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Systemic lupus: basic mechanisms and prospects for specific immunotherapy

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  • Published:
Japanese Journal of Rheumatology

Abstract

Nucleosomes are the primary immunogens that initiate the pathogenic autoimmune response in SLE. The production of pathogenic anti-nuclear antibodies in murine as well as human lupus is mediated by a MHC class-II restricted, cognate interaction between select populations of autoimmune T helper (Th) cells and autoimmune B cells that recognize epitopes in the different molecular components of the nucleosome particle. In the SNF1 model of lupus, we have localized the critical peptide autoepitopes for lupus nephritis-inducing Th cells in the core histones of nucleosomes, at amino acid positions 10–33 of H2B, and 16–39 and 71–94 of H4. Remarkably, the nephritogenic epitopes are located in the regions of histones that are also targeted by lupus autoantibodies, as well as the sites where the histones contact with DNA in the nucleosome, indicating that they are specially protected during antigen processing. The localization of the critical peptide autoepitopes in nucleosomes is a basic step towards defining how the pathogenic Th cells emerge in lupus. In addition, the pathogenic Th cells and B cells of lupus have a regulatory defect in the expression of CD40 ligand (CD40L or gp39), which mediates abnormal co-stimulatory signals sustaining the production of pathogenic autoantibodies. Immunotherapy that specifically blocks the pathogenic T and B cell interaction in lupus can be developed based on these studies.

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References

  1. Boumpas DT, Austin HA, Fessler BJet al.: Systemic lupus erythematosus: emerging concepts. Part 1: renal, neuropsychyatric, cardiovascular, pulmonary and hematologic disease.Ann Int Med 122: 940–950, 1995.

    CAS  PubMed  Google Scholar 

  2. Harley JB, Sestak AL, Willis LGet al.: A model for disease heterogeneity in systemic lupus erythematosus: relationships between histocompatibility antigens, autoantibodies, and lymphopenia or renal disease.Arthritis Rheum 32: 826–836, 1989.

    CAS  PubMed  Google Scholar 

  3. Salmon JE, Millard S, Schachter LAet al.: FcYRIIA alleles are heritable risk factors for lupus nephritis in African Americans.J Clin Invest 97: 1348–1354, 1996.

    Article  CAS  PubMed  Google Scholar 

  4. Mohan C, Datta SK: Lupus: key pathogenic mechanisms and contributing factors.Clin Immunol Immunopathol 77: 209–220, 1995.

    Article  CAS  PubMed  Google Scholar 

  5. Tan EM: Anti-nuclear antibodies: diagnostic markers for autoimmunity diseases and probes for cell biology.Adv Immunol 44: 93–151, 1989.

    Article  CAS  PubMed  Google Scholar 

  6. Hardin JA, THomas JO: Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histone H1 and H2B.Proc Natl Acad Sci USA 80: 7410–7414, 1983.

    Article  CAS  PubMed  Google Scholar 

  7. 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 179: 1317–1330, 1994.

    Article  CAS  PubMed  Google Scholar 

  8. Stewart A, Huang C, Long Aet al.: VH-gene representation in autoantibodies reflects the normal B cell repertoire.Immunol Rev 128: 101–122, 1992.

    Article  CAS  PubMed  Google Scholar 

  9. Madaio MP, Hodder S, Schwartz RSet al.: Responsiveness of autoimmune and normal mice to nucleic acid antigens.J Immunol 132: 872–876, 1984.

    CAS  PubMed  Google Scholar 

  10. Gilkeson GS, Pippen AMM, Pisetsky DS: Induction of cross-reactive anti-dsDNA antibodies in preautoimmune NZB/NZW mice by immunization with bacterial DNA.J Clin Invest 95: 1398–1402, 1995.

    Article  CAS  PubMed  Google Scholar 

  11. Datta SK, Mohan C, Desai-Mehta A: Mechanisms of the pathogenic autoimmune response in lupus: prospects for specific immunotherapy.Immunol Res 14: 132–147, 1995.

    Article  CAS  PubMed  Google Scholar 

  12. Howie JB, Helyer BJ: The immunology and pathology of NZB mice.Adv Immunol 9: 215–268, 1968.

    Article  CAS  PubMed  Google Scholar 

  13. Datta SK, Schwartz RS: Genetics of expression of xenotropic virus and autoimmunity in NZB mice.Nature 263: 412–415, 1976.

