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 Article
  • Published:

The anti-DNA antibody: origin and impact, dogmas and controversies

Nature Reviews Rheumatology volume 11, pages 530–540 (2015)Cite this article

Subjects

Key Points

  • Anti-double-stranded-DNA (dsDNA) antibodies are regarded as being central to the classification and pathogenesis of systemic lupus erythematosus

  • The nature of anti-dsDNA antibodies in clinical medicine is poorly defined; these antibodies can bind a spectrum of DNA and non-DNA structures

  • Anti-dsDNA antibodies are induced by a variety of different nucleic acids and non-DNA structures, which also determine whether the immune response is transient or sustained

  • Anti-dsDNA antibodies are pathogenic owing to their interaction with exposed chromatin, although pathogenicity by cross-reactivity with intrinsic renal structures cannot be excluded

  • Studies of the origin and impact of anti-dsDNA antibodies have provided insights into general aspects of the immune system and its control of immune tolerance

Abstract

The inclusion of 'the anti-DNA antibody' by the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) as a criterion for systemic lupus erythematosus does not convey the diverse origins of these antibodies, whether their production is transient or persistent (which is heavily influenced by the nature of the inducing antigens), the specificities exerted by these antibodies or their clinical impact—or lack thereof. A substantial amount of data not considered in clinical medicine could be added from basic immunology evidence, which could change the paradigms linked to what 'the anti-DNA antibody' is, in a pathogenic, classification or diagnostic context.

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

Figure 1: B-DNA, Z-DNA and the hapten-carrier model.
Figure 2: Cognate interaction of nucleosome-specific B cells with peptide-specific T cells.
Figure 3: A model for terminating T-cell tolerance to histones and nucleosomes.
Figure 4: Anti-B-DNA antibody profiles in the context of SLE classification criteria.
Figure 5: Pathogenicity of anti-dsDNA antibodies.
Figure 6: IgG antibodies bind chromatin fragments in murine and human lupus nephritis.

Similar content being viewed by others

References

  1. Menzel, A. E. O. & Heidelberger, M. Cell protein fractions of bovine and avian tubercle bacillus strains and of the timothy-grass bacillus. J. Biol. Chem. 124, 301–307 (1938).

    Article  CAS  Google Scholar 

  2. Sevag, M. G., Lackman, D. B. & Smolen, J. The isolation of the components of streptococcal nucleoproteins in serologically active form. J. Biol. Chem. 124, 425–436 (1938).

    Article  CAS  Google Scholar 

  3. Winkenwerder, W. L., Buell, M. V. & Howard, J. E. The sensitizing properties of the nucleic acids and their derivatives. Science 90, 356 (1939).

    Article  CAS  PubMed  Google Scholar 

  4. Ceppellini, R., Polli, E. & Celada, F. A DNA-reacting factor in serum of a patient with lupus erythematosus diffusus. Proc. Soc. Exp. Biol. Med. 96, 572–574 (1957).

    Article  CAS  PubMed  Google Scholar 

  5. Robbins, W. C., Holman, H. R., Deicher, H. & Kunkel, H. G. Complement fixation with cell nuclei and DNA in lupus erythematosus. Proc. Soc. Exp. Biol. Med. 96, 575–579 (1957).

    Article  CAS  PubMed  Google Scholar 

  6. Miescher, P. & Strassle, R. New serological methods for the detection of the L. E. factor. Vox Sang. 2, 283–287 (1957).

    Article  CAS  PubMed  Google Scholar 

  7. Seligman, M. Serology-evidence in serum from patients with disseminated lupus erythermatosus of a substance determining a precipitation reac tion with desoxyribonucleic acid [French]. C. R. Hebd. Seances Acad. Sci. 245, 243–245 (1957).

    Google Scholar 

  8. Stollar, B. D. Immunochemistry of DNA. Int. Rev. Immunol. 5, 1–22 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Stollar, B. D. Antibodies to DNA. CRC Crit. Rev. Biochem. 20, 1–36 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Madaio, M. P., Hodder, S., Schwartz, R. S. & Stollar, B. D. Responsiveness of autoimmune and normal mice to nucleic acid antigens. J. Immunol. 132, 872–876 (1984).

