Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Immunopathology and the gene therapy of lupus

Gene Therapy volume 10, pages 861–874 (2003)Cite this article

Abstract

Lupus is a chronic autoimmune inflammatory disease with complex clinical manifestations. In humans, lupus, also known as systemic lupus erythematosus (SLE), affects between 40 and 250 individuals, mostly females, in each 100 000 of the population. There are also a number of murine models of lupus widely used in studies of the genetics, immunopathology, and treatment of lupus. Human patients and murine models of lupus manifest a wide range of immunological abnormalities. The most pervasive of these are: (1) the ability to produce pathogenic autoantibodies; (2) lack of T- and B-lymphocyte regulation; and (3) defective clearance of autoantigens and immune complexes. This article briefly reviews immunological abnormalities and disease mechanisms characteristic of lupus autoimmunity and highlight recent studies on the use of gene therapy to target these abnormalities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Michet Jr CJ et al. Epidemiology of systemic lupus erythematosus and other connective tissue diseases in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1985; 60: 105–113.

    Article  PubMed  Google Scholar 

  2. Hochberg MC . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

    Article  CAS  PubMed  Google Scholar 

  3. Masi AT, Kaslow RA . Sex effects in systemic lupus erythematosus: a clue to pathogenesis. Arthritis Rheum 1978; 21: 480–484.

    Article  CAS  PubMed  Google Scholar 

  4. Roubinian JR et al. Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J Exp Med 1978; 147: 1568–1583.

    Article  CAS  PubMed  Google Scholar 

  5. Pincus T . Studies regarding a possible function for viruses in the pathogenesis of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 847–856.

    Article  CAS  PubMed  Google Scholar 

  6. Hardgrave KL, Neas BR, Scofield RH, Harley JB . Antibodies to vesicular stomatitis virus proteins in patients with systemic lupus erythematosus and in normal subjects. Arthritis Rheum 1993; 36: 962–970.

    Article  CAS  PubMed  Google Scholar 

  7. Yung RL, Richardson BC . Drug-induced lupus. Rheum Dis Clin North Am 1994; 20: 61–86.

    Article  CAS  PubMed  Google Scholar 

  8. Deapen D et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311–318.

    Article  CAS  PubMed  Google Scholar 

  9. Walport MJ . Complement and systemic lupus erythematosus. Arthritis Res 2002; 4 (Suppl 3): S279–S293.

    Article  PubMed  PubMed Central  Google Scholar 

  10. O'Shea JJ, Ma A, Lipsky P . Cytokines and autoimmunity. Nat Rev Immunol 2002; 2: 37–45.

    Article  CAS  PubMed  Google Scholar 

  11. Tsuchiya N et al. New single nucleotide polymorphisms in the coding region of human TNFR2: association with systemic lupus erythematosus. Genes Immun 2000; 1: 501–503.

    Article  CAS  PubMed  Google Scholar 

  12. Kanemitsu S et al. Association of interleukin-4 receptor and interleukin-4 promoter gene polymorphisms with systemic lupus erythematosus. Arthritis Rheum 1999; 42: 1298–1300.

    Article  CAS  PubMed  Google Scholar 

  13. Nakashima H et al. The combination of polymorphisms within interferon-gamma receptor 1 and receptor 2 associated with the risk of systemic lupus erythematosus. FEBS Lett 1999; 453: 187–190.

    Article  CAS  PubMed  Google Scholar 

  14. Schur PH . Genetics of systemic lupus erythematosus. Lupus 1995; 4: 425–437.

    Article  CAS  PubMed  Google Scholar 

  15. Ibnou-Zekri N et al. MHC-linked control of murine SLE. Curr Top Microbiol Immunol 1999; 246: 275–280.

    CAS  PubMed  Google Scholar 

  16. Tebib JG, Alcocer-Varela J, Alarcon-Segovia D, Schur PH . Association between a T cell receptor restriction fragment length polymorphism and systemic lupus erythematosus. J Clin Invest 1990; 86: 1961–1967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frank MB, McArthur R, Harley JB, Fujisaku A . Anti-Ro(SSA) autoantibodies are associated with T cell receptor beta genes in systemic lupus erythematosus patients. J Clin Invest 1990; 85: 33–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Olee T et al. Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases. J Clin Invest 1991; 88: 193–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Salmon JE et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996; 97: 1348–1354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zuniga R et al. Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. Arthritis Rheum 2001; 44: 361–367.

