Role of multinucleated giant cells in granulomatous autoinflammatory disease: Focus on NOD2-associated Blau syndrome

Granulomas are organized clusters of macrophages and other immune cells that can occur in both infectious and non-infectious diseases. In granuloma formation, macrophages differentiate into epithelioid cells, which then undergo cell fusion to form multinucleated giant cells (MGCs). Three subtypes of MGCs are distinguished, namely Langhans giant cells (LGCs), foreign body giant cells (FBGCs) and osteoclasts. Nucleotide-binding oligomerization domain 2 (NOD2) is a pattern recognition receptor in the cytosol of innate immune cells. Gain-of-function mutations in NOD2 are associated with Blau syndrome (BS). BS is a rare paediatric monogenetic disorder characterized by polyarthritis, uveitis, and dermatitis. Furthermore, granulomas can be found in various organs of BS patients. The causes, mechanisms and pathophysiological consequences of MGC and granuloma formation in inflammatory diseases are hardly known. In addition, pathways for macrophage differentiation as well as the origin and functional properties of MGCs in autoinflammatory diseases remain poorly understood. BS is a suitable model to study this and the possible role of NOD2 in granuloma formation. This research aims to elucidate the formation and functions of MGCs and granulomas in the context of infectious and non-infectious diseases. We hypothesize that mutations in NOD2 affect the function and properties of macrophages in BS. In addition, it is hypothesized that the LGC interacts with T cells, thereby contributing to granuloma formation and maintenance.