    Article  CAS  PubMed  Google Scholar 

  14. Datta SK, Schwartz RS: Mendelian segregation of loci controling xenotropic virus production in NZB crosses.Virology 83: 449–452, 1977.

    Article  CAS  PubMed  Google Scholar 

  15. Datta SK, Manny N, Andrzejewski C, Andre-Schwartz J, Schwartz RS: Genetic studies of autoimmunity and retrovirus expression in crosses of New Zealand Black mice. I. Xenotropic virus.J Exp Med 147: 854–871, 1978.

    Article  CAS  PubMed  Google Scholar 

  16. Datta SK, McConahey PJ, Manny Net al.: Genetic studies of autoimmunity and retrovirus expression in crosses of NZB mice. II. The viral envelope glycoprotein gp 70.J Exp Med 147: 872–881, 1978.

    Article  CAS  PubMed  Google Scholar 

  17. Eastcott JW, Schwartz RS, Datta SK: Genetic analysis of the inheritence of B cell hyperactivity in relation to the development of autoantibodies and glomerulonephritis in NZB×SWR crosses.J Immunol 131: 2232–2239, 1983.

    CAS  PubMed  Google Scholar 

  18. Datta SK: A search for the underlying mechanisms of systemic autoimmune disease in the NZB×SWR model.Clin Immunol Immunopathol 51: 141–156, 1989.

    Article  CAS  PubMed  Google Scholar 

  19. Sercarz EE, Datta SK: Mechanisms of autoimmunization: perspective from the mid-90s.Curr Opin Immunol 6: 875–881, 1994.

    Article  CAS  PubMed  Google Scholar 

  20. Drake CG, Babcock SK, Palmer Eet al.: Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB×NZW)F1 mice.Proc Natl Acad Sci USA 91: 4062–4066, 1994.

    Article  CAS  PubMed  Google Scholar 

  21. Morel L, Rudofsky UH, Longmate JAet al.: Polygenic control of susceptibility to murine systemic lupus erythematosus.Immunity 1: 219–229, 1994.

    Article  CAS  PubMed  Google Scholar 

  22. Kono DH, Burlingame RW, Owens DGet al.: Lupus susceptibility loci in New Zealand mice.Proc Natl Acad Sci USA 91: 10168–10172, 1994.

    Article  CAS  PubMed  Google Scholar 

  23. Kelly VE, Winkelstein A: Age and sex-related glomerulonephritis in New Zealand white mice.Clin Immunol Immunopathol 16: 142–150, 1980.

    Article  Google Scholar 

  24. Yoshiki T, Mellors RC, Strand Met al.: The viral envelope glycoprotein of murine leukemia virus and the pathogenesis of immune complex glomerulonephritis of New Zealand Mice.J Exp Med 140: 1011–1027, 1974.

    Article  CAS  PubMed  Google Scholar 

  25. Schwartz RS: Viruses and systemic lupus erythematosus.N Engl J Med 293: 132–138, 1975.

    CAS  PubMed  Google Scholar 

  26. Lewis RM, Tannenberg W, Smith Cet al.: C-type viruses and systemic lupus erythematosus.Nature 252: 78–79, 1974.

    Article  CAS  PubMed  Google Scholar 

  27. Talal N: Immunologic and viral factors in the pathogenesis of systemic lupus erythematosus.Arthritis Rheum 13: 887–894, 1970.

    Article  CAS  PubMed  Google Scholar 

  28. Lambert PH, Dixon FJ: Genesis of anti-nuclear antibody in NZB/W mice: role of genetic factors and of viral infections.Clin Exp Immunol 6: 829–839, 1970.

    CAS  PubMed  Google Scholar 

  29. Levy JA: Xenotropic C-type viruses and autoimmune disease.J Rheumatol 2: 135–148, 1975.

    CAS  PubMed  Google Scholar 

  30. Panem S, Ordonez NG, Kerstein WHet al.: C-type virus expression in systemic lupus erythematosus.N Engl J Med 295: 470–475, 1976.

    CAS  PubMed  Google Scholar 

  31. Mellors RC, Mellors JW: Antigen related to mammalian type-C RNA viral p30 proteins is located in renal glomeruli in human systemic lupus erythematosus.Proc Natl Acad Sci USA 73: 233–237, 1976.