    Article  CAS  PubMed  Google Scholar 

  21. Hatta Y et al. Association of Fc gamma receptor IIIB, but not of Fc gamma receptor IIA and IIIA polymorphisms with systemic lupus erythematosus in Japanese. Genes Immun 1999; 1: 53–60.

    Article  CAS  PubMed  Google Scholar 

  22. Tsokos GC, Liossis SN . Immune cell signaling defects in lupus: activation, anergy and death. Immunol Today 1999; 20: 119–124.

    Article  CAS  PubMed  Google Scholar 

  23. Liossis SN, Ding XZ, Dennis GJ, Tsokos GC . Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain. J Clin Invest 1998; 101: 1448–1457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shultz LD et al. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 1993; 73: 1445–1454.

    Article  CAS  PubMed  Google Scholar 

  25. DesJardin LE, Butfiloski EJ, Sobel ES, Schiffenbauer J . Hyperproliferation of BXSB B cells is linked to the Yaa allele. Clin Immunol Immunopathol 1996; 81: 145–152.

    Article  CAS  PubMed  Google Scholar 

  26. Watanabe-Fukunaga R et al. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992; 356: 314–317.

    Article  CAS  PubMed  Google Scholar 

  27. Takahashi T et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 1994; 76: 969–976.

    Article  CAS  PubMed  Google Scholar 

  28. Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK . Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996; 97: 2063–2073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lettesjo H, Burd GP, Mageed RA . CD4+ T lymphocytes with constitutive CD40 ligand in preautoimmune (NZB × NZW)F1 lupus-prone mice: phenotype and possible role in autoreactivity. J Immunol 2000; 165: 4095–4104.

    Article  CAS  PubMed  Google Scholar 

  30. Mary C et al. Dysregulated expression of the Cd22 gene as a result of a short interspersed nucleotide element insertion in Cd22a lupus-prone mice. J Immunol 2000; 165: 2987–2996.

    Article  CAS  PubMed  Google Scholar 

  31. Jiang Y et al. Genetically determined aberrant down-regulation of FcgammaRIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus. Int Immunol 1999; 11: 1685–1691.

    Article  CAS  PubMed  Google Scholar 

  32. Ho CY et al. Expression of cyclin B1 and cyclin dependent kinase inhibitor p21 in lymphocytes in patients with systemic lupus erythematosus. J Rheumatol 2002; 29: 2537–2544.

    CAS  PubMed  Google Scholar 

  33. Santiago-Raber ML et al. Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J Immunol 2001; 167: 4067–4074.

    CAS  PubMed  Google Scholar 

  34. Yasutomo K et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001; 28: 313–314.

    Article  CAS  PubMed  Google Scholar 

  35. Walport MJ . Lupus, DNase and defective disposal of cellular debris. Nat Genet 2000; 25: 135–136.

    Article  CAS  PubMed  Google Scholar 

  36. Wakeland EK, Liu K, Graham RR, Behrens TW . Delineating the genetic basis of systemic lupus erythematosus. Immunity 2001; 15: 397–408.

    Article  CAS  PubMed  Google Scholar 

  37. Lee SH et al. Decreased tumour necrosis factor-beta production in TNFB*2 homozygote: an important predisposing factor of lupus nephritis in Koreans. Lupus 1997; 6: 603–609.

    Article  CAS  PubMed  Google Scholar 

  38. Jacob CO, McDevitt HO . Tumour necrosis factor-α in murine autoimmune ‘lupus’ nephritis. Nature 1988; 331: 356–358.

    Article  CAS  PubMed  Google Scholar 

  39. Llorente L et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995; 181: 839–844.

    Article  CAS  PubMed  Google Scholar 

  40. Theofilopoulos AN, Kono DH . The genes of systemic autoimmunity. Proc Assoc Am Physicians 1999; 111: 228–240.

    Article  CAS  PubMed  Google Scholar 

  41. Fukuyama H et al. Transgenic expression of Fas in T cells blocks lymphoproliferation but not autoimmune disease in MRL-lpr mice. J Immunol 1998; 160: 3805–3811.

    CAS  PubMed  Google Scholar 

  42. Kojima T et al. Analysis of fas ligand gene mutation in patients with systemic lupus erythematosus. Arthritis Rheum 2000; 43: 135–139.

