T-cell signalling and autoimmunity: Molecular mechanisms of disease

Nature Reviews Immunology

Volumn 2, Issue 6, 2002, Pages 427-438

  Ohashi, Pamela S ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR; CBL PROTEIN; CBL PROTEIN, HUMAN; CBL PROTEIN, MOUSE; FORKHEAD TRANSCRIPTION FACTOR; LYMPHOCYTE ANTIGEN RECEPTOR; NUCLEAR PROTEIN; ONCOPROTEIN; UBIQUITIN PROTEIN LIGASE;

ALLERGIC ENCEPHALITIS; ANIMAL MODEL; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CELLULAR IMMUNITY; CROHN DISEASE; DISEASE PREDISPOSITION; IMMUNE SYSTEM; INFLAMMATION; INSULIN DEPENDENT DIABETES MELLITUS; LIPID MEMBRANE; LIPID RAFT; LYMPHADENOPATHY; MAJOR HISTOCOMPATIBILITY COMPLEX; MOUSE; MULTIPLE SCLEROSIS; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SPLENOMEGALY; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; THYROIDITIS; ULCERATIVE COLITIS; ANIMAL; BIOLOGICAL MODEL; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; METABOLISM; MOLECULAR MIMICRY;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; MICE; MODELS, IMMUNOLOGICAL; MOLECULAR MIMICRY; NUCLEAR PROTEINS; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-CBL; RECEPTORS, ANTIGEN, T-CELL; SELF TOLERANCE; SIGNAL TRANSDUCTION; T-LYMPHOCYTES; TRANSCRIPTION FACTORS; UBIQUITIN-PROTEIN LIGASES;

EID: 0036595050     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri822     Document Type: Review

References (116)

