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Structural modification of DNA—a therapeutic option in SLE?

Nature Reviews Rheumatology volume 7, pages 733–738 (2011)Cite this article

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs, with glomerulonephritis representing a frequent and serious manifestation. SLE is characterized by the presence of various autoantibodies, including anti-DNA antibodies that occur in approximately 70% of patients with SLE and which contribute to disease pathogenesis. Consequently, immunosuppressive therapies are applied in the treatment of SLE to reduce autoantibody levels. However, increasing evidence suggests that DNA—especially double-stranded DNA—constitutes an important pathogenic factor that is able to activate inflammatory responses by itself in autoimmune diseases. Therefore, modifying the structure of DNA to reduce its pathogenicity might be a more targeted approach for the treatment of SLE than immunosuppression. This article presents information in support of this strategy, and discusses the potential methods of DNA structure manipulation—in light of data obtained from mouse models of SLE—including topoisomerase I inhibition, administration of DNase I, or modification of histones using heparin or histone deacetylase inhibitors.

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Figure 1: Induction of glomerulonephritis by SLE-associated anti-dsDNA antibodies.
Figure 2: Pathways involved in internalization and sensing of dsDNA.
Figure 3: Cellular effects of topoisomerase I inhibitors in dividing and non-dividing cells.

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References

  1. Casciola-Rosen, L. A., 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).

    CAS  Google Scholar 

  2. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59 (1998).

    Article  CAS  Google Scholar 

  3. Zykova, S. N., Seredkina, N., Benjaminsen, J. & Rekvig, O. P. Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus-prone (NZB × NZW)F(1) mice. Arthritis Rheum. 58, 813–825 (2008).

    Article  CAS  Google Scholar 

  4. Wen, Z. K. et al. DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice. Rheumatology (Oxford) 46, 1796–1803 (2007).

    Article  CAS  Google Scholar 

  5. Unanue, E. & Dixon, F. J. Experimental glomerulonephritis. IV. Participation of complement in nephrotoxic nephritis. J. Exp. Med. 119, 965–982 (1964).

    Article  CAS  Google Scholar 

  6. Sylvestre, D. L. & Ravetch, J. V. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265, 1095–1098 (1994).

    Article  CAS  Google Scholar 

  7. Suzuki, K. et al. Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. Proc. Natl Acad. Sci. USA 96, 2285–2290 (1999).

    Article  CAS  Google Scholar 

  8. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).

    Article  CAS  Google Scholar 

  9. Benigni, A. et al. Involvement of renal tubular Toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. Arthritis Rheum. 56, 1569–1578 (2007).

    Article  CAS  Google Scholar 

  10. Wu, X. & Peng, S. L. Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum. 54, 336–342 (2006).

    Article  CAS  Google Scholar 

  11. Stoehr, A. D. et al. TLR9 in peritoneal B-1b cells is essential for production of protective self-reactive IgM to control TH17 cells and severe autoimmunity. J. Immunol. 187, 2953–2965 (2011).

    Article  CAS  Google Scholar 

  12. Ishii, K. J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7, 40–48 (2006).

    Article  CAS  Google Scholar 

  13. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    Article  CAS  Google Scholar 

  14. Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007).

    Article  CAS  Google Scholar 

  15. Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol. 10, 1065–1072 (2009).

    Article  CAS  Google Scholar 

  16. Muruve, D. A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008).

    Article  CAS  Google Scholar 

  17. Roberts, T. L. et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323, 1057–1060 (2009).

    Article  CAS  Google Scholar 

  18. Decker, P., Singh-Jasuja, H., Haager, S., Kötter, I. & Rammensee, H. G. Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J. Immunol. 174, 3326–3334 (2005).

    Article  CAS  Google Scholar 

  19. Hägele, H. et al. Double-stranded DNA activates glomerular endothelial cells and enhances albumin permeability via a Toll-like receptor-independent cytosolic DNA recognition pathway. Am. J. Pathol. 175, 1896–1904 (2009).

    Article  Google Scholar 

  20. Allam, R. et al. Viral RNA and DNA trigger common antiviral responses in mesangial cells. J. Am. Soc. Nephrol. 20, 1986–1996 (2009).

    Article  CAS  Google Scholar 

  21. Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  Google Scholar 

  22. Means, T. K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).

    Article  CAS  Google Scholar 

  23. Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).

    Article  CAS  Google Scholar 

  24. Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 8, 487–496 (2007).