    Article  CAS  PubMed  Google Scholar 

  43. Kontoyiannis D, Kollias G . Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor. Eur J Immunol 2000; 30: 2038–2047.

    Article  CAS  PubMed  Google Scholar 

  44. Zhou T et al. Greatly accelerated lymphadenopathy and autoimmune disease in lpr mice lacking tumor necrosis factor receptor I. J Immunol 1996; 156: 2661–2665.

    CAS  PubMed  Google Scholar 

  45. Morimoto C et al. A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody. J Clin Invest 1987; 79: 762–768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Emlen W, Niebur J, Kadera R . Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol 1994; 152: 3685–3692.

    CAS  PubMed  Google Scholar 

  47. Goto M, Tanimoto K, Horiuchi Y . Natural cell mediated cytotoxicity in systemic lupus erythematosus: suppression by antilymphocyte antibody. Arthritis Rheum 1980; 23: 1274–1281.

    Article  CAS  PubMed  Google Scholar 

  48. Linker-Israeli M, Quismorio Jr FP, Horwitz DA . CD8+ lymphocytes from patients with systemic lupus erythematosus sustain, rather than suppress, spontaneous polyclonal IgG production and synergize with CD4+ cells to support autoantibody synthesis. Arthritis Rheum 1990; 33: 1216–1225.

    Article  CAS  PubMed  Google Scholar 

  49. Ohtsuka K et al. Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol 1998; 160: 2539–2545.

    CAS  PubMed  Google Scholar 

  50. Rajagopalan S, Zordan T, Tsokos GC, Datta SK . Pathogenic anti-DNA autoantibody-inducing T helper cell lines from patients with active lupus nephritis: isolation of CD4-8-T helper cell lines that express the gamma delta T-cell antigen receptor. Proc Natl Acad Sci USA 1990; 87: 7020–7024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Horwitz DA et al. Decreased T cell response to anti-CD2 in systemic lupus erythematosus and reversal by anti-CD28: evidence for impaired T cell-accessory cell interaction. Arthritis Rheum 1997; 40: 822–833.

    Article  CAS  PubMed  Google Scholar 

  52. Gray JD, Hirokawa M, Ohtsuka K, Horwitz DA . Generation of an inhibitory circuit involving CD8+ T cells, IL-2, and NK cell-derived TGF-beta: contrasting effects of anti-CD2 and anti-CD3. J Immunol 1998; 160: 2248–2254.

    CAS  PubMed  Google Scholar 

  53. Stekman IL et al. Enhanced CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus. Arthritis Rheum 1991; 34: 459–467.

    Article  CAS  PubMed  Google Scholar 

  54. Sierakowski S, Kucharz EJ, Lightfoot RW, Goodwin JS . Impaired T-cell activation in patients with systemic lupus erythematosus. J Clin Immunol 1989; 9: 469–476.

    Article  CAS  PubMed  Google Scholar 

  55. Wong HK, Kammer GM, Dennis G, Tsokos GC . Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression. J Immunol 1999; 163: 1682–1689.

    CAS  PubMed  Google Scholar 

  56. Hasler P, Schultz LA, Kammer GM . Defective cAMP-dependent phosphorylation of intact T lymphocytes in active systemic lupus erythematosus. Proc Natl Acad Sci USA 1990; 87: 1978–1982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Solomou EE et al. Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J Immunol 2001; 166: 4216–4222.

    Article  CAS  PubMed  Google Scholar 

  58. Yi Y, McNerney M, Datta SK . 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 2000; 165: 6627–6634.

    Article  CAS  PubMed  Google Scholar 

  59. Ohtsuka K, Gray JD, Stimmler MM, Horwitz DA . The relationship between defects in lymphocyte production of transforming growth factor-beta1 in systemic lupus erythematosus and disease activity or severity. Lupus 1999; 8: 90–94.

    Article  CAS  PubMed  Google Scholar 

  60. Dau PC, Callahan J, Parker R, Golbus J . Immunologic effects of plasmapheresis synchronized with pulse cyclophosphamide in systemic lupus erythematosus. J Rheumatol 1991; 18: 270–276.

