Journal of Molecular Medicine

, Volume 83, Issue 4, pp 267–278 | Cite as

T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens



Special populations of T helper cells drive B cells to produce IgG class switched, pathogenic autoantibodies in lupus. The major source of antigenic determinants (epitopes) that trigger interactions between lupus T and B cells is nucleosomes of apoptotic cells. These epitopes can be used for antigen-specific therapy of lupus. Secondly, the autoimmune T cells of lupus are sustained because they resist anergy and activation-induced programmed cell death by markedly upregulating cyclooxygenase (COX) 2 along with the antiapoptotic molecule c-FLIP. Only certain COX-2 inhibitors block pathogenic anti-DNA autoantibody production in lupus by causing death of autoimmune T helper cells. Hence COX-2 inhibitors may work independently of their ability to block the enzymatic function of COX-2, and structural peculiarities of these select inhibitors may lead to better drug discovery and design.


Lupus Autoimmunity Apoptosis Anergy Immunotherapy 



Antigen-presenting cell


Cassitus B lymphoma oncogene


CD40 ligand


Cellular Fas-associated death domain-like interleukin 1β converting enzyme inhibitory protein




Dendritic cell


Extracellular signal regulated kinase


Fas-associated death domain


Fas ligand


Inhibitor of apoptosis protein






Systemic lupus erythematosus


T cell receptor


T helper



These studies were supported by National Institutes of Health grants R37-AR39157 and RO1-AI41985 to S.K.D.


