ERC FUNDED PROJECTS

The Aryl hydrocarbon receptor is an evolutionary conserved widely expressed transcription factor that mediates the toxicity of a substantial variety of exogenous toxins, but is also stimulated by endogenous physiological ligands. While it is known that this receptor mediates the toxicity of dioxin, this is unlikely to be its physiological function. We have recently identified selective expression of AhR in the Th17 subset of effector CD4 T cells. Ligation of AhR by a candidate endogenous ligand (FICZ) which is a UV metabolite of tryptophan causes expansion of Th17 cells and the induction of IL-22 production. As a consequence, AhR ligation will exacerbate autoimmune diseases such as experimental autoimmune encephalomyelitis. Little is known so far about the impact of AhR ligands on IL-17/IL-22 mediated immune defense functions. IL-22 is considered a pro-inflammatory Th17 cytokine, which is involved in the etiology of psoriasis, but it has also been shown to be a survival factor for epithelial cells. AhR is polymorphic and defined as high or low affinity receptor for dioxin leading to the classification of high and low responder mouse strains based on defined mutations. In humans similar polymorphisms exist and although on the whole human AhR is thought to be of low affinity in humans, there are identified mutations that confer high responder status. No correlations have been made with Th17 mediated immune responses in mice and humans. This study aims to investigate the role of AhR ligands and polymorphisms in autoimmunity as well as protective immune responses using both mouse models and human samples from normal controls as well as psoriasis patients.

1 242 352 €

Start date: 2009-02-01, End date: 2014-01-31

"Humans are equipped with a variety of intrinsic immunity or host restriction factors. These evolved under positive selection pressure for diversification and represent a first line of defence against invading viruses. Unfortunately, however, many pathogens have evolved effective antagonists against our defences. For example, the capability of HIV-1 to counteract human restriction factors that interfere with reverse transcription, uncoating and virion release has been a prerequisite for the global spread of AIDS. We are just beginning to understand the diversity and induction of antiretroviral factors and how pandemic HIV-1 group M (major) strains evolved to counteract all of them. Here, I propose to use a genetics, proteomics and evolutionary approach to discover and define as-yet-unknown antiviral effectors and their inducers. To identify novel antiviral factors, we will examine the capability of all primate genes that are under strong positive selection pressure to inhibit HIV and its simian (SIV) precursors. This examination from the evolutionary perspective of the invading pathogen will also reveal which adaptations allowed HIV-1 to cause the AIDS pandemic. Furthermore, complex peptide-protein libraries representing essentially the entire human peptidome, will be utilized to identify novel specific inducers of antiviral restriction factors. My ultimate aim is to unravel the network of inducers and effectors of antiviral immunity - the ""Anti-Virome"" - and to use this knowledge to develop novel effective preventive and therapeutic approaches based on the induction of combinations of antiviral factors targeting different steps of the viral life cycle. The results of this innovative and interdisciplinary program will provide fundamental new insights into intrinsic immunity and may offer alternatives to conventional vaccine and therapeutic approaches because most restriction factors have broad antiviral activity and are thus effective against various pathogens."

1 915 200 €

Start date: 2013-04-01, End date: 2018-03-31

Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.

2 499 593 €

Start date: 2014-03-01, End date: 2019-02-28

The proposed project aims at investigating the molecular mechanisms that activate B cell antigen receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL). While it is widely accepted that the unbroken BCR expression in CLL cells is indicative for a key role in disease development, the mechanisms that induce BCR activation and survival of malignant cells are still elusive. Using a unique reconstitution system, we have recently shown that CLL-derived BCRs possess the exceptional capacity for cell-autonomous signalling independent of external antigen. Crystallographic analyses confirmed our model that CLL-BCRs bind to intrinsic motifs in nearby BCRs on the very same cell. In addition to the BCR, several pathogenic factors influence the biological behaviour of CLL cells, but the functional hierarchy and the effect on BCR signalling are insufficiently understood. Here, we aim at investigating the structural cause of autonomous signalling as well as the characterization of important signalling pathways and their mechanistic action in CLL pathogenesis. By combining crystallography with the measurement of autonomous signalling of wild type and mutated receptors in our unique reconstitution system, we will generate a structure-function relationship for CLL-BCRs. By generating new animal models and by employing classical as well as cutting-edge approaches of biochemistry and molecular/cellular immunology, we will comprehensively characterize the signalling pathways that are activated by autonomous signalling and might be important for CLL pathogenesis. These systematic efforts are necessary to understand how various biological mechanisms operate and ultimately activate downstream pathways that result in a lymphoproliferative disease. In addition, a cohesive model of CLL pathogenesis, which elucidates the hierarchical order of pathogenic factors and their interaction with BCR signalling, may well lead to novel disease-specific preventive or therapeutic intervention.

2 256 250 €

Start date: 2016-11-01, End date: 2021-10-31