    CAS  PubMed  Google Scholar 

  61. Llorente L et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 2000; 43: 1790–1800.

    Article  CAS  PubMed  Google Scholar 

  62. Traynor AE et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet 2000; 356: 701–707.

    Article  CAS  PubMed  Google Scholar 

  63. Gottlieb AB, Lahita RG, Chiorazzi N, Kunkel HG . Immune function in systemic lupus erythematosus. Impairment of in vitro T-cell proliferation and in vivo antibody response to exogenous antigen. J Clin Invest 1979; 63: 885–892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mostoslavsky G et al. Lupus anti-DNA autoantibodies cross-react with a glomerular structural protein: a case for tissue injury by molecular mimicry. Eur J Immunol 2001; 31: 1221–1227.

    Article  CAS  PubMed  Google Scholar 

  65. Malkiel S, Kuan AP, Diamond B . Autoimmunity in heart disease: mechanisms and genetic susceptibility. Mol Med Today 1996; 2: 336–342.

    Article  CAS  PubMed  Google Scholar 

  66. Hirose N et al. A role for the polymorphism at position 247 of the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome. Arthritis Rheum 1999; 42: 1655–1661.

    Article  CAS  PubMed  Google Scholar 

  67. Reininger L et al. Intrinsic B cell defects in NZB and NZW mice contribute to systemic lupus erythematosus in (NZB × NZW) F1 mice. J Exp Med 1996; 184: 853–856.

    Article  CAS  PubMed  Google Scholar 

  68. Folzenlogen D et al. Analysis of CD80 and CD86 expression on peripheral blood B lymphocytes reveals increased expression of CD86 in lupus patients. Clin Immunol Immunopathol 1997; 83: 199–204.

    Article  CAS  PubMed  Google Scholar 

  69. Takata M et al. Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways. EMBO J 1994; 13: 1341–1349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tolnay M, Tsokos GC . Complement receptor 2 in the regulation of the immune response. Clin Immunol Immunopathol 1998; 88: 123–132.

    Article  CAS  PubMed  Google Scholar 

  71. D'Ambrosio D et al. Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc gamma RIIB1. Science 1995; 268: 293–297.

    Article  CAS  PubMed  Google Scholar 

  72. Liossis SN et al. B-cell kinase lyn deficiency in patients with systemic lupus erythematosus. J Invest Med 2001; 49: 157–165.

    Article  CAS  Google Scholar 

  73. Mason LJ, Isenberg DA . Immunopathogenesis of SLE. Baillieres Clin Rheumatol 1998; 12: 385–403.

    Article  CAS  PubMed  Google Scholar 

  74. Dauphinee MJ, Kipper SB, Wofsy D, Talal N . Interleukin 2 deficiency is a common feature of autoimmune mice. J Immunol 1981; 127: 2483–2487.

    CAS  PubMed  Google Scholar 

  75. Alcocer-Varela J, Alarcon-Segovia D . Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest 1982; 69: 1388–1392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tada Y et al. A defect in the protein kinase C system in T cells from patients with systemic lupus erythematosus. Clin Immunol Immunopathol 1991; 60: 220–231.

    Article  CAS  PubMed  Google Scholar 

  77. Phi NC et al. Cyclic AMP level of lymphocytes in patients with systemic lupus erythematosus and its relation to disease activity. Immunol Lett 1989; 23: 61–64.

    Article  CAS  PubMed  Google Scholar 

  78. Kammer GM . High prevalence of T cell type I protein kinase A deficiency in systemic lupus erythematosus. Arthritis Rheum 1999; 42: 1458–1465.

    Article  CAS  PubMed  Google Scholar 

  79. Tanaka T et al. Decreased expression of interleukin-2 binding molecules (p70/75) in T cells from patients with systemic lupus erythematosus. Arthritis Rheum 1989; 32: 552–559.

    Article  CAS  PubMed  Google Scholar 

  80. Liang HE et al. Atypical signaling defects prevent IL-2 gene expression in lpr/lpr CD4-CD8- cells. J Biomed Sci 1998; 5: 297–304.

    CAS  PubMed  Google Scholar 

  81. Sabzevari H, Propp S, Kono DH, Theofilopoulos AN . G1 arrest and high expression of cyclin kinase and apoptosis inhibitors in accumulated activated/memory phenotype CD4+ cells of older lupus mice. Eur J Immunol 1997; 27: 1901–1910.