    Article  CAS  Google Scholar 

  25. Yanai, H. et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462, 99–103 (2009).

    Article  CAS  Google Scholar 

  26. van Bruggen, M. C. et al. Heparin and heparinoids prevent the binding of immune complexes containing nucleosomal antigens to the GBM and delay nephritis in MRL/lpr mice. Kidney Int. 50, 1555–1564 (1996).

    Article  CAS  Google Scholar 

  27. Hedberg, A. et al. Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes. Arthritis Rheum. 63, 1065–1075 (2011).

    Article  CAS  Google Scholar 

  28. Napirei, M., Ludwig, S., Mezrhab, J., Klöckl, T. & Mannherz, H. G. Murine serum nucleases—contrasting effects of plasmin and heparin on the activities of DNase1 and DNase1-like 3 (DNase1l3). FEBS J. 276, 1059–1073 (2009).

    Article  CAS  Google Scholar 

  29. Reilly, C. M. et al. The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice. J. Autoimmun. 31, 123–130 (2008).

    Article  CAS  Google Scholar 

  30. Hsiang, Y. H., Lihou, M. G. & Liu, L. F. Arrest of replication forks by drug-stabilized topoisomerase I–DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 49, 5077–5082 (1989).

    CAS  PubMed  Google Scholar 

  31. Hsiang, Y. H., Hertzberg, R., Hecht, S. & Liu, L. F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem. 260, 14873–14878 (1985).

    CAS  PubMed  Google Scholar 

  32. Frese-Schaper, M., Zbaeren, J., Gugger, M., Monestier, M. & Frese, S. Reversal of established lupus nephritis and prolonged survival of New Zealand black × New Zealand white mice treated with the topoisomerase I inhibitor irinotecan. J. Immunol. 184, 2175–2182 (2010).

    Article  CAS  Google Scholar 

  33. Samaha, R. J. & Irvin, W. S. Deoxyribonucleic acid strandedness. Partial characterization of the antigenic regions binding antibodies in lupus erythematosus serum. J. Clin. Invest. 56, 446–457 (1975).

    Article  CAS  Google Scholar 

  34. Samejima, K. & Earnshaw, W. C. Trashing the genome: the role of nucleases during apoptosis. Nat. Rev. Mol. Cell Biol. 6, 677–688 (2005).

    Article  CAS  Google Scholar 

  35. Campbell, V. W. & Jackson, D. A. The effect of divalent cations on the mode of action of DNase I. The initial reaction products produced from covalently closed circular DNA. J. Biol. Chem. 255, 3726–3735 (1980).

    CAS  Google Scholar 

  36. Chitrabamrung, S., Rubin, R. L. & Tan, E. M. Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol. Int. 1, 55–60 (1981).

    Article  CAS  Google Scholar 

  37. 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  Google Scholar 

  38. Macanovic, M. et al. The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin. Exp. Immunol. 106, 243–252 (1996).

    Article  CAS  Google Scholar 

  39. Verthelyi, D., Dybdal, N., Elias, K. A. & Klinman, D. M. DNAse treatment does not improve the survival of lupus prone (NZB × NZW)F1 mice. Lupus 7, 223–230 (1998).

    Article  CAS  Google Scholar 

  40. Venkatesh, J. et al. Antigen is required for maturation and activation of pathogenic anti-DNA antibodies and systemic inflammation. J. Immunol. 186, 5304–5312 (2011).

    Article  CAS  Google Scholar 

  41. Neubert, K. et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat. Med. 14, 748–755 (2008).

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Clinical Research, University Hospital Bern, Murtenstrasse 50, P. O. Box 44, Bern, CH-3010, Switzerland

    Steffen Frese

  2. The Feinstein Institute for Medical Research, North Shore LIJ Health System, 350 Community Drive, Manhasset, 11030, NY, USA

    Betty Diamond

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  1. Steffen Frese
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Contributions

S. Frese researched the data for the article and wrote the article. B. Diamond contributed to review and/or editing of the manuscript before submission. S. Frese and B. Diamond contributed equally to discussions of the content.

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Correspondence to Steffen Frese.

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Competing interests

S. Frese has filed a patent with the European Patent Office for the treatment of autoimmune diseases by use of topoisomerase I inhibitors. B. Diamond declares no competing interests.

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Frese, S., Diamond, B. Structural modification of DNA—a therapeutic option in SLE?. Nat Rev Rheumatol 7, 733–738 (2011). https://doi.org/10.1038/nrrheum.2011.153

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