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Structural modification of DNA—a therapeutic option in SLE?

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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Authors and Affiliations

Authors

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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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