    Article  CAS  PubMed  Google Scholar 

  82. Gutierrez-Ramos JC et al. Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature 1990; 346: 271–274.

    Article  CAS  PubMed  Google Scholar 

  83. Kelley VE et al. Anti-interleukin 2 receptor antibody suppresses murine diabetic insulitis and lupus nephritis. J Immunol 1988; 140: 59–61.

    CAS  PubMed  Google Scholar 

  84. Prud'homme GJ, Kono DH, Theofilopoulos AN . Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. Mol Immunol 1995; 32: 495–503.

    Article  CAS  PubMed  Google Scholar 

  85. Graninger WB et al. Induction of systemic lupus erythematosus by interferon-gamma in a patient with rheumatoid arthritis. J Rheumatol 1991; 18: 1621–1622.

    CAS  PubMed  Google Scholar 

  86. al-Janadi M, al-Balla S, al-Dalaan A, Raziuddin S . Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases. J Clin Immunol 1993; 13: 58–67.

    Article  CAS  PubMed  Google Scholar 

  87. Jacob CO, van der Meide PH, McDevitt HO . In vivo treatment of (NZB × NZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon. J Exp Med 1987; 166: 798–803.

    Article  CAS  PubMed  Google Scholar 

  88. Ozmen L et al. Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis. Eur J Immunol 1995; 25: 6–12.

    Article  CAS  PubMed  Google Scholar 

  89. Tokano Y et al. Levels of IL-12 in the sera of patients with systemic lupus erythematosus (SLE)-relation to Th1- and Th2-derived cytokines. Clin Exp Immunol 1999; 116: 169–173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Horwitz DA et al. Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosus. Arthritis Rheum 1998; 41: 838–844.

    Article  CAS  PubMed  Google Scholar 

  91. Alleva DG, Kaser SB, Beller DI . Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/++ and New Zealand Black/White F1 lupus-prone mice and the Leishmania major-susceptible BALB/c strain. J Immunol 1998; 161: 6878–6884.

    CAS  PubMed  Google Scholar 

  92. Huang FP et al. The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRLMP-lprlpr mice. J Exp Med 1996; 183: 1447–1459.

    Article  CAS  PubMed  Google Scholar 

  93. Houssiau FA et al. IL-12 inhibits in vitro immunoglobulin production by human lupus peripheral blood mononuclear cells (PBMC). Clin Exp Immunol 1997; 108: 375–380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Davas EM et al. Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus. Clin Rheumatol 1999; 18: 17–22.

    Article  CAS  PubMed  Google Scholar 

  95. Swaak AJ, van Rooyen A, Aarden LA . Interleukin-6 (IL-6) and acute phase proteins in the disease course of patients with systemic lupus erythematosus. Rheumatol Int 1989; 8: 263–268.

    Article  CAS  PubMed  Google Scholar 

  96. Kroemer G, Martinez C . Cytokines and autoimmune disease. Clin Immunol Immunopathol 1991; 61: 275–295.

    Article  CAS  PubMed  Google Scholar 

  97. Casciola-Rosen LA, Anhalt G, Rosen A . Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994; 179: 1317–1330.

    Article  CAS  PubMed  Google Scholar 

  98. Kitani A et al. Heterogeneity of B cell responsiveness to interleukin 4, interleukin 6 and low molecular weight B cell growth factor in discrete stages of B cell activation in patients with systemic lupus erythematosus. Clin Exp Immunol 1989; 77: 31–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. McMurray RW, Hoffman RW, Nelson W, Walker SE . Cytokine mRNA expression in the B/W mouse model of systemic lupus erythematosus – analyses of strain, gender, and age effects. Clin Immunol Immunopathol 1997; 84: 260–268.

    Article  CAS  PubMed  Google Scholar 

  100. Ryffel B et al. Interleukin-6 exacerbates glomerulonephritis in (NZB × NZW)F1 mice. Am J Pathol 1994; 144: 927–937.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Finck BK, Chan B, Wofsy D . Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J Clin Invest 1994; 94: 585–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Shirai A, Conover J, Klinman DM . Increased activation and altered ratio of interferon-gamma: interleukin-4 secreting cells in MRL-lpr/lpr mice. Autoimmunity 1995; 21: 107–116.