  1. 1.
    Boumpas DT, Austin HA, Fessler BJ, Balow JE, Klippel JH, Lockshin MD (1995) Systemic lupus erythematosus: emerging concepts. I. Renal, neuropschyatric, cardiovascular, pulmonary and hematologic disease. Ann Intern Med 122:940–950PubMedGoogle Scholar
  2. 2.
    Datta SK, Patel H, Berry D (1987) Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis. J Exp Med 165:1252–1268CrossRefGoogle Scholar
  3. 3.
    Shivakumar S, Tsokos GC, Datta SK (1989) T cell receptor alpha/beta expressing double negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol 143:103–112Google Scholar
  4. 4.
    Naiki M, Chiang B-L, Cawley D, Ansari A, Rozzo SJ, Kotzin BL, Zlotnik A, Gershwin ME (1992) Generation and characterization of cloned helper T cell lines for anti-DNA responses in NZB.H-2bm12 mice. J Immunol 149:4109–4115Google Scholar
  5. 5.
    Singh RR, Kumar V, Ebling FM, Southwood S, Sette A, Sercarz EE, Hahn BH (1995) T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine SLE. J Exp Med 181:2017–2027CrossRefGoogle Scholar
  6. 6.
    Zeng D, Lee MK, Tung J, Brendolan A, Strober S (2000) Cutting edge: a role for CD1 in the pathogenesis of lupus in NZB/NZW mice. J Immunol 164:5000–5004Google Scholar
  7. 7.
    Datta SK, Schwartz RS (1976) Genetics of expression of xenotropic virus and autoimmunity in NZB mice. Nature 263:412–415Google Scholar
  8. 8.
    Sainis K, Datta SK (1988) CD4+ T cell lines with selective patterns of autoreactivity as well as CD4-/CD8-T helper cell lines augment the production of idiotypes shared by pathogenic anti-DNA autoantibodies in the NZB x SWR model of lupus nephritis. J Immunol 140:2215–2224Google Scholar
  9. 9.
    Rajagopalan S, Zordan T, Tsokos GC, Datta SK (1990) Pathogenic anti-DNA autoantibody inducing T helper cell lines from patients with active lupus nephritis: isolation of CD4-/CD8-T helper cell lines that express the gd T-cell receptor. Proc Natl Acad Sci USA 87:7020–7024Google Scholar
  10. 10.
    Adams S, Leblanc P, Datta SK (1991) Junctional region sequences of T-cell receptor b chain genes expressed by pathogenic anti-DNA autoantibody-inducing T helper cells from lupus mice: possible selection by cationic autoantigens. Proc Natl Acad Sci USA 88:11271–11275Google Scholar
  11. 11.
    Shi Y, Kaliyaperumal A, Lu L, Southwood S, Sette A, Michaels MA, Datta SK (1998) Promiscuous presentation and recognition of nucleosomal autoepitopes in lupus: role of autoimmune T cell receptor alpha chain. J Exp Med 187:367–378CrossRefGoogle Scholar
  12. 12.
    Mohan C, Adams S, Stanik V, Datta SK (1993) Nucleosome: a major immunogen for the pathogenic autoantibody-inducing T cells of lupus. J Exp Med 177:1367–1381CrossRefPubMedGoogle Scholar
  13. 13.
    Kaliyaperumal A, Mohan C, Wu W, Datta SK (1996) Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med 183:2459–2469CrossRefGoogle Scholar
  14. 14.
    Voll RE, Roth EA, Girkontaite I, Fehr H, Herrman M, Lorenz HM, Kalden JR (1997) Histone-specific Th0 and Th1 clones derived from systemic lupus erythematosus patients induce double-stranded DNA antibody production. Arthritis Rheum 40:2162–2171Google Scholar
  15. 15.
    Bruns A, Blass S, Hausdorf G, Burmester GR, Hiepe F (2000) Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. Arthritis Rheum 43:2307–2315CrossRefPubMedGoogle Scholar
  16. 16.
    Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556PubMedGoogle Scholar
  17. 17.
    Casciola-Rosen LA, Anhalt G, Rosen A (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179:1317–1330CrossRefPubMedGoogle Scholar
  18. 18.
    Shoshan Y, Mevorach D (2004) Accelerated autoimmune disease in MRL/MpJ-Fas (lpr) but not inMRL/MpJ following immunization with high load of sysngeneic late apoptotic cells. Autoimmunity 37:103–109CrossRefGoogle Scholar
  19. 19.
    Bondanza A, Zimmermann VS, Dell’Antonio G, Dal Cin E, Capobianco A, Sabbadini MG, Manfredi AA, Rovere-Querini P (2003) Cutting edge: dissociation between autoimmune response and clinical disease after vaccination with dendritic cells. J Immunol 170:24–27Google Scholar
  20. 20.
    Kaliyaperumal A, Michaels MA, Datta SK (2002) Naturally processed chromatin peptides reveal a major autoepitope that primes pathogenic T and B cells of lupus. J Immunol 168:2530–2537Google Scholar
  21. 21.
    Lu L, Kaliyaperumal A, Boumpas DT, Datta SK (1999) Major peptide autoepitopes for nucleosome-specific T cells of human lupus. J Clin Invest 104:345–355Google Scholar
  22. 22.
    Wu HY, Ward FJ, Staines NA (2002) Histone peptide-induced nasal tolerance: suppression of murine lupus. J Immunol 169:1126–1134Google Scholar
  23. 23.
    Fujio K, Okamoto A, Tahara H, Abe M, Jiang Y, Kitamura T, Hirose S, Yamamoto K (2004) Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease. J Immunol 173:2118–2125Google Scholar
  24. 24.
    Suen J-L, Chuang Y-H, Tsai B-Y, Yau PM, Chiang B-L (2004) Treatment of murine lupus using nucleosomal T cell epitopes identified by bone marrow-derived dendritic cells. Arthritis Rheum 50:3250–3259Google Scholar
  25. 25.
