Study of granuloma and giant cell formation in autoinfammatory diseases: focus on NOD2-associated Blau syndrome and Crohn's disease

Granulomas are organized aggregates of predominantly macrophages which fuse into multinucleated giant cells. In infectious diseases, granuloma formation is seen as a response of the immune system to remove persistent pathogens. However, granulomas are also seen in immune disorders without any obvious infectious trigger, including autoimmune and autoinflammatory diseases. In these disorders it is not known why granulomas arise and how giant cells are formed, and little information is available about their pathophysiological properties. In this project we will address the process of giant cell and granuloma formation in Blau syndrome and Crohn's disease, two granulomatous autoinflammatory disorders associated with genetic mutations in NOD2, an intracellular pathogen recognition receptor that may have a role in giant cell formation. Experiments will be performed with blood cells of these patients and healthy controls, and in mice with a NOD2 mutation. Using complementary and cutting-edge technologies, including live cell analysis, advanced flow cytometry, RNA sequencing and proteomics, we will identify the molecular and functional changes in macrophages during the fusion process. Biopsies from granulomas of patients represent an opportunity to validate our findings. The results obtained will provide new insights into the pathophysiology of multinucleated giant cells and granulomas in multiple diseases ranging from infections to autoimmune and autoinflammatory diseases to cancer.