    CAS  PubMed  Google Scholar 

  11. Pisetsky, D. S. & Vrabie, I. A. Antibodies to DNA: infection or genetics? Lupus 18, 1176–1180 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Lafer, E. M. et al. Polyspecific monoclonal lupus autoantibodies reactive with both polynucleotides and phospholipids. J. Exp. Med. 153, 897–909 (1981).

    Article  CAS  PubMed  Google Scholar 

  13. Mostoslavsky, G. et al. Lupus anti-DNA autoantibodies crossreact with a glomerular structural protein: a case for tissue injury by molecular mimicry. Eur. J. Immunol. 31, 1221–1227 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Putterman, C. & Diamond, B. Immunization with a peptide surrogate for double-stranded DNA (dsDNA) induces autoantibody production and renal immunoglobulin deposition. J. Exp. Med. 188, 29–38 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. DeGiorgio, L. A. et al. A subset of lupus anti-DNA antibodies crossreacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Stollar, B. D. Why the difference between B-DNA and Z-DNA? Lupus 6, 327–328 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Shlomchik, M. et 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 

  18. Marion, T. N., Krishnan, M. R., Steeves, M. A. & Desai, D. D. Affinity maturation and autoimmunity to DNA. Curr. Dir. Autoimmun. 6, 123–153 (2003).

    Article  PubMed  Google Scholar 

  19. Radic, M. Z. & 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 

  20. Desai, D. D., Krishnan, M. R., Swindle, J. T. & Marion, T. N. Antigen-specific induction of antibodies against native mammalian DNA in nonautoimmune mice. J. Immunol. 151, 1614–1626 (1993).

    CAS  PubMed  Google Scholar 

  21. Rekvig, O. P., Bendiksen, S. & Moens, U. Immunity and autoimmunity induced by polyomaviruses: clinical, experimental and theoretical aspects. Adv. Exp. Med. Biol. 577, 117–147 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Rekvig, O. P. Anti-dsDNA antibodies as a classification criterion and a diagnostic marker for SLE: critical remarks. Clin. Exp. Immunol. 179, 5–10 (2014).

    Article  PubMed Central  CAS  Google Scholar 

  23. Compagno, M. et al. Low diagnostic and predictive value of anti-dsDNA antibodies in unselected patients with recent onset of rheumatic symptoms: results from a long-term follow-up Scandinavian multicentre study. Scand. J. Rheumatol. 42, 311–316 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Krishnan, M. R., Wang, C. & Marion, T. N. Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice. Kidney Int. 82, 184–192 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Seredkina, N., van der Vlag, J., Berden, J., Mortensen, E. & Rekvig, O. P. Lupus nephritis: enigmas, conflicting models and an emerging concept. Mol. Med. 19, 161–169 (2013).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Pisetsky, D. S. The role of innate immunity in the induction of autoimmunity. Autoimmun. Rev. 8, 69–72 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Krieg, A. M. & Vollmer, J. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol. Rev. 220, 251–269 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Medzhitov, R. & Janeway, C. A. Jr. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Christensen, S. R. & Shlomchik, M. J. Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin. Immunol. 19, 11–23 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Schwartz, R. H. T cell clonal anergy. Curr. Opin. Immunol. 9, 351–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Foster, M. H. T cells and B cells in lupus nephritis. Semin. Nephrol. 27, 47–58 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Sandel, P. C. & Monroe, J. G. Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. Immunity 10, 289–299 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Ehrlich, P. &, Morgenroth, J. Ueber Haemolysine: dritte Mittheilung [German]. Berlin Klin. Wochenschr. 37, 453–458 (1900).

    Google Scholar 

  35. Ehrlich, P. Ueber Hämolysine: fünfte Mittheilung [German]. Berlin Klin. Wochenschr. 38, 251–257 (1901).

    Google Scholar 

  36. Silverstein, A. M. Autoimmunity versus horror autotoxicus: the struggle for recognition. Nat. Immunol. 2, 279–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Blix, U., Iland, C. N. & Stacey, M. The serological activity of desoxypentosenucleic acids. Br. J. Exp. Pathol. 35, 241–251 (1954).

