Priority Research Area Asthma and Allergy

Biochemical Immunology

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Projects

The research work of the group of Biochemical Immunology is dedicated to the investigation of pathophysiological processes in the effector phase of allergic asthma. Our research projects are centered to studies investigating the function of neutrophils and mast cells in allergic events. Our goal is to clarify the mechanisms by which neutrophils and mast cells contribute to the pathogenesis of asthma both during initiation and during exacerbation episodes and to analyze by which regulatory processes their activation and recruitment are controlled. Specific foci are the role of mast cell and neutrophil proteases, which are investigated in the context of their surrounding epithelial and endothelial barriers. In a new core project we investigate whether chronic inflammatory processes in asthma and COPD can be accompanied and regulated by autoimmune reactions.

 

CARE: Neutrophil proteinases as a pathomechanism in asthma and COPD

Neutrophils play an essential role as first-line effector cells in host defense against microbial invaders. However, neutrophil defense mechanisms such as proteinases or reactive oxygen metabolites have only a low selectivity and require an effective self-protection of the host by ubiquitously present inhibitors and scavengers. This delicate balance between host defense and tissue protection may be disturbed under certain pathological conditions, and the release of ROS and aggressive proteinases lead to at least partially irreversible damage to the tissue. Although the relevance of proteinases in the pathogenesis of asthma and COPD is well known, therapeutic approaches with corresponding inhibitors have remained largely unsuccessful. We are trying to identify reasons for this and aim to increase the efficiency of biologically effective proteinase inhibitors by novel strategies. In studies in vitro as well as in animal models in vivo, we were able to demonstrate that adherence of neutrophils is a prerequisite for proteolytical tissue damage. Activation-induced neutrophil adhesion creates a closed space between cell and substrate in which proteases and reactive oxygen species can exert tissue damaging without being accessible to exogenous inhibitors. In current studies, we examine whether the concurrent pharmacological attack on cell adherence and proteases could be a new therapeutic route in the treatment of chronic obstructive pulmonary disease.

 

CARE: Mast cells and mast cell proteinases as regulators of asthma

The pro-pathogenic function of mast cells and their mediators in allergic asthma is well described. Interestingly, most studies addressing the function of these cells in disease were focused on the analysis of the acute response to an allergen, while their role in chronic disease is much less understood. According to our hypothesis, the function of biologically active mediators may change completely during the course of the disease, so that a protective effect can evolve from an initially pathogenic mediator and vice versa. Therefore, the consideration of the chronicity in the mode of action of a mediator could be of central importance for the evaluation of its utility as a therapeutic target. We investigate this change in function using mast cell chymase and its murine equivalent MCP-4 as an example. Based on several findings in vitro, chymase has been suggested as a proinflammatory factor in the past. By contrast, recent results derived from an acute asthma model in vivo strongly indicate a protective role of mMCP-4 in this disease, excluding inhibition of the enzyme as a therapeutic strategy. Using MCP-4-deficient mice, we were able to show in a chronic asthma model that the effect of chymase changes from a protective to a pro-pathogenic function in the course of inflammation. In further investigations, we clarify causes and mechanisms of MCP-4 functional change during the course of the disease and examine the potential use of the enzyme as a potential therapeutic target in the treatment of allergic asthma.

 

INDIVIDUALIZED MEDICINE: Functional autoantibodies as novel biomarkers in asthma and COPD

While in the past autoimmunity has been associated primarily with rheumatic diseases, recent findings suggest an involvement of autoimmune processes in the pathogenesis of further, non-rheumatoic chronic disorders, too. Our investigations focused here on the role of so-called functional autoantibodies, which intervene in immunoregulation via a direct activation of cytokine and chemokine receptors. In a clinical pilot study within the DZL we are examining asthmatic and COPD patients whether functional autoantibodies to various receptors can be detected in these diseases. Initial results indicate that all three disease phenotypes express a characteristic signature of autoantibodies. By further characterization of such antibodies we will attempt to establish a new class of prognostic and diagnostic biomarkers for asthma and COPD. Since these antibodies may play a role in the regulation of disease processes, we also hope to identify new therapeutic targets here. In novel animal models, the efficacy of receptor agonists or antagonists as adjuvant therapeutics will be tested.