    Article  CAS  PubMed  Google Scholar 

  32. Markenson JA, Phillips PE: Type-C viruses in systemic lupus erythematosus.Arthritis Rheum 21: 266–270, 1978.

    Article  CAS  PubMed  Google Scholar 

  33. Strand M, August JT: Type-C RNA virus gene expression in human tissue.J Virol 14: 1584–1596, 1974.

    CAS  PubMed  Google Scholar 

  34. Krieg AM, Steinberg AD: Analysis of thymic endogenous retroviral expression in murine lupus. Genetic and immune studies.J Clin Invest 86: 809–816, 1990.

    Article  CAS  PubMed  Google Scholar 

  35. Datta SK, Owen FL, Womack JEet al.: 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: 1539–1544, 1982.

    CAS  PubMed  Google Scholar 

  36. Pisetsky DS, McCarty GA, Peters DV: Mechanisms of autoantibody production in autoimmune MRL mice.J Exp Med 152: 1302–1310, 1980.

    Article  CAS  PubMed  Google Scholar 

  37. Cohen PL, Eisenberg RA: Anti-idiotypic antibodies to the Coomb’s antibody in NZB F1 mice.J Exp Med 156: 173–180, 1982.

    Article  CAS  PubMed  Google Scholar 

  38. Chiang B-L, Bearer E, Ansari Aet al.: The bm12 mutation and autoantibodies to dsDNA in NZB.H-2bm12 mice.J Immunol 145: 94–101, 1990.

    CAS  PubMed  Google Scholar 

  39. Jiang Y, Hirose S, Hamano Yet al.: Mapping of a gene for the increased susceptibility of B1 cells to Mott cell formation in murine autoimmune disease.J Immunol 158: 992–997, 1997.

    CAS  PubMed  Google Scholar 

  40. Gavalchin J, Nicklas J, Eastcott JWet al.: Lupus prone (SWR×NZB)F1 mice produce potentially nephritogenic autoantibodies inherited from the normal SWR parent.J Immunol 134: 885–894, 1985.

    CAS  PubMed  Google Scholar 

  41. Gavalchin J, Seder RA, Datta SK: The NZB×SWR model of lupus nephritis. I. Cross-reactive idiotypes of monoclonal anti-DNA antibodies in relation to antigenic specificity, charge and allotype. Identification of interconnected idiotype families inherited from the normal SWR and the autoimmune NZB parents.J Immunol 138: 128–137, 1987.

    CAS  PubMed  Google Scholar 

  42. Gavalchin J, Datta SK: The NZB×SWR model of lupus nephritis. II. Autoantibodies deposited in renal lesions show a restricted idiotypic diversity.J Immunol 138: 138–148, 1987.

    CAS  PubMed  Google Scholar 

  43. Datta SK, Gavalchin J: The origins of pathogenic anti-DNA idiotypes in the (NZB×SWR)F1 model of lupus nephritis.Ann NY Acad Sci 475: 47–58, 1986.

    Article  CAS  PubMed  Google Scholar 

  44. Datta SK, Patel H, Berry D: 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: 1252–1268, 1987.

    Article  CAS  PubMed  Google Scholar 

  45. Shivakumar S, Tsokos GC, Datta SK: T cell receptor α/β 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: 103–112, 1989.

    CAS  PubMed  Google Scholar 

  46. Vlahakos DV, Foster MH, Adams Set al.: Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites.Kidney Int 41: 1690–1700, 1992.

    Article  CAS  PubMed  Google Scholar 

  47. O’Keefe TL, Bandyopadhyay S, Datta SKet al.: variable region sequences of an idiotypically connected family of pathogenic anti-DNA autoantibodies.J Immunol 144: 4275–4283, 1990.

    PubMed  Google Scholar 

  48. Tillman DM, Jou N-T, Hill RJet al.: Both IgM and IgG anti-DNA antibodies are the products of clonally selective B cell stimulation in (NZB×NZW)F1 mice.J Exp Med 176: 761–779, 1992.

    Article  CAS  PubMed  Google Scholar 

  49. Shlomchik MJ, Mascelli M, Shan Het al.: Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.J Exp Med 171: 265–292, 1990.

    Article  CAS  PubMed  Google Scholar 

  50. Tsao BP, Ebling FM, Roman Cet al.: Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus.J Clin Invest 85: 530–540, 1990.

    Article  CAS  PubMed  Google Scholar 

  51. Kieber-Emmons T, Foster MH, Williams WVet al.: Structural properties of a subset of nephritogenic anti-DNA antibodies.Immunol Res 13: 172–185, 1994.