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Yamamoto, S. et al. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN-mediated [correction of INF] natural killer activity. J. Immunol. 148, 4072–4076 (1992).

    CAS  PubMed  Google Scholar 

  40. Klinman, D. M., Yi, A. K., Beaucage, S. L., Conover, J. & Krieg, A. M. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc. Natl Acad. Sci. USA 93, 2879–2883 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sato, Y. et al. Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352–354 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Rock, K. L., Benacerraf, B. & Abbas, A. K. Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. J. Exp. Med. 160, 1102–1113 (1984).

    Article  CAS  PubMed  Google Scholar 

  43. Sundar, K. et al. Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. J. Autoimmun. 23, 127–140 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Cerutti, M. L., Zarebski, L. M., de Prat, G. G. & Goldbaum, F. A. A viral DNA-binding domain elicits anti-DNA antibodies of different specificities. Mol. Immunol. 42, 327–333 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Moens, U. et 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  PubMed Central  Google Scholar 

  46. Van Ghelue, M., Moens, U., Bendiksen, S. & Rekvig, O. P. Autoimmunity to nucleosomes related to viral infection: a focus on hapten-carrier complex formation. J. Autoimmun. 20, 171–182 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Edgington, S. M. & Stollar, B. D. Immunogenicity of Z-DNA depends on the size of polynucleotide presented in complexes with methylated BSA. Mol. Immunol. 29, 609–617 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Rekvig, O. P. & Nossent, J. C. Anti-double-stranded DNA antibodies, nucleosomes, and systemic lupus erythematosus: a time for new paradigms? Arthritis Rheum. 48, 300–312 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Biermann, M. H. et al. The role of dead cell clearance in the aetiology and pathogenesis of systemic lupus erythematosus: dendritic cells as potential targets. Expert. Rev. Clin. Immunol. 10, 1151–1164 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Fenton, K. The effect of cell death in the initiation of lupus nephritis. Clin. Exp. Immunol. 179, 11–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Schroeder, K., Herrmann, M. & Winkler, T. H. The role of somatic hypermutation in the generation of pathogenic antibodies in SLE. Autoimmunity 46, 121–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Ghosh, A. & Bansal, M. A glossary of DNA structures from A to Z. Acta Crystallogr. D. Biol. Crystallogr. 59, 620–626 (2003).

    Article  PubMed  CAS  Google Scholar 

  53. Ha, S. C., Lowenhaupt, K., Rich, A., Kim, Y. G. & Kim, K. K. Crystal structure of a junction between B-DNA and Z-DNA reveals two extruded bases. Nature 437, 1183–1186 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Rothenburg, S., Koch-Nolte, F. & Haag, F. DNA methylation and Z.-DNA formation as mediators of quantitative differences in the expression of alleles. Immunol. Rev. 184, 286–298 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Rekvig, O. P. et al. Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen. A molecular basis for induction of antibodies to DNA and eukaryotic transcription factors. J. Clin. I nvest. 99, 2045–2054 (1997).

    Article  CAS  Google Scholar 

  56. Hahn, B. H. Antibodies to DNA. N. Engl. J. Med. 338, 1359–1368 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Tan, E. M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).

    Article  CAS  PubMed  Google Scholar 

  58. Petri, M. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 64, 2677–2686 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  59. Widom, J. A relationship between the helical twist of DNA and the ordered positioning of nucleosomes in all eukaryotic cells. Proc. Natl Acad. Sci. USA 89, 1095–1099 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Richmond, T. J. & Davey, C. A. The structure of DNA in the nucleosome core. Nature 423, 145–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Griffith, J., Bleyman, M., Rauch, C. A., Kitchin, P. A. & Englund, P. T. Visualization of the bent helix in kinetoplast DNA by electron microscopy. Cell 46, 717–724 (1986).

    Article  CAS  PubMed  Google Scholar 

  62. Stollar, B. D. The experimental induction of antibodies to nucleic acids. Methods Enzymol. 70, 70–85 (1980).

    Article  CAS  PubMed  Google Scholar 

  63. Isenberg, D. A., Manson, J. J., Ehrenstein, M. R. & Rahman, A. Fifty years of anti-dsDNA antibodies: are we approaching journey's end? Rheumatology (Oxford) 46, 1052–1056 (2007).

