The role of Dectin-2 in immune complex-mediated inflammation

The formation of autoantibody-immune complexes (aab-ICs) is a hallmark of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus or the inflammatory form of epidermolysis bullosa acquisita, and IC-mediated pathologies are a significant cause of morbidity in humans. It is therefore of great importance to identify pathways and components mediating IC-induced pathologies. In preliminary in vivo studies, we observed a marked mitigation in aab-mediated experimental arthritis and a significantly reduced response to ICs in neutrophils and macrophages in vitro in mice lacking Dectin-2, an Fc receptor -chain associated CLR. Based on our preliminary findings, we hypothesize a fundamental functional role of Dectin-2 (known as Clec4n, Clec6) as pro-inflammatory type II FcR in the recognition of aab/ICs on myeloid cells. Accordingly, the main research questions of the planned project comprise: (1) How does Dectin-2 affect innate immune cells in aab-induced experimental arthritis? (2) Is Dectin-2 directly involved in vitro IC-stimulated cell responses of neutrophils and macrophages? (3) Is the recognition of ICs by Dectin-2 based on the glycosylation status of IgG-ICs? (4) Does Dectin-2 contribute to other immune complex mediated diseases? and (5) Does Dectin-2 play a role in aab-IC-stimulated human myeloid cells from healthy donors and patients with RA? To address these issues, Dectin-2 deficient mice will be used in aab-triggered, Fc receptor-dependent inflammatory models mimicking RA and dermatitis, and for IC-stimulated neutrophil or macrophage assays. Ig glycovariants will be studied in vitro for Dectin-2 binding and Dectin-2 variants or HoxB8 cells for rescue experiments. For translational aspects, Dectin-2 expression and its contribution in aab-IC recognition will be analysed in myeloid cells from RA patients. This project aims to identify Dectin-2 as a novel pro-inflammatory mediator of IC-mediated pathologies such as RA, inflammatory skin diseases, but also glomerulonephritis. By further clarifying, whether recognition of glycosylations in Igs might serve as targets for Dectin-2 binding, possibly delineates glycosylation of Igs and Dectin-2 as additional novel strategy for IC-mediated pathologies.