1. Andre, I. et al. Checkpoints in the progession of autoimmune disease: lessons from diabetes models. Proc. Natl Acad. Sci. USA 93, 2260-2263 (1996).
2. Wakeland, E. K., Liu, K., Graham, R. R. & Behrens, T. W. Delineating the genetic basis of systemic lupus erythematosus. Immunity 15, 397-408 (2001).
3. Falcone, M. & Sarvetnick, N. Cytokines that regulate autoimmune responses. Curr. Opin. Immunol. 11, 670-676 (1999).
4. O'Shea, J. J., Ma, A. & Lipsky, P. E. Cytokines and autoimmunity. Nature Rev. Immunol. 2, 37-45 (2002).
5. Gorelik, L. & Flavell, R. A. Transforming growth factor-β in T-cell biology. Nature Rev. Immunol. 2, 46-53 (2002).
6. Demetriou, M., Granovsky, M., Quaggin, S. & Dennis, J. W. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409, 733-739 (2001)
7. Chui, D. et al. Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc. Natl Acad. Sci. USA 98, 1142-1147 (2001).
8. Balomenos, D. et al. The cell-cycle inhibitor p21 controls T-cell proliferation and sex-linked lupus development. Nature Med. 6, 171-176 (2000).
9. Santiago-Raber, M.-L. et al. Role of cyclin-kinase inhibitor p21 in systemic autoimmunity. J. Immunol. 167, 4067-4074 (2001).
10. Lu, Q. & Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro-3 family. Science 293, 306-311 (2001).
11. Ohashi, P. S. T-cell selection and autoimmunity: flexibility and tuning. Curr. Opin. Immunol. 8, 808-814 (1996).
12. Sebzda, E. et al. Selection of the T-cell repertoire. Annu. Rev. Immunol. 17, 829-874 (1999).
13. Mariathasan, S., Zakarian, A., Bouchard, D. & Ohashi, P. S. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J. Immunol. 167, 4966-4973 (2001).
14. Pircher, H., Hoffmann-Rohrer, U., Moskophidis, D., Zinkernagel, R. M. & Hengartner, H. Lower receptor avidity required for thymic clonal deletion than for effector T-cell function. Nature 351, 482-485 (1991).
15. Yagi, J. & Janeway, C. A. Ligand thresholds at different stages of T-cell development. Int. Immunol. 2, 83-69 (1990).
16. + T cells. Nature Immunol. 1, 107-111 (2000).
17. Surh, C. D. & Sprent, J. Homeostatic T-cell proliferation: how far can T cells be activated to self-ligands? J. Exp. Med. 192, F9-F14 (2000).
18. Garza, K. M., Chan, V. S. F. & Ohashi, P. S. T-cell tolerance and autoimmunity. Rev. Immunogenet. 2, 2-17 (2000).
19. Carbone, F. R., Kurts, C., Bennett. S. R. M., Miller, J. F. A. P. & Heath, W. R. Cross-presentation: a general mechanism for CTL immunity and tolerance. Immunol. Today 8, 368-373 (1998).
20. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245-252 (1998).
21. Pulendran, B., Palucka, K. & Banchereau, J. Sensing pathogens and tuning immune responses. Science 293, 253-256 (2001).
22. Diehl, L. et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nature Med. 5, 774-779 (1999).
23. + T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nature Med. 5, 780-787 (1999).
24. Garza, K. M. et al. Role of antigen-presenting cells in mediating tolerance and autoimmunity. J. Exp. Med. 191, 2021-2027 (2000).
25. Bansal-Pakala, P., Jember, A. G. H. & Croft, M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nature Med. 7, 907-912 (2001).
26. bm12 mice. J. Immunol. 150, 4702-4712 (1993).
27. Thomas-Vaslin, V. et al. Abnormal T-cell selection on NOD thymic epithelium is sufficient to induce autoimmune manifestations in C57BL/6 athymic nude mice. Proc. Natl Acad. Sci. USA 94, 4598-4603 (1997).
28. Geng, L., Solimena, M., Flavell, R. A., Sherwin, R. S. & Hayday, A. C. Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease. Proc. Natl Acad. Sci. USA 95, 10055-10060 (1998).
29. Lühder, F., Katz, J., Benoist, C. & Mathis, D. Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities. J. Exp. Med. 187, 379-387 (1998).
30. Ridgway, W. M. & Fathman, C. G. MHC structure and autoimmune T-cell repertoire development. Curr. Opin. Immunol. 11, 638-642 (1999).
31. Marrack, P., Kappler, J. & Kotzin, B. L. Autoimmune disease: why and where it occurs. Nature Med. 7, 899-905 (2001).
32. Goldrath, A. W., Bogatzki, L. Y. & Bevan, M. J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557-564 (2000).
33. Borlado, L. R. et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J. 14, 895-903 (2000). An important paper that shows directly that T-cell-specific expression of active PI3K leads to autoimmunity and tumour development in vivo.
34. 3 can lead to the activation of many downstream events, this paper is important because it is the first study to show directly that PKB is responsible for the phenotype of altered lymphocyte homeostasis. In addition, it also shows that PKB-mediated T-cell survival is sufficient to alter B-cell homeostasis.
35. Heath, W. R. & Carbone, F. R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47-64 (2001).
36. Krammer, P. H. CD95's deadly mission in the immune system. Nature 407, 789-795 (2000).
37. Sabelko-Downes, K. A. Russell, J. H. The role of Fas ligand in vivo as a cause and regulator of pathogenesis Curr. Opin. Immunol. 12,330-335 (2000).
38. Ohashi, P. S. et al. Ablation of 'tolerance' and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305-317 (1991).
39. Hawiger, D. et al. Dendritic cells induce peripheral T-cell unresponsiveness under steady-state conditions in vivo J. Exp. Med. 194, 769-779 (2001).