    Article  CAS  Google Scholar 

  64. Amital, H. et al. Treatment with a laminin-derived peptide suppresses lupus nephritis. J. Immunol. 175, 5516–5523 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Wellmann, U. et al. The evolution of human anti-double-stranded DNA autoantibodies. Proc. Natl Acad. Sci. USA 102, 9258–9263 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Olins, A. L. & Olins, D. E. Spheroid chromatin units (v bodies). Science 183, 330–332 (1974).

    Article  CAS  PubMed  Google Scholar 

  67. Kornberg, R. D. & Lorch, Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. de Graaf, C. A. & van Stenseel, B. Chromatin organization: form to function. Curr. Opin. Genet. Dev. 23, 185–190 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. van Steensel, B. Chromatin: constructing the big picture. EMBO J. 30, 1885–1895 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Woodcock, C. L. & Ghosh, R. P. Chromatin higher-order structure and dynamics. Cold Spring Harb. Perspect. Biol. 2, a000596 (2010).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  72. Haugbro, K., Nossent, J. C., Winkler, T., Figenschau, Y. & Rekvig, O. P. Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity. Ann. Rheum. Dis. 63, 386–394 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Compagno, M. et al. Clinical phenotype associations with various types of anti-dsDNA antibodies in patients with recent onset of rheumatic symptoms. Results from a multicentre observational study. Lupus Sci. Med. 1, e000007 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  74. Neogi, T., Gladman, D. D., Ibanez, D. & Urowitz, M. Anti-dsDNA antibody testing by Farr and ELISA techniques is not equivalent. J. Rheumatol. 33, 1785–1788 (2006).

    CAS  PubMed  Google Scholar 

  75. Rekvig, O. P., van der Vlag, J. & Seredkina, N. Anti-nucleosome antibodies—a critical reflection on their specificities and diagnostic impact. Arthritis Rheumatol. 66, 1061–1069 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Marion, T. N. et al. Immunoglobulin variable-region structures in immunity and autoimmunity to DNA. Tohoku J. Exp. Med. 173, 43–63 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Williams, R. C. Jr, Malone, C. C., Meyers, C., Decker, P. & Muller, S. Detection of nucleosome particles in serum and plasma from patients with systemic lupus erythematosus using monoclonal antibody 4H7. J. Rheumatol. 28, 81–94 (2001).

    CAS  PubMed  Google Scholar 

  78. Kramers, K. et al. Specificity of monoclonal anti-nucleosome auto-antibodies derived from lupus mice. J. Autoimmun. 9, 723–729 (1996).

    Article  CAS  PubMed  Google Scholar 

  79. Stemmer, C., Briand, J. P. & Muller, S. Mapping of linear histone regions exposed at the surface of the nucleosome in solution. J. Mol. Biol. 273, 52–60 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell co-stimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Voll, R. E. et al. Histone-specific TH0 and TH1 clones derived from systemic lupus erythematosus patients induce double-stranded DNA antibody production. Arthritis Rheum. 40, 2162–2171 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Datta, S. K. Production of pathogenic antibodies: cognate interactions between autoimmune T and B cells. Lupus. 7, 591–596 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Rekvig, O. P. et al. Molecular analyses of anti-DNA antibodies induced by polyomavirus BK in BALB/c mice. Scand. J. Immunol. 41, 593–602 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Craft, J. E. & Hardin, J. A. Linked sets of antinuclear antibodies: what do they mean? J. Rheumatol. Suppl. 14 (Suppl. 13), 106–109 (1987).

    PubMed  Google Scholar 

  85. Radic, M., Herrmann, M., van der Vlag, J. & Rekvig, O. P. Regulatory and pathogenetic mechanisms of autoantibodies in SLE. Autoimmunity 44, 349–356 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Munoz, L. E., Lauber, K., Schiller, M., Manfredi, A. A. & Herrmann, M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 6, 280–289 (2010).

