Forschungsinteresse

Head of the research group on allergic asthma at the Institute for Systemic Inflammation Research.

Allergic asthma is one of the most prevalent diseases of the western world. It develops in genetically susceptible individuals as a chronic inflammatory disorder of the upper airways leading to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Allergic asthma arises from an inappropriate immune response against harmless aeroallergens. The major form of the disease is characterized by a strong airway eosinophilia, airway hyperresponsiveness, strong mucus production and Th2 maladaptive immune responses.

Many studies have highlighted the multiple roles of the anaphylatoxins (ATs) C3a and C5a and their cognate C3a and C5a receptors (C3aR, C5aR1 and C5aR2) during the sensitization and effector phase of allergic asthma (for review see Laumonnier et al. Mol. Immunol. 2017). The AT receptors belong to the family of seven-transmembrane receptors and translate humoral immune responses into cellular inflammatory responses through the activation of guanine-nucleotide binding (G)-proteins or, in the case of C5aR2, through the activation of the b-arrestin signalling pathway. The ATs are polypeptides generated by cleavage of the complement proteins C3 and C5.  C3 and C5 loci have been associated with allergic asthma and C3a as well as C5a are present in the bronchoalvelar lavage fluid of allergic asthma patients.ATs are also generated in small amounts in the airways under non-asthmatic conditions. The underlying mechanisms include the spontaneous or apoptotic cell-mediated hydrolysis of C3 and the consecutive activation of the alternative pathway of complement. Under asthmatic conditions, such pathways are amplified by direct cleavage of C3 and C5 by allergen- or cell-derived proteases. After their generation, ATs act as chemotactic factors that support the recruitment and activation of inflammatory or regulatory cells.

Pro-allergic and pro-inflammatory functions have been reported for C3aR in many experimental allergic asthma models suggesting a key role for C3a in the effector phase of the disease. In contrast, the C5aR1-mediated functions in allergic asthma are more complex. Activation of C5aR1 drives allergic inflammation during the effector phase. In contrast, targeting C5aR1 during allergen sensitization results in aggravation of the asthmatic phenotype, suggesting a protective role. In addition, C5aR1 has been shown to be important for the exacerbation of the disease through the establishment of Th17 responses. Finally, C5aR2 has been described as an important receptor for the development of the allergic asthma.