    Article  CAS  PubMed  Google Scholar 

  52. Diamond B, Katz JB, Paul Eet al.: The role of somatic mutation in the pathogenic anti-DNA response.Annu Rev Immunol 10: 731–757, 1992.

    Article  CAS  PubMed  Google Scholar 

  53. Radic MZ, Weigert M: Genetic and structural evidence for antigen selection of anti-DNA antibodies.Annu Rev Immunol 12: 487–520, 1994.

    Article  CAS  PubMed  Google Scholar 

  54. Ebling F, Hahn BH: Restricted subpopulations of DNA antibodies in kidneys of mice with systemic lupus: comparison of antibodies in serum and renal eluates.Arthritis Rheum 23: 392–403, 1980.

    Article  CAS  PubMed  Google Scholar 

  55. Gauthier VJ, Mannik M: A small proportion of cationic antibodies in immune complexes is sufficient to mediate their deposition in glomeruli.J Immunol 145: 3348–3352, 1990.

    CAS  PubMed  Google Scholar 

  56. Schmiedke TMJ, Stockl FW, Weber Ret al.: Histones have high affinity for the glomerular basement membrane. Relevance for immune complex formation in lupus nephritis.J Exp Med 169: 1879–1894, 1989.

    Article  Google Scholar 

  57. Kramers C, Hylkema MN, van Bruggen MCJet al.: Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membranein vivo.J Clin Invest 94: 568–577, 1994.

    Article  CAS  PubMed  Google Scholar 

  58. Mohan C, Adams S, Stanik Vet al.: Nucleosome: a major immunogen for the pathogenic autoantibody-inducing T cells of lupus.J Exp Med 177: 1367–1381, 1993.

    Article  CAS  PubMed  Google Scholar 

  59. Ohnishi K, Ebling FM, Mitchell Bet al.: Comparison of pathogenic and non-pathogenic murine antibodies to DNA: antigen binding and structural characteristics.Int Immunol 6: 817–827, 1994.

    Article  CAS  PubMed  Google Scholar 

  60. Suenaga R, Abdou NI: Cationic and high affinity serum IgG anti-dsDNA antibodies in active lupus nephritis.Clin Exp Immunol 94: 418–422, 1993.

    CAS  PubMed  Google Scholar 

  61. Suzuki N, Harada T, Mizushima Yet al.: Possible pathogenic role of cationic anti-DNA autoantibodies in the development of nephritis in patients with systemic lupus erythematosus.J Immunol 151: 1128–1136, 1993.

    CAS  PubMed  Google Scholar 

  62. Winkler TH, Fehr H, Kalden JR: Analysis of immunoglobulin variable region genes from human IgG anti-DNA hybridomas.Eur J Immunol 22: 1719–1728, 1992.

    Article  CAS  PubMed  Google Scholar 

  63. Ghatak S, Sainis K, Owen FLet al.: T cell receptor β and I-Aβ chain genes of normal SWR mice are linked with the development of lupus nephritis in NZB×SWR crosses.Proc Natl Acad Sci USA 84: 6850–6853, 1987.

    Article  CAS  PubMed  Google Scholar 

  64. O’Keefe TL, Datta SK, Imanishi-Kari T: Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germline gene that belongs to a large VH gene subfamily.Eur J Immunol 22: 619–624, 1992.

    Article  PubMed  Google Scholar 

  65. Rajagopalan S, Zordan T, Tsokos GCet al.: 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 γ/δ T cell receptor.Proc Natl Acad Sci USA 87: 7020–7024, 1990.

    Article  CAS  PubMed  Google Scholar 

  66. Sainis K, Datta SK: 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×SWR model of lupus nephritis.J Immunol 140: 2215–2224, 1988.

    CAS  PubMed  Google Scholar 

  67. Adams S, Zordan T, Sainis Ket al.: T cell receptor Vβ genes exspressed by IgG anti-DNA autoantibody inducing T cells in lupus nephritis: forbidden receptors and double negative T cells.Eur J Immunol 20: 1435–1443, 1990.

    Article  CAS  PubMed  Google Scholar 

  68. Adams S, Leblanc P, Datta SK: Junctional region seuences of T-cell receptor β 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: 11271–11275, 1991.

    Article  CAS  PubMed  Google Scholar 

  69. Mao C, Osman GE, Adams Set al.: T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice.J Immunol 152: 1462–1470, 1994.