    Article  PubMed  Google Scholar 

  87. Andreassen, K., Moens, U., Nossent, H., Marion, T. N. & Rekvig, O. P. 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, 2449–2460 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Andreassen, K. et al. T cell autoimmunity to histones and nucleosomes is a latent property of the normal immune system. Arthritis Rheum. 46, 1270–1281 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Jenkins, M. K. The role of cell division in the induction of clonal anergy. Immunol. Today 13, 69–73 (1992).

    Article  CAS  PubMed  Google Scholar 

  90. Dure, M. & Macian, F. IL-2 signalling prevents T cell anergy by inhibiting the expression of anergy-inducing genes. Mol. Immunol. 46, 999–1006 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Rekvig, O. P. & van der Vlag, J. . The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved. Semin. Immunopathol. 36, 301–311 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Smeenk, R. J. et al. Anti-dsDNA: choice of assay in relation to clinical value. Rheumatol. Int. 11, 101–107 (1991).

    Article  CAS  PubMed  Google Scholar 

  93. Winfield, J. B., Faiferman, I. & Koffler, D. Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis. J. Clin. Invest. 59, 90–96 (1977).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Smeenk, R. & Aarden, L. The use of polyethylene glycol precipitation to detect low-avidity anti-DNA antibodies in systemic lupus erythematosus. J. Immunol. Methods 39, 165–180 (1980).

    Article  CAS  PubMed  Google Scholar 

  95. Isenberg, D. A. Autoantibodies: markers of disease or pathogenic? Ann. N. Y. Acad. Sci. 823, 256–262 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Rose, N. R. & Bona, C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol. Today 14, 426–430 (1993).

    Article  CAS  PubMed  Google Scholar 

  97. Falkow, S. Molecular Koch's postulates applied to bacterial pathogenicity—a personal recollection 15 years later. Nat. Rev. Microbiol. 2, 67–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Izui, S., Lambert, P. H., Fournie, G. J., Turler, H. & Miescher, P. A. Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identificantion of circulating DNA and renal localization of DNA-anti-DNA complexes. J. Exp. Med. 145, 1115–1130 (1977).

    Article  CAS  PubMed  Google Scholar 

  99. Mjelle, J. E., Kalaaji, M. & Rekvig, O. P. Exposure of chromatin and not high affinity for dsDNA determines the nephritogenic impact of anti-dsDNA antibodies in (NZB×NZW)F1 mice. Autoimmunity 42, 104–111 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Xie, C., Liang, Z., Chang, S. & Mohan, C. Use of a novel elution regimen reveals the dominance of polyreactive antinuclear autoantibodies in lupus kidneys. Arthritis Rheum. 48, 2343–2352 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Van Bruggen, M. C., Kramers, C., Hylkema, M. N., Smeenk, R. J. & Berden, J. H. Significance of anti-nuclear and anti-extracellular matrix autoantibodies for albuminuria in murine lupus nephritis; a longitudinal study on plasma and glomerular eluates in MRL/l mice. Clin. Exp. Immunol. 105, 132–139 (1996).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Yung, S., Cheung, K. F., Zhang, Q. & Chan, T. M. Anti-dsDNA antibodies bind to mesangial annexin II in lupus nephritis. J. Am. Soc. Nephrol. 21, 1912–1927 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Sun, K. H. et al. Anti-dsDNA autoantibody crossreacts with the C-terminal hydrophobic cluster region containing phenylalanines in the acidic ribosomal phosphoprotein P1 to exert a cytostatic effect on the cells. Biochem. Biophys. Res. Commun. 263, 334–339 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Mjelle, J. E., Rekvig, O. P. & Fenton, K. A. Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis. Ann. Rheum. Dis. 66, 1661–1668 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Ehrenstein, M. R. et al. Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kidney Int. 48, 705–711 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Fenton, K. A., Tommeras, B., Marion, T. N. & Rekvig, O. P. Pure anti-dsDNA mAbs need chromatin structures to promote glomerular mesangial deposits in BALB/c mice. Autoimmunity 43, 179–188 (2009).

    Article  Google Scholar 

  107. Adu, D., Dobson, J. & Williams, D. G. DNA-anti-DNA circulating complexes in the nephritis of systemic lupus erythematosus. Clin. Exp. Immunol. 43, 605–614 (1981).