    Zinger H, Eilat E, Meshorer A, Mozes E (2003) Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB x NZW) F1 mice via active suppression. Int Immunol 15:205–214CrossRefGoogle Scholar
  26. 26.
    Zhang X, Smith DS, Guth A, Wysocki LJ (2001) A receptor presentation hypothesis for T cell help that recruits autoreactive B cells. J Immunol 166:1562–1571Google Scholar
  27. 27.
    Monneaux F, Muller S (2002) Epitope spreading in systemic lupus erythematosus: identification of triggering peptide sequences. Arthritis Rheum 46:1430–1438Google Scholar
  28. 28.
    Greidinger EL, Gazitt T, Jaimes KF, Hoffman RW (2004) Human T cell clones specific for heterogeneous nuclear ribonucleoprotein A2 autoantigen from connective tissue disease patients assist in autoantibody production. Arthritis Rheum 50:2216–2222Google Scholar
  29. 29.
    Riemekasten G, Langnickel D, Ebling FM, Karpouzas G, Kalsi J, Herberth G, Tsao BP, Henklein P, Langer S, Burmester GR, Radbruch A, Hiepe F, Hahn BH (2003) Identification and characterization of SmD183–119-reactive T cells that provide T cell help for pathogenic anti-double-stranded DNA antibodies. Arthritis Rheum 48:475–485Google Scholar
  30. 30.
    Busser BW, Adair BS, Erikson J, Laufer TM (2003) Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance. J Clin Invest 112:1361–1371CrossRefGoogle Scholar
  31. 31.
    Deshmukh US, Gaskin F, Lewis JE, Kannapell CC, Fu SM (2003) Mechanisms of autoantibody diversification to SLE-related autoantigens. Ann NY Acad Sci 987:91–98Google Scholar
  32. 32.
    Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK (1996) Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97:2063–2073Google Scholar
  33. 33.
    Desai-Mehta A, Mao C, Rajagopalan S, Robinson T, Datta SK (1995) Structure and specificity of T-cell receptors expressed by pathogenic anti-DNA autoantibody-inducing T cells in human lupus. J Clin Invest 95:531–541Google Scholar
  34. 34.
    Andreassen K, Moens U, Nossent H, Marion TN, Rekvig OP (1999) Termination of human T cell tolerance to histones by presentation of histones and polyomavirus T antigen provided that T antigen is complexed with nucleosomes. Arthritis Rheum 42:2449–2460Google Scholar
  35. 35.
    Bieganowska KD, Ausubel LJ, Modabber Y, Slovik E, Messersmith W, Hafler DA (1997) Direct ex vivo analysis of activated, Fas-sensitive autoreactive T cells in human autoimmune disease. J Exp Med 185:1585–1594CrossRefPubMedGoogle Scholar
  36. 36.
    Kammer GM, Perl, A, Richardson BC, Tsokos GC (2002) Abnormal T cell signal transduction in systemic lupus erythromatosus. Arthritis Rheum 46:1139–1154Google Scholar
  37. 37.
    Shlomchik MJ, Craft JE, Mamula MJ (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 1:147–153Google Scholar
  38. 38.
    Eastcott JW, Schwartz RS, Datta SK (1983) Genetic analysis of the inheritence of B cell hyperactivity in relation to the development of autoantibodies and glomerulonephritis in NZB x SWR crosses. J Immunol 131:2232–2239Google Scholar
  39. 39.
    Dieker JW, van der Vlag J, Berden JH (2002) Triggers for anti-chromatin autoantibody production in SLE. Lupus 11:856–864CrossRefGoogle Scholar
  40. 40.
    Kono DH, Theofilopoulos AN (2000) Genetic studies in systemic autoimmunity and aging. Immunol Res 21:111–122CrossRefGoogle Scholar
  41. 41.
    Wakeland EK, Liu K, Graham RR, Behrens TW (2001) Delineating the genetic basis of systemic lupus erythematosus. Immunity 15:397–408CrossRefPubMedGoogle Scholar
  42. 42.
    Mohan C, Alas E, Morel L, Ping Y, Wakeland EK (1998) Genetic dissection of SLE pathogenesis: Sle 1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosome. J Clin Invest 101:1362–1372Google Scholar
  43. 43.
    Rozzo SJ, Allard JD, Choubey D, Vyse TJ, Izui S, Peltz G, Kotzin BL (2001) Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity 15:435–443CrossRefPubMedGoogle Scholar
  44. 44.
    Harley JB, Moser KL, Gaffney PM, Behrens TW (1998) The genetics of human systemic lupus erythematosus. Curr Opin Immunol 10:690–696CrossRefPubMedGoogle Scholar
  45. 45.
    Sobel ES, Satoh M, Chen Y, Wakeland EK, Morel L (2002) The major murine systemic lupus erythematosus susceptibility locus sle1 results in abnormal functions of both B and T cells. J Immunol 169:2694–2700Google Scholar
  46. 46.
    Erikson J, Radic MZ, Camper SA, Hardy RR, Carmack C, Weigert M (1991) Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349:331–334CrossRefGoogle Scholar
  47. 47.
    Chen C, Nagy Z, Radic MZ, Hardy RR, Huszar D, Camper SA, Weigert M (1995) The site and stage of anti-DNA B-cell deletion. Nature 373:252–255CrossRefGoogle Scholar
  48. 48.
    Datta SK, Stollar BD, Schwartz RS (1983) Normal mice express idiotypes related to autoantibody idiotypes of lupus mice. Proc Natl Acad Sci USA 80:2723–2727Google Scholar
  49. 49.
    Conger JD, Pike BL, Nossal GJ (1987) Clonal analysis of the anti-DNA repertoire of murine B lymphocytes. Proc Natl Acad Sci USA 84:2931–2935Google Scholar
  50. 50.
    Ray SK, Putterman C, Diamond B (1996) Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc Natl Acad Sci USA 93:2019–2024CrossRefGoogle Scholar
  51. 51.
    Stewart A, Huang C, Long A, Stollar B, Schwartz R (1992) VH-gene representation in autoanitbodies reflects the normal B cell repertoire. Immunol Rev 128:101–122Google Scholar
  52. 52.
    Datta SK (2003) Major peptide autoepitopes for nucleosome-centered T and B cell interaction in human and murine lupus. Ann NY Acad Sci 987:79–90Google Scholar
  53. 53.
    Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898Google Scholar
  54. 54.
    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351CrossRefGoogle Scholar
  55. 55.
    Kurosaka K, Takahashi M, Watanabe N, Kobayashi Y (2003) Silent cleanup of very early apoptotic cells by macrophages. J Immunol 171:4672–4679Google Scholar
  56. 56.
    Steinman RM, Turley S, Mellman I, Inaba K (2000) The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 191:411–416CrossRefGoogle Scholar
  57. 57.
    Mevorach D, Zhou JL, Song X, Elkon KB (1998) Systemic exposure to irradiated apoptotic cells induces autoanitbody production. J Exp Med 188:387–392CrossRefGoogle Scholar
  58. 58.
    Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC, Roubey RA, Earp HS, Matsushima G, Reap EA (2002) Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med 196:135–140CrossRefGoogle Scholar
  59. 59.
    Rumore P, Steinman C (1990) Endogenous circulating DNA in systemic lupus erythematosus. Occurrences as multimeric complexes bound to histones. J Clin Invest 86:69–74Google Scholar
  60. 60.
    Manderson AP, Botto M, Walport MJ (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431–456CrossRefGoogle Scholar
  61. 61.
    Sekine H, Reilly CM, Molano ID, Garnier G, Circolo A, Ruiz P, Holers VM, Boackle SA, Gilkeson GS (2001) Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice. J Immunol 166:6444–6451Google Scholar
  62. 62.
    Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250CrossRefPubMedGoogle Scholar
  63. 63.
    Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF, Ramsey-Goldman R, Peterson MGE, Kimberly RP (1996) FcYRIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97:1348–1354Google Scholar
  64. 64.
    Ren Y, Tang J, Mok MY, Chan AW, Wu A, Lau CS (2003) Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum 48:2888–2897CrossRefPubMedGoogle Scholar
  65. 65.
    Vassilopoulos D, Kovacs B, Tsokos GC (1995) TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus. J Immunol 155:2269–2281Google Scholar
  66. 66.
    Liossis S-N, Kovacs B, Dennis G, Kammer GM, Tsokos GC (1996) B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J Clin Invest 98:2549–2557Google Scholar
  67. 67.
    Chen Z, Koralov SB, Kelsoe G (2000) Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med 192:1339–1352CrossRefGoogle Scholar
  68. 68.
    Datta SK (2000) Positive selection for autoimmunity. Nat Med 6:259–261Google Scholar
  69. 69.
    Vratsanos GS, Jung S, Park YM, Craft J (2001) CD4 (+) T cells from lupus-prone mice are hyperresponsive to T cell receptor engagement with low and high affinity peptide antigens: a model to explain spontaneous T cell activation in lupus. J Exp Med 193:329–337CrossRefGoogle Scholar
  70. 70.
    Boackle SA, Holers VM, Chen X, Szakonyi G, Karp DR, Wakeland EK, Morel L (2001) Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity 15:775–785CrossRefGoogle Scholar
  71. 71.
    Yung R, Powers D, Johnson K, Amento E, Carr D, Laing T, Yang J, Chang S, Hemati N, Richardson B (1996) Mechanisms of drug induced lupus. II. T cells overexpressing LFA 1 becomes autoreactive and cause a lupus like disease in syngeneic mice. J Clin Invest 97:2866–2871Google Scholar
  72. 72.
    Bouzahzah F, Jung S, Craft J (2003) CD4+ T cells from lupus-prone mice avoid antigen-specific tolerance induction in vivo. J Immunol 170:741–748Google Scholar
  73. 73.
    Kretz-Rommel A, Rubin RL (1997) A metabolite of the lupus-inducing drug procainamide prevents anergy induction in T cell clones. J Immunol 158:4465–4470Google Scholar
  74. 74.
    Moutsopoulos JM, Boehm-Truitt M, Kassan SS, Chused TM (1977) Demonstration of activation of B lymphocytes in New Zealand black mice at birth by an immunoradiometric assay for murine IgM. J Immunol 119:1639–1644Google Scholar
  75. 75.
    Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J (2001) Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 294:1540–1543CrossRefPubMedGoogle Scholar
  76. 76.
    Datta SK, Owen FL, Womack JE, Riblet RJ (1982) Analysis of recombinant inbred lines derived from autoimmune (NZB) and high leukemia (C58) strains: independent multigenic systems control B cell hyperactivity, retrovirus expression and autoimmunity. J Immunol 129:1539–1544Google Scholar
  77. 77.
    Sobel ES, Katagiri T, Katagiri K, Morris SC, Cohen PL, Eisenberg RA (1991) An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity. J Exp Med 173:1441–1449CrossRefGoogle Scholar
  78. 78.
    Mamula MJ, Fatenejad S, Craft J (1994) B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol 152:1453–1461Google Scholar