    Article  CAS  PubMed  Google Scholar 

  103. Dueymes M et al. Relationship of interleukin-4 to isotypic distribution of anti-double-stranded DNA antibodies in systemic lupus erythematosus. Int Arch Allergy Immunol 1993; 101: 408–415.

    Article  CAS  PubMed  Google Scholar 

  104. Richaud-Patin Y, Alcocer-Varela J, Llorente L . High levels of TH2 cytokine gene expression in systemic lupus erythematosus. Rev Invest Clin 1995; 47: 267–272.

    CAS  PubMed  Google Scholar 

  105. Rus V et al. Expression of cytokine- and chemokine-related genes in peripheral blood mononuclear cells from lupus patients by cDNA array. Clin Immunol 2002; 102: 283–290.

    Article  CAS  PubMed  Google Scholar 

  106. Santiago ML et al. Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome. J Exp Med 1997; 185: 65–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hagiwara E, Gourley MF, Lee S, Klinman DK . Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum 1996; 39: 379–385.

    Article  CAS  PubMed  Google Scholar 

  108. Ishida H et al. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 1994; 179: 305–310.

    Article  CAS  PubMed  Google Scholar 

  109. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mongan AE, Ramdahin S, Warrington RJ . Interleukin-10 response abnormalities in systemic lupus erythematosus. Scand J Immunol 1997; 46: 406–412.

    Article  CAS  PubMed  Google Scholar 

  111. Lacki JK, Samborski W, Mackiewicz SH . Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins. Clin Rheumatol 1997; 16: 275–278.

    Article  CAS  PubMed  Google Scholar 

  112. Jacob CO et al. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 1990; 87: 1233–1237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mitamura K et al. Impaired tumour necrosis factor-alpha (TNF-alpha) production and abnormal B cell response to TNF-alpha in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 1991; 85: 386–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jones BM, Liu T, Wong RW . Reduced in vitro production of interferon-gamma, interleukin-4 and interleukin-12 and increased production of interleukin-6, interleukin-10 and tumour necrosis factor-alpha in systemic lupus erythematosus. Weak correlations of cytokine production with disease activity. Autoimmunity 1999; 31: 117–124.

    Article  CAS  PubMed  Google Scholar 

  115. Cope AP et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997; 185: 1573–1584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tanaka Y et al. Production of B cell-stimulating factors by B cells in patients with systemic lupus erythematosus. J Immunol 1988; 141: 3043–3049.

    CAS  PubMed  Google Scholar 

  117. Sierakowski S, Kucharz EJ, Lightfoot Jr RW, Goodwin JS . Interleukin-1-production by monocytes from patients with systemic lupus erythematosus. Clin Rheumatol 1987; 6: 403–407.

    Article  CAS  PubMed  Google Scholar 

  118. Brennan DC, Yui MA, Wuthrich RP, Kelley VE . Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury. J Immunol 1989; 143: 3470–3475.

    CAS  PubMed  Google Scholar 

  119. Schorlemmer HU, Kanzy EJ, Langner KD, Kurrle R . Immunoregulation of SLE-like disease by the IL-1 receptor: disease modifying activity on BDF1 hybrid mice and MRL autoimmune mice. Agents Actions 1993; 39: C117–C120.

    Article  CAS  PubMed  Google Scholar 

  120. Border WA, Ruoslahti E . Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest 1992; 90: 1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lowrance JH et al. Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice. J Exp Med 1994; 180: 1693–1703.

    Article  CAS  PubMed  Google Scholar 

  122. Prud'homme GJ, Lawson BR, Theofilopoulos AN . Anticytokine gene therapy of autoimmune diseases. Expert Opin Biol Ther 2001; 1: 359–373.

    Article  CAS  PubMed  Google Scholar 

  123. Suarez-Pinzon WL, Rabinovitch A . Approaches to type 1 diabetes prevention by intervention in cytokine immunoregulatory circuits. Int J Exp Diabetes Res 2001; 2: 3–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Prud'homme GJ, Piccirillo CA . The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J Autoimmun 2000; 14: 23–42.

    Article  CAS  PubMed  Google Scholar 

  125. Racke MK et al. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol 1991; 146: 3012–3017.

    CAS  PubMed  Google Scholar 

  126. Kuruvilla AP et al. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci USA 1991; 88: 2918–2921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Raz E et al. Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci USA 1993; 90: 4523–4527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Piccirillo CA, Chang Y, Prud'homme GJ . TGF-beta1 somatic gene therapy prevents autoimmune disease in nonobese diabetic mice. J Immunol 1998; 161: 3950–3956.

