Role of the complement system and neutrophil activation in livedoid vasculopathy

• Applicant: Professor Dr. Stefan Werner Schneider
• Subject Area: Dermatology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525178846

Livedoid vasculopathy (LV) is an orphan disease affecting the microcirculation of the skin. Thrombotic occlusions of blood vessels produce tissue necrosis, ulceration and severe pain. The acting pathological mechanisms are largely unexplored and current knowledge on molecular drivers of LV is based on case reports and few clinical studies. In the here proposed project, we aim to gain further insights into the acting molecular mechanisms and in particular, into the role of the complement system and neutrophils. We and other have previously shown that thrombosis promotes the activation of the complement system and in turn neutrophil recruitment and activation. Strong activation of neutrophils triggers the release of chromosomal DNA, commonly referred to as neutrophil extra cellular traps (NETs). In diseases similar to LV, such antiphospholipid syndrome, intravascular NETs have been associated to hypercoagulation and thrombosis. In the here proposed project, we will investigate the pathophysiological connection of the complement system, coagulation and NET formation in LV using a translational approach. Analyses of patients’ samples will be supported by a recently developed organ-on-chip in vitro model mimicking LV. In preliminary studies, we found the deposition of complement factors and the accumulation of NET releasing neutrophils in affected blood vessel sections of LV patients. In our organ-on-chip model, blood clotting was also associated with complement activation and NET release. In the frame of the planned research project, we will specifically investigate the pathophysiological relevance of plasma molecules frequently reported to be elevated in LV patients such as lipoprotein(a), homocystein and antiphospholipid antibodies. In the last part of the project, we will evaluate in our in vitro model system the potential of novel therapeutic strategies such as the inhibition of the complement system.

• DFG Programme: Research Grants