Abstracts (complete list) - Wissenschaft Online

Katharina Randers, Telja Pursche, Doreen Finke, Kirsten Jacobsen, Robert Hoerster,
Christian Brockmann, Holger Hennig, Tony Marion, Sigfried Goerg
Apoptotic DNA is able to induce in vivo IFN α production
within the splenic marginal zone via a TLR dependent
pathway.
Introduction: Systemic lupus erythematosus is a multigenic autoimmune disease related
to impaired waste disposal and elevated levels of Interferon alpha. Here we provide
evidence that targeting of apoptotic DNA towards the splenic marginal zone explains
TLR-9 pathway dependent elevated levels of Interferon alpha in lupus susceptible
complement C4 deficient mice.
Methods: Levels of intravascular DNA of wt mice or C4null mice were determined by
ELISA and TUNEL dotblot assay. C57/Bl6 wildtype mice were injected with 4 µg
apoptotic or native DNA with or without prior treatment with chloroquin. Splenic CD11b
cells were isolated 6h later by magnetic cell sorting, mRNA was purified and IFN α and
TLR9 were measured by RT-PCR.
Results: We found that the levels of DNA were significantly higher in serum of C4null
mice than in wt mice, but TUNEL dotblot assay detected apoptotic DNA in both mice.
Application of apoptotic DNA showed a significant increase of Interferon alpha mRNA
and TLR-9 in CD11b+ cells whereas native DNA resulted just in a minimal increase.
Prior treatment with chloroquine reduced the expression of Interferon alpha and TLR-9
mRNA in CD11b+ cells.
Conclusion: Here we demonstrate that untreated C4null mice have elevated levels of
intravascular DNA, which may be of apoptotic origin and that targeting of apoptotic DNA
towards the marginal zone increases levels of Interferon mRNA in C4null mice as well as
in wt mice. Blockade of in vivo TLR signal transduction with chloroquine prevented the
apoptotic DNA dependent interferon alpha activation, demonstrating that endogenous
apoptotic DNA plays an important role for the induction of interferon alpha SLE.