    CAS  PubMed  Google Scholar 

  70. Desai-Mehta A, Mao C, Rajagopalan Set al.: Structure and specificity of T-cell receptors expressed by pathogenic anti-DNA autoantibody-inducing T cells in human lupus.J Clin Invest 95: 531–541, 1995.

    Article  CAS  PubMed  Google Scholar 

  71. Jorgensen JL, Esser U, Reay PAet al.: Mapping T cell receptor/peptide contacts by variant peptide immunization of single-chain transgenics.Nature 355: 224–230, 1992.

    Article  CAS  PubMed  Google Scholar 

  72. Atkinson MJ, Bell DA, Singhal SK: A naturally occuring polyclonal B cell activator of normal and autoantibody responces.J Immunol 135: 2524–2533, 1985.

    CAS  PubMed  Google Scholar 

  73. Datta SK, Rajagopalan S, O’Keefe TLet al.: Pathogenic anti-DNA autoantibodies and pathogenic autoantibody-inducing T cells. InMolecular Immunobiology of Self-Reactivity (Bona CA, Kaushik A, Eds), pp. 133–153. Marcel Decker, New York, 1992.

    Google Scholar 

  74. Rumore P, Steinman C: Endogenous circulating DNA in systemic lupus erythematosus. Occurrences as multimeric complexes bound to histones.J. Clin Invest 86: 69–74, 1990.

    Article  CAS  PubMed  Google Scholar 

  75. Fournie GJ, Lule J, Dueymes J-Met al.: Plasma DNA in patients undergoing hemodialysis at hemofiltration: cytolysis in artificial kidney is responsible for the release of DNA in circulation.Am J Nephrol 9: 384–391, 1989.

    Article  CAS  PubMed  Google Scholar 

  76. Atanassov C, Briand JP, Bonnier Det al.: New Zealand white rabbits immunized with RNA-complexed total histones develop an autoimmune-like response.Clin Exp Immunol 86: 124–133, 1991.

    CAS  PubMed  Google Scholar 

  77. Rothfield NF, Stollar BD: The relation of immunoglobulin class, pattern of anti-nuclear antibody, and complement-fixing antibodies to DNA in sera from patients with systemic lupus erythematosus.J Clin Invest 46: 1785–1794, 1967.

    CAS  PubMed  Google Scholar 

  78. Burlingame RW, Rubin RL, Balderas RSet al.: Genesis and evolution of antichromatin autoantibodies in murine lupus implicates immunization with self antigen.J Clin Invest 91: 1687–1696, 1993.

    Article  CAS  PubMed  Google Scholar 

  79. Burlingame TW, Boey ML, Starkebaum Get al.: The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.J. Clin Invest 94: 184–192, 1994.

    Article  CAS  PubMed  Google Scholar 

  80. Chabre H, Amoura Z, Piette J-Cet al.: Presence of nucleosome-restricted antibodies in patients with systemic lupus erythematosus.Arthritis Rheum 38: 1485–1491, 1995.

    Article  CAS  PubMed  Google Scholar 

  81. Bernstein KA, DiValerio R, Lefkowith JB: Glomerular binding activity in MRLlpr serum consists of antibodies that bind to a DNA/histone/type IV collagen complex.J Immunol 154: 2424–2433, 1995.

    CAS  PubMed  Google Scholar 

  82. O’Hehir RE, Garman RD, Greenstein JLet al.: The specificity and regulation of T cell responsiveness to allergens.Ann Rev Immunol 9: 67–95, 1991.

    Article  Google Scholar 

  83. Kaliyaperumal A, Mohan C, Wu Wet al.: Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus.J Exp Med 183: 2459–2469, 1996.

    Article  CAS  PubMed  Google Scholar 

  84. Rothstein TL, Wang JKM, Panka DJet al.: Protection against Fas-dependent Th-1 mediated apoptosis by antigen receptor engagement in B cells.Nature 374: 163–165, 1995.

    Article  CAS  PubMed  Google Scholar 

  85. Suda T, Nagata S: Purification and characterization of the Fas-ligand that induces apoptosis.J Exp Med 179: 873–879, 1994.

    Article  CAS  PubMed  Google Scholar 

  86. Singh RR, Hahn BH, Sercarz EE: Neonatal peptide exposure can prime T cells and upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated immunity.J Exp Med 183: 1613–1622, 1996.

