The Research Groups of the Clinic of Rheumatology / Immunology / Allergology (RIA) headed by Prof. Dr. P. Villiger, Dr. F. Förger, Prof. Dr. M. Seitz, PD Dr. D. Aeberli, Prof. Dr. Bachmann and Prof. Dr. B. Trueb are investigating scientific questions in the areas of immunology and chronic inflammation, with the goal of elaborating and understanding the molecular mechanisms of the disease. Our research projects are supported by the Swiss National Science Foundation and by various private foundations.
Head Prof. Dr. Peter Villiger, Dr. Frauke Förger, Prof. Dr. Michael Seitz, PD Dr. Daniel Aeberli
We are investigating the molecular mechanisms of chronic inflammatory diseases in humans. Our projects focus on
- the regulation of regulatory T cells and gene microarray analysis of blood cells from rheumatoid arthritis patients during pregnancy and
- the regulation of osteoclast progenitors in rheumatic diseases. In addition to our basic science research, several clinical studies are being conducted to establish the validity of new diagnostic tests as well as new medications for future clinical use.
Osteoclastogenesis in Chronic Inflammation:
Head Prof. Dr. Michael Seitz, PD Dr. Daniel Aeberli
Inflammation induced osteoclastogenesis is largely dependent on TNF. The mechanisms of anti-TNF response however is not known yet, particularly in terms of the migration of osteoclast precursor cells (OPCs), interaction with the endothelium and migration into the inflammation prone site, the joint. We hypothesize that the rapid and sustained downregulation of osteoclastogenesis by TNF inhibition (through infliximab) might be mediated not only by apoptosis induction of OPCs but also by reduced monocyte/OPC mobilization from bone marrow into peripheral tissues and by reduced attachment of OPCs to peripheral bone tissue and subsequently reduced differentiation into mature osteoclasts.
We have started to investigate this research hypothesis in a murine model of chronic antigen induced arthritis (AIA) in CCR2-RFP/CX3CR1-EGFP knock-in mice with and without intraperitoneal injection of anti-TNF/infliximab either before or at the onset of arthritic symptoms. Twophoton intravital microscopy (2PIVM) is used to image track sequences of transendothelial migration of endogenously labeled OPCs (and monocytes) into arthritic joints. Diapedesis of OPCs, attachement to bone matrix and differentiation into osteoclasts are investigated in serial sections of skull, femura and knees by histochemistry in mice sacrificed after 2PIVM. Recruitment of OPCs from bone marrow into peripheral tissues are monitored by FACS analysis of cellular components of bone marrow, peripheral blood and spleen.
This is a interdisciplinary research project supported by a grant from the Swiss National Foundation. Members of the research team are the followings: Prof.M.Seitz, S.Uster (PhD student), PD D.Aeberli (Department of Rheumatology, Clinical Immunology & Allergology, University Hospital of Bern), Prof.W.Hofstetter (Group of Bone Biology and Orthopaedic Research, Department of BioMedical Research, University of Bern), Prof.B.Engelhardt, PD J.Stein (Theodor-Kocher Institute, University of Bern).
Bone and Cartilage Biology:
Head Prof. Dr. Beat Trueb
We are investigating a novel growth factor receptor (FGFRL1), which belongs to the FGF receptors and which is primarily found in cartilage. The function of the novel receptor is being studied in mice with a targeted disruption of the FGFRL1 gene (knock-out mice). The effects of the receptor on cell proliferation, differentiation and apoptosis are being analyzed in cell cultures. Mutations in the gene for FGFRL1 are being investigated in human patients suffering from congenital skeletal diseases (craniosynostosis). Finally, the receptor is being prepared in recombinant form in order to study its interactions with other proteins.
Immunology Research: Head Prof. Dr. Martin Bachmann / Stv. PD Dr. Monique Vogel
1. Group Prof. Dr. M. Bachmann/PD Dr. M. Vogel
Research of the Bachmann group has been dominated by the question how immune responses are regulated and how innate immune responses influence adaptive immunity. Viruses, virus-like particles and bacteria have been used to probe the protective capacity of the induced immune responses. Key problems that have been addressed are how optimal T and B cell responses are induced and maintained and how they are influenced by toll-like receptor stimulation. Understanding the cellular networks of the immune system is of significant medical interest since i) prophylactic vaccines, which are the most effective medical intervention known to date, are based on the induction of long-lived immune responses and ii) a deregulated immune system is the underlying cause of many chronic diseases and autoimmunity.
In the last 10 years, we have taken the basic research performed in mice one step further and several clinical trials have been performed or are now ongoing. Clinical proof of concept has been obtained in 4 different indications (Smoking cessation, allergy, asthma, hypertension and influenza virus). Our research will focus on applied research, translating fundamental research into novel medicines. With the unique experience of Monique Vogel, an important pillar of our research activities will be in the field of allergy, where we will study basic and applied aspects of IgE regulation and mast cell biology.
Prof. Dr. M. Bachmann/PD Dr. M. Vogel
2. Group Dr. Alexander Eggel
Type-2 immunity in health and disease: Our major research interests focus on the biologic mechanisms underlying both beneficial as well as pathogenic type 2 immune responses. On the one hand we are trying to get a better understanding on how allergies evolve and to develop alternative treatment approaches directly interfering with the allergic cascade. On the other hand we are investigating the development of age-related disorders and how they are linked to alterations in type 2 immune responses. In our studies we integrate molecular, cellular and systemic approaches to identify important biological mechanisms involved in the pathophysiology of a disease.
Please visit the external Group Website for more information.
Dr. A. Eggel
3. Group Dr. Daniel Yerly
Our main topic of interest is drug allergy. Whereas the adaptive immune system is supposed to recognize large molecular structures from microorganisms for immune protections, small molecular compounds like drugs can activate the immune system in particular situations. In severe cases the activation of the immune system becomes out of control and puts the life of the affected individual at stake. In our research we try to understand the cellular and molecular mechanisms involved in drug allergic reactions.
HLA associated drug hypersensitivity reactions
Some genetic factors (HLAs) have been identified to be associated with hypersensitivity reactions to particular drugs. For example Abacavir, an effective drug used in the treatment of HIV infection causes hypersensitivity reactions only in individuals carrying the HLA-B*57:01 allele (~5% of the European population). On this topic, we are developing models to investigate the interactions between HLA molecules, the drug and the immune T cell receptor.
Metamizole induced agranulocytosis
Metamizole is a painkiller with antipyretic properties. Although this drug is very effective, its safety profile is not totally secure. In rare cases, treatment with metamizole can lead to life-threatening agranulocytosis. We aim to identify whether the adaptive immune system could be activated by metamizole and then play a cytotoxic role toward granulocyte precursor cells.
Link between T cell activation mechanisms and allergic symptoms
In drug hypersensitivity reactions, drug-reacting T cells can often be found in the blood of allergic patients or in the lesions directly. Two different models can explain the activation of T cell by drug: the hapten model for which antigenic peptides are covalently modified by the drug or its metabolites; or the pi model (Pharmacological Interaction), for which interactions are mediated by van der Waals interactions only and so no covalent modifications are necessary. Until now, the clinical relevance of each model is not clear. We are running a study investigating whether the broad range and the severity of the symptoms of drug allergy (urticarial, maculo-papular erythema, Steven-Johnson Syndrome, DRESS) can be correlated with the activation mechanism of involved drug-reacting T cells.
Dr. D. Yerly