  79. 79.
    Jongstra-Bilen J, Vukusic B, Boras K, Wither JE (1997) Resting B cells from autoimmune lupus-prone NZB and (NZB x NZW) F1 mice are hyper-responsive to T cell-derived stimuli. J Immunol 159:5810–5820Google Scholar
  80. 80.
    Lian Z-X, Kikuchi K, Yang G-X, Ansari AA, Ikehara S, Gershwin ME (2004) Expansion of bone marrow IFN-a-producing dendritic cells in New Zealand black (NZB) mice: high level expression of TLR9 and secretion of IFN-a in NZB bone marrow. J Immunol 173:5283–5289Google Scholar
  81. 81.
    Ohtsuka K, Gray JD, Stimmler MM, Toro B, Horwitz DA (1998) Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol 160:2539–2545Google Scholar
  82. 82.
    Singh RR, Ebling FM, Albuquerque DA, Saxena V, Kumar V, Giannini EH, Marion TN, Finkelman FD, Hahn BH (2002) Induction of autoantibody production is limited in nonautoimmune mice. J Immunol 169:587–594Google Scholar
  83. 83.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061CrossRefPubMedGoogle Scholar
  84. 84.
    Bagavant H, Thompson C, Ohno K, Setiady Y, Tung KSK (2002) Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease. Int Immunol 14:1397–1406CrossRefGoogle Scholar
  85. 85.
    Foy TM, Laman JD, Ledbetter JA, Aruffo A, Claassen E, Noelle RJ (1994) gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med 180:157–163CrossRefGoogle Scholar
  86. 86.
    Lederman S, Yellin MJ, Inghirami G, Lee JJ, Knowles DM, Chess L (1992) Molecular interaction mediating T-B lymphocyte collaboration in human lymphoid follicles. Role T cell-B cell activating molecule (5c8 antigen) and CD40 in contact-dependent help. J Immunol 149:3817–3826Google Scholar
  87. 87.
    Roy M, Waldschmidt T, Aruffo A, Ledbetter JA, Noelle RJ (1993) The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol 151:2497–2510Google Scholar
  88. 88.
    Mohan C, Shi Y, Laman JD, Datta SK (1995) Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 154:1470–1480Google Scholar
  89. 89.
    Koshy M, Berger D, Crow MK (1996) Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 98:826–837Google Scholar
  90. 90.
    Yi Y, McNerney M, Datta SK (2000) Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. J Immunol 165:6627–6634Google Scholar
  91. 91.
    Higuchi T, Aiba Y, Nomura T, Matsuda J, Mochida K, Suzuki M, Kikutani H, Honjo T, Nishioka K, Tsubata T (2002) Cutting edge: ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J Immunol 168:9–12Google Scholar
  92. 92.
    Devi BS, Van Noordin S, Krausz T, Davies KA (1998) Peripheral blood lymphocytes in SLE—hyperexpression of CD154 on T and B lymphocytes and increased number of double negative T cells. J Autoimmunity 11:471–475CrossRefGoogle Scholar
  93. 93.
    Blossom S, Gilbert KM (1999) Antibody production in autoimmune BXSB mice. CD40L expressing B cells need fewer signals for polyclonal antibody synthesis. Clin Exp Immunol 118:147–153CrossRefGoogle Scholar
  94. 94.
    Grammer AC, McFarland RD, Heaney J, Darnell BF, Lipsky PE (1999) Expression, regulation and function of B cell-expressed CD154 in germinal centers. J Immunol 163:4150–4159Google Scholar
  95. 95.
    Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334CrossRefPubMedGoogle Scholar
  96. 96.
    Appleman LJ, Boussiotis VA (2003) T cell anergy and costimulation. Immunol Rev 192:161–180CrossRefGoogle Scholar
  97. 97.
    Heissmeyer V, NMacian F, Im S, Varma R, Feske S, Venuprasad K, Gu H, Liu Y-C, Dustin ML, Rao A (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5:255–265Google Scholar
  98. 98.
    Lupher ML, Rao N, Eck MJ, Band H (1999) The Cbl protooncoprotein: a negative regulator of immune receptor signal transduction. Immunol Today 20:375–382CrossRefGoogle Scholar
  99. 99.
    Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC (1999) The tyrosine kinase negative regulator c-Cbl RING type, E2 dependent, ubiquitin-protein ligase. Science 286:309–312CrossRefGoogle Scholar
  100. 100.
    Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H (2002) c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol 3:1192–1199Google Scholar
  101. 101.
    Bachmaier K, Krawczyk C, Kozieradzki I, Kong Y-Y, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H, Lipkowitz S, Penninger JM (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adapter Cbl-b. Nature 403:211–216CrossRefGoogle Scholar
  102. 102.
    Enyedy EJ, Nambiar MP, Liossis SN, Dennis G, Kammer GM, Tsokos GC (2001) Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum 44:1114–1121Google Scholar
  103. 103.
    Tsytsykova AV, Tsitsikov EN, Geha RS (1996) The CD40L promoter contains NF-AT-binding motifs which require AP-1 binding for activation of transcription. J Biol Chem 271:3763–3770CrossRefGoogle Scholar
  104. 104.
    Schubert LA, King G, Cron RQ, Lewis DB, Aruffo A, Hollenbaugh D (1995) The human gp39 promoter: two distinct NF-AT-binding elements contribute independently to transcriptional activation. J Biol Chem 270:29624–29627CrossRefGoogle Scholar
  105. 105.
