Scientists of the University Hospital Bonn, Germany have now discovered which signaling pathway of the innate immune system promotes autoimmune symptoms following sun-induced DNA damage. The results are now published online in the academic journal Immunity.
Sunlight can damage DNA: Dr. Winfried Barchet (centre), and his co-workers at the Institute of Clinical Chemistry and Clinical Pharmacology visualize their findings using black tubing to represent the DNA double helix. Nadine Gehrke (on the far left), Christina Mertens (far right) and Thomas Zillinger (fourth from the right) share first authorship on the publication.
(c) Photo: Anna-Maria Herzner/UKB
Lupus erythematosus (LE) is an autoimmune disorder in which the immune system erroneously attacks the body’s own tissues. Where most people merely suffer sunburn, LE prone patients may develop severe redness and inflammation in sun-exposed skin. Immunologists of the University Hospital Bonn together with the Dermatologists Profs. Thomas Tüting and Jörg Wenzel have now discovered an immune mechanism that triggers LE skin lesions.
„We have shown how the UV component of sunlight may cause DNA damage in cells, and in consequence lead to an alarm response from the innate immune system“, reports Dr. Winfried Barchet, head of the Emmy Noether-research team „Immunorecognition of viral nucleic acids in the cytosol“ at the Institute of Clinical Chemistry and Clinical Pharmacology at the university clinics of Bonn.
How DNA damage produces a false alarm
High-energy UV irradiation damages DNA in the nuclei of living cells that in consequence perish, and release the UV-altered DNA. In lupus patients this triggers a troublesome signaling cascade: „The innate immune system usually detects viruses via their nucleic acids. Here however, this state of emergency is declared erroneously due to the crash in the body’s own DNA,“ says Dr. Barchet. The majority of the innate immune receptors that detect viral nucleic acids and in consequence activate inflammatory immune defense mechanisms are now known.
„For the induction of lupus symptoms, according to our data, the decisive role is played by the very recently discovered immune receptor cGAMP-Synthase (cGAS)“, says Dr. Barchet. DNA released from dying cells is taken up by immune cells and then degraded by the enzyme TREX1. When the cellular DNA is UV damaged, however, TREX1 is ineffective according to the results of the Bonn researchers. Damaged DNA accumulates and activates the cGAS signaling pathway, thus ringing a false alarm for the immune system
The researchers were also able to support this concept with a mouse model in which a gene defect makes them prone to develop lupus-like autoimmune disease. When the immunologists injected DNA damaged by UV-light into the skin, the animals locally developed typical lupus symptoms: skin swelling and inflammation, infiltration of immune cells that eventually attacked skin tissue. Control injections of intact DNA, in contrast, did not cause such skin alterations.
„These signaling events may explain why lupus patients are prone to UV-light induced skin lesions“, says the researcher. This study is the first to implicate the cGAS receptor in this autoimmune disorder. Dr. Barchet envisions potential targets for novel lupus therapies: „With a suitable inhibitor of the cGAS signaling cascade, it may become possible to suppress sunlight induced symptoms of the disease. On the other hand, it is puzzling why the immune system has evolved and maintained such a potentially harmful mechanism. We believe that in healthy individuals it must have an important function in the defense against pathogens that we would very much like to understand as well,“ says Dr. Barchet.
Dr. Barchet is a member of the ImmunoSensation cluster of excellence (Speaker: Prof. Dr. Gunther Hartmann) of the University of Bonn that is funded for 5 years with a total of 30 million Euro.
Publication: „Oxidative Damage of DNA Confers Resistance to Cytosolic Nuclease TREX1 Degradation and Potentiates STING-Dependent Immune Sensing”, Fachjournal „Immunity“
Contact:Dr. rer. nat. Winfried Barchet
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Life Sciences
17.07.2018 | Information Technology
17.07.2018 | Power and Electrical Engineering