40. den Boer, A. et al. Longevity of antigen presentation and activation status of APC are decisive factors in the balance between CTL immunity versus tolerance. J. Immunol. 167, 2522-2528 (2001).
41. Schild, H. J. Rötzschke, O., Kalbacher, H. & Rammensee, H.-G. Limit of T-cell tolerance to self-proteins by peptide presentation. Science 247, 1587-1589 (1990).
42. Goverman, J. et al. Transgenic mice that express a myelin basic protein-specific T-cell receptor develop spontaneous autoimmunity. Cell 72, 551-560 (1993).
43. Damian, R. T. Molecular mimicry: antigen sharing by parasite and host and its consequences. Am. Nat. XCVIII, 129-149 (1964).
44. Oldstone, M. B. A. Molecular mimicry and autoimmune disease. Cell 50, 819-820 (1987).
45. Oldstone, M. B. A. Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319-331 (1991).
46. Benoist, C. & Mathis, D. Autoimmunity provoked by infection: how good is the case for T-cell epitope mimicry? Nature Immunol. 2, 797-801 (2001).
47. Zhang, Z.-X., Yang, L., Young, K. J., DuTemple, B. & Zhang, L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nature Med. 6, 782-789 (2000).
48. + T cells in autoimmune diabetes. Nature Immunol. 2, 1117-1125 (2001).
49. Shevach, E. M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423-449 (2000).
50. Tsui, E. W. L. & Tsui, H. W. Molecular basis of the motheaten phenotype. Immunol. Rev. 138, 185-206 (1994).
51. Helgason, C. D. et al. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology and a shortened lifespan. Genes Dev. 12, 1610-1620 (1998).
52. Majeti, R. et al. An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103, 1059-1070 (2000).
53. Jacobsen, M. et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nature Genet. 26, 495-499 (2000).
54. Lynch, K. P. & Weiss, A. A CD45 polymorphism associated with multiple sclerosis disrupts an exonic splicing silencer. J. Biol. Chem. 276, 24341-24347 (2001).
55. Thien, C. B. F. & Langdon, W. Y. CBL: many adaptations to regulate protein-tyrosine kinases. Nature Rev. Mol. Cell Biol. 2, 294-305 (2001).
56. Joazeiro, C. A. et al. The tyrosine-kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286, 309-312 (1999).
57. Murphy, M. A. et al. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol. Cell Biol. 18, 4872-4882 (1998).
58. Naramura, M., Kole, H. K., Hu, R.-J. & Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl Acad. Sci. USA 95, 15547-15552 (1998).
59. Bachmaler, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211-216 (2000).
60. Chiang, Y. J. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216-220 (2000). References 59 and 60 were the first to show an important negative regulatory role for Cbl-b in altered T-cell function and autoimmunity.
61. Viola, A. & Lanzavecchia, A. T-cell activation determined by T-cell receptor number and tunable thresholds. Science 273, 104-106 (1996).
62. Bachmann, M. E. et al. Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation. Immunity 7, 549-557 (1997).
63. Nicholson. L. B. et al. Heteroclitic proliferative responses and changes in cytokine profile induced by altered peptides: implications for autoimmunity. Proc. Natl Acad. Sci. USA 95, 264-269 (1998).
64. Krawczyk, C. et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13, 463-473 (2000).
65. Chan, T. O., Rittenhouse, S. E. & Tsichlis, P. N. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu. Rev. Biochem. 68, 965-1014 (1999).
66. Jimenez, C. et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J. 17, 743-753 (1998).
67. +/-mice. Science 265, 2122-2125 (1999). This study provides the first link between Pten and Fas-mediated apoptosis in vivo.
68. L levels, and NF-κB activation in vivo. J. Exp. Med. 191, 1721-1733 (2000).
69. Russell, J. H., Rush, B., Weaver, C. & Wang, R. Mature T cells of autoimmune lprllpr mice have a defect in antigen-stimulated suicide. Proc. Natl Acad. Sci. USA 90, 4409-4413 (1993).
70. Singer, G. G. & Abbas, A. K. The Fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T-cell receptor transgenic mice. Immunity 1, 365-371 (1994).
71. Bonfoco, E. et al. Inducible nonlymphoid expression of Fas ligand is responsible for superantigen-induced peripheral deletion of T cells. Immunity 9, 711-720 (1998).
72. Sytwu, H.-K., Liblau, R. L. & McDevitt, H. O. The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T-cell receptor transgenic mice. Immunity 5, 17-30 (1996).
73. Hildeman, D. A. et al. Reactive oxygen species regulate activation-induced T-cell apoptosis. Immunity 10, 735-744 (1999).
74. Nguyen, L. T. et al. TNF receptor 1 (TNFR1) and CD95 are not required for T-cell deletion after virus infection but contribute to peptide-induced deletion under limited conditions. Eur. J. Immunol. 30, 683-688 (2000).
75. Reich, A., Korner, H., Sedgwick, J. D. & Pircher, H. Immune down-regulation and peripheral deletion of CD8 T cells does not require TNF receptor ligand interactions nor CD95. Eur. J. Immunol. 30, 678-682 (2000).
76. Nagata, S. & Suda, T. Fas and Fas ligand: lpr and gld mutations. Immunol. Today 16, 39-43 (1995).
77. Cohen, P. L. & Eisenberg, R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu. Rev. Immunol. 9, 243-269 (1991).
78. Rieux-Laucat, F. et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268, 1347-1349 (1995).
