Group leader: Diana Wouters PhD
The complement system is part of the innate immune response. Upon activation of complement powerful inflammatory reactions are induced, that may lead to disease when not properly controlled. To prevent this, complement regulatory proteins are present both in plasma (such as C1-inhibitor, factor I and factor H (fH)) and on host cell membranes (such as CD55 (DAF) and CD59). We are interested in the genetic variation and therapeutic application of proteins that regulate complement activation.
We study the molecular organization of the lectin pathway and investigate why complement activation is attenuated in pediatric oncology patients. More recently, we started a new research line in which we aim to get insight in the mechanisms by which Neisseria meningitides exploits the alternative complement pathway inhibitor fH and fH-related proteins 1-5 (fHR1-5) to increase its survival in human blood. These studies are done in close collaboration with Prof Taco Kuijpers (Emma Children’s hospital, Academic Medical Centre).
In addition, we are studying complement-mediated red blood cell (RBC) destruction as occurring in autoimmune hemolytic anemia (AIHA) as well as during storage of red blood cells for transfusion (so called storage lesion). In AIHA the classical pathway of complement is activated by auto-antibodies against RBC antigens. We are trying to unravel the mechanisms of complement activation on damaged RBCs, since this is still unknown. The result of complement deposition on RBCs is accelerated clearance via complement receptors on phagocytic cells or intravascular hemolysis.
C1-inhibitor (C1-inh) is a major therapeutic product of Sanquin. We compare properties of recombinant C1-inh with plasma-derived C1-inh and investigate the effects of (glycosylated) C1-inh on neutrophil/endothelial cell interaction. In collaboration with Sanquin Plasma Products and Shire we are exploring possible new fields of clinical application for C1-Inh. In collaboration with Prof Hans Niessen (Department of Pathology, VUmc) we demonstrated in a rat burn wound model that systemic treatment with C1-inh improves the local healing of burn wounds and reduces inflammation in the heart. We will further explore the possibility of C1-inh as therapeutic intervention for burn wound patients. We also showed in an ex vivo model for acute vein graft injury that C1-inh protects against endothelial loss under arterial blood pressure.
- Wouters D, Stephan F, Strengers P, de Haas M, Brouwer C, Hagenbeek T, van Oers MHJ, Zeerleder S. C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia. Blood 2013; 121:1242-44.
- Begieneman MPV, Kubat B, Ulrich MMW, Hahn NE, Stumpf Y, Tempelaars M, Middelkoop E, Zeerleder S, Wouters D, Ham van SM, Niessen HWM, Krijnen PAJ. Prolonged C1-inhibitor administration improves local healing of burn wounds and reduces myocardial inflammation in a rat burn wound model. Burn Care Res 2012; 33(4):544-51.
- Krijnen PA, Kupreishvili K, de Vries MR, Schepers A, Stooker W, Vonk AB, Eijsman L, Van Hinsbergh VW, Zeerleder S, Wouters D, van Ham M, Quax PH, Niessen HW. C1-esterase inhibitor protects against early vein graft remodeling under arterial blood pressure. Atherosclerosis 2012; 220(1):86-92.