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Eilat, D. Crossreactions of anti-DNA antibodies and the central dogma of lupus nephritis. Immunol. Today 6, 123–127 (1985).

    Article  CAS  PubMed  Google Scholar 

  109. Fenton, K. et al. Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZB×NZW)F1 mice. PLoS ONE 4, e8474 (2009).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  110. Kalaaji, M., Sturfelt, G., Mjelle, J. E., Nossent, H. & Rekvig, O. P. Critical comparative analyses of anti-α-actinin and glomerulus-bound antibodies in human and murine lupus nephritis. Arthritis Rheum. 54, 914–926 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Kalaaji, M., Mortensen, E., Jorgensen, L., Olsen, R. & Rekvig, O. P. Nephritogenic lupus antibodies recognize glomerular basement membrane-associated chromatin fragments released from apoptotic intraglomerular cells. Am. J. Pathol. 168, 1779–1792 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Kalaaji, M. et al. Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis. Kidney Int. 71, 664–672 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Seredkina, N., Zykova, S. N. & Rekvig, O. P. Progression of murine lupus nephritis is linked to acquired renal Dnase1 deficiency and not to upregulated apoptosis. Am. J. Pathol. 175, 97–106 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. van der Vlag, J. & Berden, J. H. Lupus nephritis: role of antinucleosome autoantibodies. Semin. Nephrol. 31, 376–389 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. LeBlanc, B. A., Urowitz, M. B. & Gladman, O. D. Serologically active, clinically quiescent systemic lupus erythematosus—longterm followup. J. Rheumatol. 21, 174–175 (1994).

    CAS  PubMed  Google Scholar 

  116. Gladman, D. D., Urowitz, M. B. & Keystone, E. C. Serologically active clinically quiescent systemic lupus erythematosus: a discordance between clinical and serologic features. Am. J. Med. 66, 210–215 (1979).

    Article  CAS  PubMed  Google Scholar 

  117. Grootscholten, C. et al. Deposition of nucleosomal antigens (histones and DNA) in the epidermal basement membrane in human lupus nephritis. Arthritis Rheum. 48, 1355–1362 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Hedberg, A., Fismen, S., Fenton, K. A., Mortensen, E. S. & Rekvig, O. P. Deposition of chromatin-IgG complexes in skin of nephritic MRL-lpr/lpr mice is associated with increased local matrix metalloprotease activities. Exp. Dermatol. 19, e265–e274 (2010).

    Article  PubMed  Google Scholar 

  119. Fismen, S. et al. Circulating chromatin-anti-chromatin antibody complexes bind with high affinity to dermo-epidermal structures in murine and human lupus nephritis. Lupus 18, 597–607 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Huerta, P. T., Kowal, C., DeGiorgio, L. A., Volpe, B. T. & Diamond, B. Immunity and behaviour: antibodies alter emotion. Proc. Natl Acad. Sci. USA 103, 678–683 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rajan, T. V. The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation. Trends Immunol. 24, 376–379 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Krishnan, M. R., Jou, N. T. & Marion, T. N. Correlation between the amino acid position of arginine in VH-CDR3 and specificity for native DNA among autoimmune antibodies. J. Immunol. 157, 2430–2439 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author thanks Rod Wolstenholme, Section for Dissemination Services, for expert help in preparing Figures 1,2,3,4,5, and Hege Lynum Pedersen and Professor Bjarne Østerud, both from the Department of Medical Biology, Faculty of Health Sciences, Tromsø, Norway, for critical reading of the manuscript and for helpful suggestions. This study was supported by the University of Tromsø as Milieu Support.

Author information

Authors and Affiliations

  1. Department of Medical Biology, RNA and Molecular Pathology Research Group, Faculty of Health Sciences, University of Tromsø, Tromsø, N-9037, Norway

    Ole P. Rekvig

Authors
  1. Ole P. Rekvig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ole P. Rekvig.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rekvig, O. The anti-DNA antibody: origin and impact, dogmas and controversies. Nat Rev Rheumatol 11, 530–540 (2015). https://doi.org/10.1038/nrrheum.2015.69

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2015.69

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing