Priority Research Area Chronic Lung Diseases

Immunology and Cell Biology

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Projects

Leibniz-Gemeinschaft „ImmunoPROteasomes in LUNG health and disease“ – PRO-LUNG

We here explore the concept that the inducible nature of the immunoproteasome enables dynamic adaptation of proteasome function in immune and stress responses. In particular, we aim to understand whether standard, immuno- and the various types of mixed proteasomes have distinct functions e.g. by localizing to distinct cell types or subcellular sites, degrading different substrates, or by interacting with defined proteasome regulators. Solving these questions is key for a detailed understanding of the function of immunoproteasomes in health and disease. It will pave the way for validation of the immunoproteasome as a therapeutic target allowing specific inhibition of single or multiple immunoproteasome subunits in disease with novel site-specific immunoproteasome inhibitors that are currently being developed.

 

Leibniz Center for Infection: “Sex-specific regulation of immunoproteasome function determines response to infection“ (together with Bianca Schneider, FZB)

In this project, we investigate the (biological) sex-specific regulation of the immunoproteasome and whether this might contribute to the stronger immune responses against infections in females. We are using influenza and tuberculosis-related infection models in female and male mice to dissect the immunoproteasome related immune response as well as in vitro cellular models for sex-hormone treatment. The aim is to unravel the molecular basis of sex-related regulation of the immunoproteasome, which may enable us to develop sex-specific diagnostic tools and target the immunoproteasome therapeutically in a sex-related manner.

 

Regulation of MrgprB2-mediated mast cell activation by tetraspanin CD37

MC receptor associated with nociception and type 2 inflammation is MrgprB2 (Mas-related G-protein coupled receptor member B2). MrgprB2 is receptor sensing heterocyclic chemical compounds, endo-/exogenous peptides, and neuropeptides involved in the perception of pain and itch. MrgprB2 ligands are chemical compounds and bioactive peptides which induce MC activation, their degranulation, selective release of different mediators and local or systemic inflammation.

How MrgprB2-mediated MC degranulation is regulated, and whether membrane proteins affect MrgprB2-ligand binding and specificity, is unknown. We identified tetraspanin CD37 as regulator of MrgprB2-mediated MC response. Our initial findings indicate the existence of stimulus-specific regulatory mechanisms of MrgprB2-mediated MC response and characterize CD37 as negative regulator of MrgprB2-mediated MC activation.

 

Epitope-specific CD37 targeting in mouse as tool to modulate B cell function

CD37 is glycosylated membrane protein highly expressed in B cells. As other tetraspanins CD37 is involved in regulation of incoming receptor-derived signals, lateral membrane protein interactions and intracellular signal processing. Here we are characterizing mouse CD37-specific monoclonal antibodies and investigating the effects of epitope-specific CD37 targeting in vitro and in vivo. Targeting of different CD37-epitopes had differential effects on purified B cells in vitro and resulted in depletion of different B cell subsets in vivo. We aim to dissect mechanisms responsible for B cell depletion potentially interesting for treatment of autoimmune diseases and induction of immune response important in development of new vaccine technologies in further experiments.