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Since the discovery of anti-DNA antibodies, DNA has been the subject of fascination as a target of autoimmunity in systemic lupus erythematosus (SLE).1 As the material of heredity, DNA is usually hidden from the immune system in the safe confines of the cell nucleus. How then can DNA become an autoantigen? The answer lies in DNA’s capacity for geographic translocation. Like many molecules, DNA can move around the cell and even escape outside, especially during cell death.2 Depending on the mechanism, cell death can induce inflammation, providing adjuvant activity to induce anti-DNA production. Another mechanism for antibody induction is cross-reactivity with another foreign or even self-antigen during infection, a setting for intense immune activation. The genetic background of the individual may influence these responses.3
Once outside the cell, DNA can display immunological properties by forming immune complexes with anti-DNA antibodies. These complexes have two key roles in disease: deposition in the kidney to incite nephritis and stimulation of cytokine production via interaction with both Toll-like receptor (TLR) and non-TLR internal nucleic acid sensors that operate in various subcellular compartments.4 The location of these sensors contrasts with that of TLR receptors such as TLR4, which are found on the cell membrane. While the response to infection is usually conceptualised as beginning in the extracellular space in the blood or tissue, the intracellular space is also an important site of host defence, with internal nucleic acid sensors key to activation of innate immunity
During infection, these internal sensors can bind DNA (as well as RNA) from intracellular bacterial or viral infection and trigger the same systems as those activated by extracellular pathogen associated molecular patterns.5–7 Mitochondrial DNA (mtDNA) can also trigger these sensors during cell stress since mitochondria can leak or release their DNA.8 9 Genetically …
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