    Article  CAS  PubMed  Google Scholar 

  87. Nakajima A, Hiroshe S, Yagita Het al.: Roles of IL-4 and IL-12 in the development of lupus in NZB/W F1 mice.J Immunol 158: 1466–1472, 1997.

    CAS  PubMed  Google Scholar 

  88. Elkon KB, Marshak-Rothstein A: B cells in systemic autoimmune disease: recent insights from Fas-deficient mice and men.Curr Opin Immunol 8: 852–859, 1996.

    Article  CAS  PubMed  Google Scholar 

  89. Datta SK, Kaliyaperumal A: Nucleosome-driven autoimmune response in lupus — pathogenic T helper cell epitopes and costimulatory signals.Ann NY Acad Sci 815: 155–170, 1997.

    Article  CAS  PubMed  Google Scholar 

  90. Lake P, Mitchison NA: Regulatory mechanisms in the immune response to cell-surface antigens.Cold Spring Harbor Symp Quant Biol 41: 589–595, 1976.

    Google Scholar 

  91. Lehman P, Forsthuber T, Miller Tet al.: Spreading of T cell autoimmunity to cryptic determinants of an autoantigen.Nature 358: 155–157, 1992.

    Article  Google Scholar 

  92. Ando DG, Sercarz EE, Hahn BH: Mechanisms of T and B cell collaboration in thein vitro production of anti-DNA antibodies in the NZB/NZW F1 murine SLE model.J Immunol 138: 3185–3190, 1987.

    CAS  PubMed  Google Scholar 

  93. Sobel ES, Kakkanaiah VN, Kakkanaiah Met al.: T-B collaboration for autoantibody production inlpr mice is cognate and MHC-restricted.J Immunol 152: 6011–6016, 1994.

    CAS  PubMed  Google Scholar 

  94. Naiki M, Chiang B-L, Cawley Det al.: Generation and characterization of cloned helper T cell lines for anti-DNA responses in NZB.H-2bm12 mice.J Immunol 149: 4109–4115, 1992.

    CAS  PubMed  Google Scholar 

  95. Portanova JP, Arndt RE, Kotzin BL: Selective production of autoantibodies in graft-versus-host induced and spontaneous murine lupus. Predominant reactivity with histone regions accessible in chromatin.J Immunol 140: 755–760, 1988.

    CAS  PubMed  Google Scholar 

  96. Mamula MJ, Fatenejad S, Craft J: B cells process and present lupus autoantigens that initiate autoimmune T cell responses.J Immunol 152: 1453–1461, 1994.

    CAS  PubMed  Google Scholar 

  97. James JA, Gross T, Scofield RHet al.: Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B′-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity.J Exp Med 181: 453–461, 1995.

    Article  CAS  PubMed  Google Scholar 

  98. Desai DD, Krishnan MR, Swindle JTet al.: Antigen-specific induction of antibodies against native mammalian DNA in nonautoimmune mice.J Immunol 151: 1614–1626, 1993.

    CAS  PubMed  Google Scholar 

  99. Kanai Y, Takeda O, Kanai Yet al.: Novel autoimmune phenomena inducedin vivo by a new DNA binding protein Nuc: a study on MRL/n mice.Immunol Lett 39: 83–89, 1994.

    Article  Google Scholar 

  100. Fredriksen K, Osei A, Sundsfjord Aet al.: On the biological origin of anti-dsDNA antibodies: systemic lupus erythematosus related anti-dsDNA antibodies are induced by polyomavirus BK in lupus-prone (NZB×NZW)F1 hybrids, but not in normal mice.Eur J Immunol 24: 66–70, 1994.

    Article  CAS  PubMed  Google Scholar 

  101. Moens U, Seternes O-M, Hey AWet al.:In vivo expression of a single viral DNA-binding protein generates systemic lupus erythematosus-related autoimmunity to double-stranded DNA and histones.Proc Natl Acad Sci USA 92: 12393–12397, 1995.

    Article  CAS  PubMed  Google Scholar 

  102. Noelle RJ, Ledbetter JA, Aruffo A: CD40 and its ligand, and essential ligand-receptor pair for thymus-dependent B cell activation.Immunol Today 13: 431–433, 1992.

    Article  CAS  PubMed  Google Scholar 

  103. Lederman S, Yellin MJ, Inghirami Get al.: Molecular interaction mediating T-B lymphocyte collaboration in human lymphoid follicles. Role of T cell-B cell activating molecule (5c8 antigen) and CD40 in contact-dependent help.J Immunol 149: 3817–3826, 1992.

