DNA Remnants Trigger Immune Response

Researchers working with a Drosophila model have found that DNA remnants from dead cells can elicit an immune response in the fly, which suggests that an analogous autoimmune response could be triggered in humans. The finding was reported in the October 15, 2002, issue of Genes and Development.

Drosophila was selected for ease of study and because the process of apoptosis is similar in both the fruit fly and in mammalian cells. Both fly and mammalian cells contain several different enzymes that specifically degrade DNA (DNase). During apoptosis, caspase-activated DNase (CAD) is released from its inhibitor, ICAD, and thereby activated to digest DNA inside the dying cell. Macrophages also contain DNases, including lysosomal DNase II enzymes that are thought to play a role in apoptotic DNA degradation.

Investigators from Osaka University (Japan) engineered strains of flies deficient in ICAD, DNase II, or both ICAD and DNase II in order to determine the relative contributions of each of these enzymes to apoptotic DNA degradation and the physiological consequences of this process. They found that ICAD-deficient flies do not express CAD (ICAD is required for the normal folding of the CAD protein and therefore its activity) and so no apoptotic DNA fragmentation occurred. The DNase II-deficient flies were able to digest DNA inside the dying cells, but degraded DNA accumulated and activated an innate immune response. Finally, flies deficient in both ICAD and DNase II lacked apoptotic DNA degradation abilities and displayed an enhanced immune response.

"If our results in Drosophila can be applied to mammalian systems, they suggest that DNA of the dying cells must be properly deposited. Otherwise, we will suffer from an immune response, like septic shock,” explained senior author Dr. Shigekazu Nagata. "Further research is needed to determine if undigested apoptotic DNA can elicit an immune response in humans, but if so, this finding could open up a whole new list of possible culprits behind human autoimmune disease.”



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Osaka University