79. Fisher, G. H. et al. Dominant interfering Fas gene mutations. Cell 81, 935-946 (1995).
80. Sneller, M. C. et al. Clinical, immunologic and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89, 1341-1348 (1997).
81. Vidal, S., Kono, D. H. & Theofilopoulos, A. N. Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6 lpr mice. J. Clin. Invest. 101, 696-702 (1998).
82. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999).
83. Kops, G., J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630-634 (1999).
84. Rena, G., Guo, S., Cichy, S. C., Unterman, T. G. & Cohen, P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J. Biol. Chem. 274, 17179-17183 (1999).
85. Tang, E. D., Nunez, G., Barr, F. G. & Guan, K.-L. Negative regulation of the forkhead transcription factor FKHR by Akt. J. Biol. Chem. 274, 16741-16746 (1999).
86. Dijkers, P. F., Medema, R. H., Lammers, J.-W. J., Koenderman, L. & Coffer, P. J. Expression of the proapoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10, 1201-1204 (2000).
87. Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286,1735-1738 (1999). The first study to show that Bim has a crucial role in autoimmunity.
88. Kaestner, K. H., Knöchel, W. & Martinez, D. E. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 14, 142-146 (2000).
89. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoprolirative disorder of the scurfy mouse. Nature Genet. 27, 68-73 (2001). Identification of the genetic defect in the scurfy mouse as affecting a new Fox-family member.
90. Clark, L. B. et al. Cellular and molecular characterization of the scurfy mouse mutant. J. Immunol. 162, 2546-2554 (1999).
91. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18-20 (2001).
92. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20-21 (2001). Identification of the IPEX genetic defect in humans as affecting a Fox transcription factor.
93. Fang, D. & Liu, Y.-C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nature Immunol. 2, 870-875 (2001).
94. Parry, R. V. et al. Ligation of the T-cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B. Eur. J. Immunol. 27, 2495-2501 (1997).
95. Ahmed, N. N., Grimes, H. L., Bellacosa, A., Chan, T. O. & Tsichlis, P. N. Transduction of inteleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc. Natl Acad. Sci. USA 94, 3627-3632 (1997).
96. Reif, K., Burgering, B. M. T. & Cantrell, D. A. Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J. Biol. Chem. 272, 14426-14433 (1997).
97. Pallard, C. et al. Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors. Immunity 10, 525-535 (1999).
98. Blume-Jensen, P., Janknecht, R. & Hunter, T. The kit receptor promotes cell survival via activation of PI3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr. Biol 8, 779-782 (1998).
99. Tilton, B. et al. Signal transduction by CXC chemokine receptor 4. Stromal cell-derived factor-1 stimulates prolonged protein kinase-B and extracellular signal-regulated kinase-2 activation in T lymphocytes. J. Exp. Med. 192, 313-324 (2000).
100. Sotsios, Y. & Ward, S. G. Phosphoinositide 3-kinase: a key biochemical signal for cell migration in response to chemokines. Immunol. Rev. 177, 217-235 (2000).
101. Swat, W. et al. SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development. Immunity 8, 625-634 (1998).
102. Ranger, A. M., Oukka, M., Rengarajan, J. & Glimcher, L. H. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9, 627-635 (1998).
103. Peng, S. L., Gerth, A. J., Ranger, A. M. & Glimcher, L. H. NFATc1 and NFATc2 together control both T- and B-cell activation and differentiation. Immunity 14, 13-20 (2001).
104. Hiroaki, H., Ago, T., Ito, T., Sumimoto, H. & Kohda, D. Solution structure of the PX domain, a target of the SH3 domain. Nature Struct. Biol. 8, 526-530 (2001).
105. Xu, J., Liu, D., Gill, G. & Songyang, Z. Regulation of cytokine-independent survival kinase (CISK) by the Phoxhomology domain and phosphoinositides. J. Cell Biol. 154, 699-705 (2001).
106. Vanhaesebroeck, B. & Alessi, D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561-576 (2000).
107. Toker, A. & Newton, A. C. Cellular signaling: pivoting around PDK-1. Cell 103, 185-188 (2000).
108. Cantley, L. C. & Neel, B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/ AKT pathway. Proc. Natl Acad. Sci. USA 96, 4240-4245 (1999).
109. Maehama, T. & Dixon, J. E. The tumor suppressor PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate. J. Biol. Chem. 273, 13375-13378 (1998).
110. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29-39 (1998).
111. March, M. E. & Ravichandran, K. Regulation of the immune response by SHIP. Semin. Immunol. 14, 37-47 (2002).
112. Liu, Q. et al. SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid-cell survival. Genes Dev. 13, 786-791 (1999).
113. Wang, H.-Y. et al. Cbl promotes ubiquitination of the T-cell receptor ζ through an adaptor function of Zap-70. J. Biol. Chem. 276, 26004-26011 (2001).
114. Fang, D. et al. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J. Biol. Chem. 276, 4872-4878 (2001).
115. Turner, M. et al. A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes. Immunity 7, 451-460 (1997).
116. Kong, Y.-Y. et al. Vav regulates peptide-specific apoptosis in thymocytes. J. Exp. Med. 188, 2099-2111 (1998).