    CAS  PubMed  Google Scholar 

  104. Clark EA, Ledbetter JA: How B and T cells talk to each other.Nature 367: 425–428, 1994.

    Article  CAS  PubMed  Google Scholar 

  105. Roy M, Waldschmidt T, Aruffo Aet al.: The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells.J Immunol 151: 2497–2510, 1993.

    CAS  PubMed  Google Scholar 

  106. Banchereau J, Bazan F, Blanchard Det al.: The CD40 antigen and its ligand.Annu Rev Immunol 12: 881–922, 1994.

    Article  CAS  PubMed  Google Scholar 

  107. Spriggs MK, Armitage RJ, Stockbine Let al.: Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion.J Exp Med 176: 1543–1550, 1992.

    Article  CAS  PubMed  Google Scholar 

  108. Mohan C, Shi Y, Laman JDet al.: Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis.J Immunol 154: 1470–1480, 1995.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Durie FH, Fava RA, Foy TMet al.: Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40.Science 261: 1328–1330, 1993.

    Article  CAS  PubMed  Google Scholar 

  111. Durie FH, Aruffo A, Ledbetter Jet al.: Antibody to ligand of CD40, gp39, blocks the occurence of the acute and chronic forms of graft-versus-host disease.J Clin Invest 94: 1333–1338, 1994.

    Article  CAS  PubMed  Google Scholar 

  112. Hill A, Chapel H: X-linked immunodeficiency. The fruits of cooperation.Nature 361: 494, 1993

    Article  CAS  PubMed  Google Scholar 

  113. Singh RR, Kumar V, Ebling FMet al.: T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine SLE.J Exp Med 181: 2017–2027, 1995.

    Article  CAS  PubMed  Google Scholar 

  114. Early GS, Zhao W, Burns CM: Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand Black × New Zealand White mice: Response correlates with the absence of an anti-antibody response.J Immunol 157: 3159–3164, 1996.

    CAS  PubMed  Google Scholar 

  115. Yellin MJ, D’Agati V, Parkinson Get al.: Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides.Arthritis Rheum 40: 124–134, 1997.

    Article  CAS  PubMed  Google Scholar 

  116. Koshy M, Berger D, Crow MK: Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes.J Clin Invest 98: 826–837, 1996.

    Article  CAS  PubMed  Google Scholar 

  117. Grammer AC, Bergman MC, Miura Yet al.: The CD40 ligand expressed by human B cells costimulates B cell responses.J Immunol 154: 4996–5010, 1995.

    CAS  PubMed  Google Scholar 

  118. Facchetti F, Appiani C, Salvi Let al.: Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in limphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells.J Immunol 154: 6624–6633, 1995.

    CAS  PubMed  Google Scholar 

  119. Ware CF, Crowe PD, Vanarsdale TLet al.: Tumor necrosis factor (TNF) receptor family expression in T lymphocytes. Differential regulation of the type I TNF receptor during activation of resting and effector T cells.J Immunol 147: 4229–4238, 1991.

    CAS  PubMed  Google Scholar 

  120. Ranheim EA, Kipps TJ: Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.J Exp Med 177: 925–935, 1993.

    Article  CAS  PubMed  Google Scholar 

  121. Kennedy MK, Mohler KM, Shanebeck KDet al.: Induction of B cell costimulatory function by recombinant murine CD40 ligand.Eur J Immunol 24: 116–123, 1994.

    Article  CAS  PubMed  Google Scholar 

  122. Stuber E, Strober W, Neurath M: Blocking the CD40L-CD40 interactionsin vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.J Exp Med 183: 693–698, 1996.

    Article  CAS  PubMed  Google Scholar 

  123. Klaus SJ, Pinchuk LM, Ochs HDet al.: Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction.J. Immunol 152: 5643–5652, 1994.

    CAS  PubMed  Google Scholar 

  124. de Boer M, Kasran A, Kwekkeboom Jet al.: Ligation of B7 with CD28/CTLA-4 on T cells results in CD40 ligand expression, IL-4 secretion and efficient help for antibody production by B cells.Eur J Immunol 23: 3120–3125, 1993.

    Article  PubMed  Google Scholar 

  125. Karandikar N, Vanderlugt CL, Walunas TLet al.: CTLA-4: a negative regulator of autoimmune disease.J Exp Med 184: 783–788, 1996.