    CAS  PubMed  Google Scholar 

  129. Raz E et al. Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery. Lupus 1995; 4: 286–292.

    Article  CAS  PubMed  Google Scholar 

  130. Huggins ML et al. Modulation of the autoimmune response in lupus mice by oral administration of attenuated Salmonella typhimurium expressing the IL-2 and TGF-beta genes. Ann NY Acad Sci 1997; 815: 499–502.

    Article  CAS  PubMed  Google Scholar 

  131. Huggins ML et al. Modulation of autoimmune disease in the MRL-lpr/lpr mouse by IL-2 and TGF-beta1 gene therapy using attenuated Salmonella typhimurium as gene carrier. Lupus 1999; 8: 29–38.

    Article  CAS  PubMed  Google Scholar 

  132. Hagiwara E et al. IL-12-encoding plasmid has a beneficial effect on spontaneous autoimmune disease in MRL/MP-lpr/lpr mice. Cytokine 2000; 12: 1035–1041.

    Article  CAS  PubMed  Google Scholar 

  133. Salomon B, Bluestone JA . Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 2001; 19: 225–252.

    Article  CAS  PubMed  Google Scholar 

  134. Najafian N, Sayegh MH . CTLA4-Ig: a novel immunosuppressive agent. Expert Opin Invest Drugs 2000; 9: 2147–2157.

    Article  CAS  Google Scholar 

  135. Takiguchi M et al. CTLA4IgG gene delivery prevents autoantibody production and lupus nephritis in MRL/lpr mice. Life Sci 2000; 66: 991–1001.

    Article  CAS  PubMed  Google Scholar 

  136. Prud'homme GJ, Chang Y . Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein. Gene Therapy 1999; 6: 771–777.

    Article  CAS  PubMed  Google Scholar 

  137. Chang Y, Prud'homme GJ . Intramuscular administration of expression plasmids encoding interferon-gamma receptor/IgG1 or IL-4/IgG1 chimeric proteins protects from autoimmunity. J Gene Med 1999; 1: 415–423.

    Article  CAS  PubMed  Google Scholar 

  138. Prud'homme GJ . Gene therapy of autoimmune diseases with vectors encoding regulatory cytokines or inflammatory cytokine inhibitors. J Gene Med 2000; 2: 222–232.

    Article  CAS  PubMed  Google Scholar 

  139. Hartikka J et al. An improved plasmid DNA expression vector for direct injection into skeletal muscle. Hum Gene Ther 1996; 7: 1205–1217.

    Article  CAS  PubMed  Google Scholar 

  140. Theofilopoulos AN, Koundouris S, Kono DH, Lawson BR . The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity. Arthritis Res 2001;3: 136–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lawson BR et al. Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc. J Clin Invest 2000; 106: 207–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Mir LM et al. High-efficiency gene transfer into skeletal muscle mediated by electric pulses. Proc Natl Acad Sci USA 1999; 96: 4262–4267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Krieg AM . CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002; 20: 709–760.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

RA Mageed is supported by grants from Arthritis Research Campaign, UK. The studies of GJ Prud'homme described in this review were supported by the Juvenile Diabetes Research Foundation International, the Canadian Diabetes Association, the National Cancer Institute of Canada, and in collaboration with Dr AN Theofilopoulos of the Scripps Research Institute, La Jolla, CA by NIH Grants AR31203, AG15061, and AR39555. We thank Vical Inc. (San Diego, CA) for providing the VR1255 expression plasmid used in some of the studies described in the review.

Author information

Authors and Affiliations

  1. Department of Immunology and Molecular Pathology, Royal Free and University College School of Medicine, London, UK

    R A Mageed

  2. Department of Laboratory Medicine and Pathobiology, St Michael's Hospital and University of Toronto, Toronto, Ontario, Canada

    G J Prud'homme

Authors
  1. R A Mageed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G J Prud'homme
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mageed, R., Prud'homme, G. Immunopathology and the gene therapy of lupus. Gene Ther 10, 861–874 (2003). https://doi.org/10.1038/sj.gt.3302016

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302016

Keywords

This article is cited by

Search

Advanced search

Quick links