    Ford GS, Barnhart B, Shone S, Covey LR (1999) Regulation of CD154 (CD40L) mRNA stability during T cell activation. J Immunol 162:4037–4044Google Scholar
  106. 106.
    Hamilton BJ, Genin A, Cron RQ, Rigby WF (2003) Delineation of a novel pathway that regulates CD154 (CD40 ligand) expression. Mol Cell Biol 23:510–525CrossRefGoogle Scholar
  107. 107.
    Jury EC, Kabouridis PS, Flores-Borja F, Mageed RA, Isenberg DA (2004) Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J Clin Invest 113:1176–1187CrossRefGoogle Scholar
  108. 108.
    Krishnan S, Nambiar MP, Warke VG, Fisher CU, Mitchell J, Delaney N, Tsokos GC (2004) Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in sytemic lupus erythematosus. J Immunol 172:7821–7831Google Scholar
  109. 109.
    Krawczyk C, Bachmaier K, Sasaki T, Jones GR, Snapper BS, Bouchard D, Kozieradzki I, Ohashi SP, Alt WF, Penninger MJ (2000) Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13:463–473Google Scholar
  110. 110.
    Sohn HW, Gu H, Pierce SK (2003) Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J Exp Med 197:1511–1524CrossRefGoogle Scholar
  111. 111.
    Anandasabapathy N, Ford GS, Bloom D, Holness C, Paragas V, Seroogy C, Skrenta H, Hollenhorst M, Fathman CG, Soares L (2003) GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18:535–547CrossRefGoogle Scholar
  112. 112.
    Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V (2003) Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197:711–723CrossRefPubMedGoogle Scholar
  113. 113.
    Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 100:2601–2605CrossRefGoogle Scholar
  114. 114.
    Vallin H, Perers A, Alm GV, Ronnblom L (1999) Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol 163:6306–6313Google Scholar
  115. 115.
    Kalled SL, Cutler AH, Burkly LC (2001) Apoptosis and altered dendritic cell homeostasis in lupus nephritis are limited by anti-CD154 treatment. J Immunol 167:1740–1747Google Scholar
  116. 116.
    Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:595–598CrossRefGoogle Scholar
  117. 117.
    Kim SJ, Gershov D, Ma X, Brot N, Elkon KB (2002) I-PLA (2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. J Exp Med 196:655–665CrossRefGoogle Scholar
  118. 118.
    Jiang N, Reich CF 3rd, Monestier M, Pisetsky DS (2003) The expression of plasma nucleosomes in mice undergoing in vivo apoptosis. Clin Immunol 106:139–147CrossRefGoogle Scholar
  119. 119.
    Licht R, van Bruggen MC, Oppers-Walgreen B, Rijke TP, Berden JH (2001) Plasma levels of nucleosomes and nucleosome-autoantibody complexes in murine lupus: effects of disease progression and lipopolyssacharide administration. Arthritis Rheum 44:1320–1330Google Scholar
  120. 120.
    Sandler AD, Chihara H, Kobayashi G, Zhu X, Miller MA, Scott DL, Krieg AM (2003) CpG Oligonucleotides enhance the tumor antigen-specific immune response of a granulocyte macrophage colony-stimulating factor-based vaccine strategy in neuroblastoma. Cancer Res 63:394–399Google Scholar
  121. 121.
    Radic MZ, Weigert M (1994) Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu Rev Immunol 12:487–520Google Scholar
  122. 122.
    Ando DG, Sercarz EE, Hahn BH (1987) Mechanisms of T and B cell collaboration in the in vitro production of anti-DNA antibodies in the NZB/NZW F1 murine SLE model. J Immunol 138:3185–3190Google Scholar
  123. 123.
    Gavalchin J, Datta SK (1987) The NZB x SWR model of lupus nephritis. II. Autoantibodies deposited in renal lesions show a restricted idiotypic diversity. J Immunol 138:138–148Google Scholar
  124. 124.
    Rovere P, Sabbadini MG, Vallinoto C, Fascio U, Recigno M, Crosti M, Ricciardi-Castagnoli P, Balestrieri G, Tincani A, Manfredi AA (1999) Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory context: role of opsonizing anti-beta2-glycoprotein I antibodies. Arthritis Rheum 42:1412–1420Google Scholar
  125. 125.
    Peng SL, McNiff JM, Madaio MP, Ma J, Owen MJ, Flavell RA, Hayday AC, Craft J (1997) alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. J Immunol 158:2464–2470Google Scholar
  126. 126.
    Kaliyaperumal A, Michaels MA, Datta SK (1999) Antigen-specific therapy of murine lupus nephritis using nucleosomal peptides: tolerance spreading impairs pathogenic function of autoimmune T and B cells. J Immunol 162:5775–5783Google Scholar
  127. 127.
    Daikh DI, Finck BK, Linsley PS, Hollenbaugh D, Wofsy D (1997) Long-term iinhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 159:3104–3108Google Scholar
  128. 128.
    Sun Y, Chen HM, Subudhi SK, Chen J, Koka R, Chen L, Fu Y-X (2002) Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 8:1405–1411CrossRefPubMedGoogle Scholar
  129. 129.
    Early GS, Zhao W, Burns CM (1996) Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice: response correlates with the absence of an anti-antibody response. J Immunol 157:3159–3164Google Scholar
  130. 130.
    Wang X, Huang W, Mihara M, Sinha J, Davidson A (2002) Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus. J Immunol 168:2046–2053Google Scholar
  131. 131.