    Article  CAS  PubMed  Google Scholar 

  126. Lederman S, Yellin MJ, Cleary AMet al.: T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death.J Immunol 152: 2163–2171, 1994.

    CAS  PubMed  Google Scholar 

  127. Liu Y-J, Joshua DE, Williams GTet al.: Mechanism of antigen driven selection in germinal centers.Nature 342: 929–931, 1989.

    Article  CAS  PubMed  Google Scholar 

  128. Tsubata T, Wu J, Honjo, T: B cell apoptosis induced by antigen receptor croos-linking is blocked by a T cell signal through CD40.Nature 364: 645–648, 1993.

    Article  CAS  PubMed  Google Scholar 

  129. Parry SL, Hasbold J, Holman Met al.: Hypercross-linking surface IgM or IgD receptors on mature B cells induces apoptosis that is reversed by costimulation with IL-4 and anti-CD40.J Immunol 152: 2821–2829, 1994.

    CAS  PubMed  Google Scholar 

  130. Schattner EJ, Elkon KB, Yoo D-Het al.: CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway.J Exp Med 182: 1557–1565, 1995.

    Article  CAS  PubMed  Google Scholar 

  131. Wang Z, Karras JG, Howard RGet al.: Induction ofbcl-x by CD40 engagement rescues sIg-induced apoptosis in murine B cells.J Immunol 155: 3722–3725, 1995.

    CAS  PubMed  Google Scholar 

  132. Ray SK, Putterman C, Diamond B: Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease.Proc Natl Acad Sci USA 93: 2019–2024, 1996.

    Article  CAS  PubMed  Google Scholar 

  133. Gleichmann E, van Elven EH, van der Veen JPW: A systemic lupus erythematosus (SLE) like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE.Eur J Immunol 12: 152–159, 1982.

    Article  CAS  PubMed  Google Scholar 

  134. Kammer GM, Khan I, Malemud C: Deficient type I protein kinase A isozyme activity in systemic lupus erythematosus T lymphocytes.J. Clin Invest 94: 422–430, 1994.

    Article  CAS  PubMed  Google Scholar 

  135. Vassilopoulos D, Kovacs B, Tsokos GC: TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus.J Immunol 155: 2269–2281, 1995.

    CAS  PubMed  Google Scholar 

  136. Albertini RJ, O’Neil JP, Nicklas JAet al.: Alterations of thehprt gene in normal humanin vivo-derived 6-thioguanine resistant T lymphocytes.Nature 316: 369–371, 1985.

    Article  CAS  PubMed  Google Scholar 

  137. Allegretta M, Nicklas JA, Sriram Set al.: T cells responsive to myelin basic protein in patients with multiple sclerosis.Science 247: 718–721, 1990.

    Article  CAS  PubMed  Google Scholar 

  138. Theocharis S, Sfikakis PP, Lipnick RNet al.: Characterization ofin vivo mutated T cell clones from patients with systemic lupus erythematosus.Clin Immunol Immunopathol 74: 135–142, 1995.

    Article  CAS  PubMed  Google Scholar 

  139. Dong X, Hamilton KJ, Satoh Met al.: Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen.J Exp Med 179: 1243–1252, 1994.

    Article  CAS  PubMed  Google Scholar 

  140. Koutouzov S, Cabrespines A, Amoura Zet al.: Binding of nucleosomes to a cell surface receptor: redistribution and endocytosis in the presence of lupus antibodies.Eur J Immunol 26: 472–486, 1996.

    Article  CAS  PubMed  Google Scholar 

  141. DeMagistris MT, Alexander J, Coggeshall Met al.: Antigen analog-Major histocompatibility complexes act as antagonists at the T cell receptor.Cell 68: 625–634, 1992.

    Article  CAS  Google Scholar 

  142. Sloan-Lancaster J, Evavold BD, Allen PM: Th2 cell clonal anergy as a consequence of partial activation.J Exp Med 180: 1195–1205, 1994.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Medicine and Microbiology-Immunology, and Multipurpose Arthritis Center, Northwestern University Medical School, 60611, Chicago, IL, USA

    Syamal K. Datta

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Datta, S.K. Systemic lupus: basic mechanisms and prospects for specific immunotherapy. Japanese Journal of Rheumatology 7, 247–261 (1997). https://doi.org/10.1007/BF03041327

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