson C, Fischer RE, Hsu AP, Choi Y, Wang J, Dale JK, et al.  Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet. 1998; In press
  76. Le Deist F, Emile JF, Rieux-Laucat F, Benkerrou M, Roberts I, Brousse N, et al.  Clinical, immunological, and pathological consequences of Fas-deficient conditions. Lancet. 1996;348:719–723
  77. Wu J, Wilson J, He J, Xiang L, Schur PH, Mountz JD. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest. 1996;98:1107–1113
  78. Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994;152:3685–3692
  79. Georgescu L, Vakkalanka RK, Elkon KB, Crow MK. Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. J Clin Invest. 1997;100:2622–2633
  80. Fuss IJ, Strober W, Dale JK, Fritz S, Pearlstein GR, Puck JM, et al.  Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity. J Immunol. 1997;158:1912–1918
  81. Mitsiades N, Poulaki V, Kotoula V, Mastorakos G, Tseleni-Balafouta S, Koutras DA, et al.  Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 1998;83:2199–2203
  82. Giordano C, Stassi G, De Maria R, Todaro M, Richiusa P, Papoff G, et al.  Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto’s thyroiditis. Science. 1997;275:960–963
  83. Hayashi N, Mita E. Fas system and apoptosis in viral hepatitis. J Gastroenterol Hepatol. 1997;12:S223–S226
  84. Shiota G, Oyama K, Noguchi N, Takano Y, Kitaoka S, Kawasaki H. Clinical significance of serum soluble Fas ligand in patients with acute self-limited and fulminant hepatitis. Res Commun Mol Pathol Pharmacol. 1998;101:3–12
  85. Druilhe A, Cai Z, Haile S, Chouaib S, Pretolani M. Fas-mediated apoptosis in cultured human eosinophils. Blood. 1996;87:2822–2830
  86. Wedi B, Raap U, Lewrick H, Kapp A. Delayed eosinophil programmed cell death in vitro: a common feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis. J Allergy Clin Immunol. 1997;100:536–543
  87. Luttmann W, Opfer A, Dauer E, Foerster M, Matthys H, Eibel H, et al.  Differential regulation of CD95 (Fas/APO-1) expression in human blood eosinophils. Eur J Immunol. 1998;28:2057–2065
  88. Simon HU, Yousefi S, Schranz C, Schapowal A, Bachert C, Blaser K. Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia. J Immunol. 1997;158:3902–3908
  89. Simon HU, Yousefi S, Dommann-Scherrer CC, Zimmermann DR, Bauer S, Barandun J, et al.  Expansion of cytokine-producing CD4-CD8- T cells associated with abnormal Fas expression and hypereosinophilia. J Exp Med. 1996;183:1071–1082
  90. Gougeon ML, Lecoeur H, Dulioust A, Enouf MG, Crouvoiser M, Goujard C, et al.  Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J Immunol. 1996;156:3509–3520
  91. Badley AD, McElhinny JA, Leibson PJ, Lynch DH, Alderson MR, Paya CV. Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J Virol. 1996;70:199–206
  92. Chen H, Yip YK, George I, Tyorkin M, Salik E, Sperber K. Chronically HIV-1-infected monocytic cells induce apoptosis in cocultured T cells. J Immunol. 1998;161:4257–4267
  93. Gandhi RT, Chen BK, Straus SE, Dale JK, Lenardo MJ, Baltimore D. HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism. J Exp Med. 1998;187:1113–1122
  94. Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, et al.  Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science. 1996;274:1363–1366
  95. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, et al.  Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998;396:699–703
  96. Shima Y, Nishimoto N, Yoshizaki K, Kishimoto T. Fas antigen/APO-1 (CD95) expression on myeloma cells. Leuk Lymphoma. 1996;23:521–531
  97. Xu FH, Sharma S, Gardner A, Tu Y, Raitano A, Sawyers C, et al.  Interleukin-6-induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway. Blood. 1998;92:241–251
  98. Landowski TH, Qu N, Buyuksal I, Painter JS, Dalton WS. Mutations in the Fas antigen in patients with multiple myeloma. Blood. 1997;90:4266–4270
  99. Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, et al.  Lethal effect of the anti-Fas antibody in mice. Nature. 1993;364:806–809
  100. Fujisawa K, Asahara H, Okamoto K, Aono H, Hasunuma T, Kobata T, et al.  Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. J Clin Invest. 1996;98:271–278
  101. Zhang H, Yang Y, Horton JL, Samoilova EB, Judge TA, Turka LA, et al.  Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest. 1997;100:1951–1957

☆ Drs Siegel and Fleisher prepared this manuscript in their private capacity, and no official endorsement or support by the National Institutes of Health should be inferred.

☆☆ Reprint requests: Thomas A. Fleisher, MD, Bldg 10, Rm 2C306, 10 Center Dr, MSC 1508, Bethesda, MD 20892-1508.

★ 1/1/98210

PII: S0091-6749(99)70412-4

The Journal of Allergy and Clinical Immunology
Volume 103, Issue 5 , Pages 729-738 , May 1999

Article Tools

* Image Usage & Resolution