    Shiono H, Roxanis I, Zhang W, Sims GP, Meager A, Jacobson LW, Liu JL, Matthews I, Wong YL, Bonifati M, Micklem K, Stott DI, Todd JA, Beeson D, Vincent A, Willcox N (2003) Scenarios for autoimmunization of T and B cells in myasthenia gravis. Ann NY Acad Sci 998:237–256CrossRefGoogle Scholar
  132. 132.
    Wang XB, Kakoulidou M, Giscombe R, Qiu Q, Huang D, Pirskanen R, Lefvert AK (2002) Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence. J Neuroimmunol 130:224–232CrossRefGoogle Scholar
  133. 133.
    Cedeno S, Cifarelli DF, Blasini AM, Paris M, Placeres F, Alonso G, Rodriguez MA (2003) Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells. Clin Immunol 106:41–49CrossRefGoogle Scholar
  134. 134.
    Jury EC, Kabouridis PS, Abba A, Mageed RA, Isenberg DA (2003) Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum 48:1343–1354Google Scholar
  135. 135.
    Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Morel-Fourrier B, Brouet JC, Alarcon-Segovia D, Galanaud P, Emilie D (1995) Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of systemic lupus erythematosus. J Exp Med 181:839–844CrossRefPubMedGoogle Scholar
  136. 136.
    Van Laethem F, Baus E, Smyth LA, Andris F, Bex F, Urbain J, Kioussis D, Leo O (2001) Glucocorticoids attenuate T cell receptor signaling. J Exp Med 193:803–814CrossRefGoogle Scholar
  137. 137.
    Niculescu F, Nguyen P, Niculescu T, Rus H, Rus V, Via CS (2003) Pathogenic T cells in murine lupus exhibit spontaneous signaling activity through phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Arthritis Rheum 48:1071–1079Google Scholar
  138. 138.
    Van Parijs L, Abbas AK (1998) Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280:243–248CrossRefGoogle Scholar
  139. 139.
    Lenardo MJ (2003) Molecular regulation of T lymphocyte homeostasis in the healthy and diseased immune system. Immunol Res 27:387–398CrossRefGoogle Scholar
  140. 140.
    Rathmell JC, Thompson CB (2002) Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109:S97–S107CrossRefGoogle Scholar
  141. 141.
    Green DR, Droin N, Pinkoski M (2003) Activation-induced cell death in T cells. Immunol Rev 193:70–81CrossRefGoogle Scholar
  142. 142.
    Nagata S (1999) Fas ligand-induced apoptosis. Annu Rev Genet 33:29–55CrossRefGoogle Scholar
  143. 143.
    Marrack P, Kappler J (2004) Control of T cell viability. Annu Rev Immunol 22:765–787CrossRefGoogle Scholar
  144. 144.
    Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629CrossRefGoogle Scholar
  145. 145.
    Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195CrossRefPubMedGoogle Scholar
  146. 146.
    Kirchhoff S, Muller WW, Li-Weber M, Krammer PH (2000) Up-regulation of c-FLIPshort and reduction of activation-induced cell death in CD28-costimulated human T cells. Eur J Immunol 30:2765–2774Google Scholar
  147. 147.
    Van Parijs L, Refaeli Y, Abbas AK, Baltimore D (1999) Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes. Immunity 11:763–770CrossRefGoogle Scholar
  148. 148.
    Wu W, Rinaldi L, Fortner KA, Russell JQ, Tschopp J, Irvin C, Budd RC (2004) Cellular FLIP long form-transgenic mice manifest a Th2 cytokine bias and enhanced allergic airway inflammation. J Immunol 172:4724–4732Google Scholar
  149. 149.
    Nachmias B, Ashhab Y, Ben-Yehuda D (2004) The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 14:231–243CrossRefGoogle Scholar
  150. 150.
    Jesenberger V, Jentsch S (2002) Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol 3:112–121Google Scholar
  151. 151.
    Salvador JM, Hollander MC, Nguyen AT, Kopp JB, Barisoni L, Moore JK, Ashwell JD, Fornace AJ Jr (2002) Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Immunity 16:499–508CrossRefGoogle Scholar
  152. 152.
    Ohsako S, Hara M, Harigai M, Fukasawa C, Kashiwazaki S (1994) Expression and function of Fas antigen and bcl-2 in human systemic lupus erythematosus lymphocytes. Clin Immunol Immunopathol 73:109–114CrossRefGoogle Scholar
  153. 153.
    Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S, Harris AW (1991) Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci USA 88:8661–8665Google Scholar
  154. 154.
    Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151PubMedGoogle Scholar
  155. 155.
    Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, Brookes AJ, Tentler D, Kristjansdottir H, Grondal G, Bolstad AI, Svenungsson E, Lundberg I, Sturfelt G, Jonssen A, Truedsson L, Lima G, Alcocer-Varela J, Jonsson R, Gyllensten UB, Harley JB, Alarcon-Segovia D, Steinsson K, Alarcon-Riquelme ME (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669CrossRefPubMedGoogle Scholar
  156. 156.
    Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP (1999) Impaired Fas response and autoimmunity in Pten+/- mice. Science 285:2122–2125CrossRefGoogle Scholar
  157. 157.
    Chikuma S, Bluestone JA (2003) CTLA-4 and tolerance: the biochemical point of view. Immunol Res 28:241–253CrossRefGoogle Scholar
  158. 158.
    Lawson BR, Baccala R, Song J, Croft M, Kono DH, Theofilopoulos AN (2004) Deficiency of the Cyclin Kinase Inhibitor p21 (WAF-1/CIP-1) Promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. J Exp Med 199:547–557CrossRefGoogle Scholar
