Dr. rer. nat., Medical School Hannover, Germany, 1999
Diploma in Biology, Georg August University Goettingen, Germany, 1995
Postoctoral Fellow in the Institute of Cell Biology and Immunology at the University Stuttgart, Germany, 2000-2007
Graduate Student in the Institute of Molecular Biology at the Medical School in Hannover, Germany, 1996-1999
Student at The Scripps Research Institute, San Diego, U.S.A., 1993-1996
--- Immunoregulation and molecular mechanisms of signal initiation by Tumour Necrosis Factor (TNF) ---
The pleiotropic and multifunctional cytokine tumour necrosis factor (TNF) is a prominent proinflammatory mediator associated with the pathophysiology of several acute and chronic diseases including rheumatoid arthritis and Crohn’s disease. To date, agents that block the action of TNF are of great benefit for many patients. However, TNF is not simply a proinflammatory cytokine but rather a complex molecule with immunoregulatory and anti-inflammatory functions required for an intact immune response. Therefore it is not astonishing that unselective blocking of TNF increases also the risk of infectious diseases, such as tuberculosis, and potentially cancer affecting all currently available TNF therapeutics and limit them to only a subset of patients.
TNF is produced as a bioactive membrane bound type II protein (mTNF) and can be processed to the soluble form (sTNF) by metalloproteases. Whereas the diversity of cellular responses mediated by sTNF has been thoroughly studied during the last two decades, mTNF gained major interest much later. In particular, mTNF was found to be essential for maintaining the innate immunity.
Both forms of TNF bind to their homolog membrane receptors, TNFR1 and TNFR2. Whereas TNFR1 is constitutively expressed in most tissues, TNFR2 is highly regulated in its cellular surface expression. Extensive studies analysing the function of TNFR1 show a key role of TNFR1 in cellular effects mediated by TNF. The physiological role of TNFR2 is not in detail understood due to the lack of assay systems that define TNFR2-mediated cellular responses after sTNF treatment. However, animal models ascribed rather neuroprotective and anti-inflammatory functions to TNFR2. The identification of mTNF rather than sTNF as a potent natural ligand for TNFR1 and TNFR2 showed that mTNF expressing cells induce cellular responses in target cells that could not be induced by TNFR1 itself, identifying a new functional role of TNFR2 especially in locally rather than systemic TNF effects.
Our own data show that one important difference of sTNF and mTNF in the lack of activation of TNFR2 is on the level of receptor-signalling complex formation. Besides high affinity binding of sTNF to TNFR2, sTNF is not capable of recruiting cytoplasmic adaptor molecules into the TNFR2 signalling complex. Analysis of the molecular basis of the differential responsiveness of TNFR towards sTNF discovered receptor clustering regulated by TNFR's distinct transmembrane proximal stalk region as crucial player in cotrollling this key property. Consequently, understanding early steps in TNFR signalling is a major interest of my research.
A further focus of my research is to understand in more detail immunoregulatory functions of the two TNF receptors, TNFR1 and TNFR2. In particular their opposing functions and the crosstalk between these receptors in antigen-presenting cells and T lymphocytes is of major interest.
Overall, my research aims for a more detailed understanding of the interplay of TNFR in the regulation of immune responses and for the identification of new molecular targets to modulate receptor-specifically TNF responses.
Supervision of postdocs, research assistants, PhD and MRes students
German Research Council (Deutsche Forschungsgemeinschaft, DFG)
JGW Patterson Foundation
Krippner-Heidenreich A, Grunwald I, Scheurich P, Pfizenmaier K: Polypetides of the members of the TNF ligand family and use thereof. 2005235669; 24.03.2005