  159. 159.
    Drappa J, Kamen LA, Chan E, Georgiev M, Ashany D, Marti F, King PD (2003) Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice. J Exp Med 198:809–821CrossRefPubMedGoogle Scholar
  160. 160.
    Theofilopoulos AN, Dixon FJ (1985) Murine models of systemic lupus erythematosus. Adv Immunol 37:269–390Google Scholar
  161. 161.
    Zhou T, Su X, Wu J, Cheng J (1996) Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. Clin Immunol Immunopathol 80:S2–S14CrossRefGoogle Scholar
  162. 162.
    Vaishnaw AK, Toubi E, Ohsako S, Drappa J, Buys S, Estrada J, Sitarz A, Zemel L, Chu JL, Elkon KB (1999) The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations. Arthritis Rheum 42:1833–1842Google Scholar
  163. 163.
    Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC (1996) Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-alpha. Clin Immunol Immunopathol 81:293–302CrossRefGoogle Scholar
  164. 164.
    Xu L, Zhang L, Yi Y, Kang HK, Datta SK (2004) Human lupus T cells resist inactivation and escape death by upregulating COX-2. Nat Med 10:411–415Google Scholar
  165. 165.
    Pablos JL, Santiago B, Carreira PE, Galindo M, Gomez-Reino JJ (1999) Cyclooxygenase-1 and −2 are expressed by human T cells. Clin Exp Immunol 115:86–90CrossRefGoogle Scholar
  166. 166.
    Lin Z, Fillmore GC, Um TH, Elenitoba-Johnson KS, Lim MS (2003) Comparative microarray analysis of gene expression during activation of human peripheral blood T cells and leukemic Jurkat T cells. Lab Invest 83:765–776Google Scholar
  167. 167.
    Mitchell T, Hildeman D, Kedl R, Teague T, Schaefer B, White J, Zhu Y, Kappler J, Marrack P (2001) Immunological adjuvants promote activated T cell survival via induction of Bcl-3. Nat Immunol 2:397–402Google Scholar
  168. 168.
    Stack E, DuBois RN (2001) Role of cyclooxygenase inhibitors for the prevention of colorectal cancer. Gastroenterol Clin North Am 30:1001–1010Google Scholar
  169. 169.
    Zhu J, Song X, Lin HP, Young DC, Yan S, Marquez VE, Chen CS (2002) Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J Natl Cancer Inst 94:1745–1757Google Scholar
  170. 170.
    Lin MT, Lee RC, Yang PC, Ho FM, Kuo ML (2001) Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem 276:48997–49002CrossRefGoogle Scholar
  171. 171.
    Jones RG, Elford AR, Parsons MJ, Wu L, Krawczyk CM, Yeh WC, Hakem R, Rottapel R, Woodgett JR, Ohashi PS (2002) CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. J Exp Med 196:335–348CrossRefGoogle Scholar
  172. 172.
    Berg-Brown NN, Gronski MA, Jones RG, Elford AR, Deenick EK, Odermatt B, Littman DR, Ohashi PS (2004) PKCq signals activation versus tolerance In Vivo. J Exp Med 199:743–752CrossRefGoogle Scholar
  173. 173.
    Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ (1998) Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28-T cells from rheumatoid arthritis patients. J Immunol 161:1018–1025Google Scholar
  174. 174.
    Sharief MK, Semra YK (2001) Heightened expression of survivin in activated T lymphocytes from patients with multiple sclerosis. J Neuroimmunol 119:358–364CrossRefGoogle Scholar
  175. 175.
    Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK (1998) Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8:615–623CrossRefGoogle Scholar
  176. 176.
    Zheng Y, Vig M, Lyons J, Van Parijs L, Beg AA (2003) Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med 197:861–874CrossRefGoogle Scholar
  177. 177.
    Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J (2000) The caspase-8 inhibitor FLIP promotes activation of NF-kB and Erk signaling pathways. Curr Biol 10:640–648CrossRefPubMedGoogle Scholar
  178. 178.
    Dixon DA, Balch GC, Kedersha N, Anderson P, Zimmerman GA, Beauchamp RD, Prescott SM (2003) Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. J Exp Med 198:475–481CrossRefGoogle Scholar
  179. 179.
    Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182CrossRefPubMedGoogle Scholar
  180. 180.
    Parfenova H, Parfenov VN, Shlopov BV, Levine V, Falkos S, Pourcyrous M, Leffler CW (2001) Dynamics of nuclear localization sites for COX-2 in vascular endothelial cells. Am J Physiol Cell Physiol 281:C166–C178Google Scholar
  181. 181.
    Ballif BA, Mincek NV, Barratt JT, Wilson ML, Simmons DL (1996) Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated protein. Proc Natl Acad Sci USA 93:5544–5549CrossRefGoogle Scholar
  182. 182.
    Lander SA, Wallace DJ, Weisman MH (2002) Celecoxib for systemic lupus erythematosus: case series and literature review of the use of NSAIDs in SLE. Lupus 11:340–347CrossRefGoogle Scholar
  183. 183.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–1533CrossRefPubMedGoogle Scholar

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© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Departments of Medicine and Microbiology-Immunology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

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