Unraveling the mechanisms of antibody-dependent inflammation

Antibodies cannot only bind to and neutralize pathogens, but have several additional effector functions. The most frequently mentioned “textbook” effector functions include antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In this thesis, we further establish an important additional effector function of human antibodies: antibody-dependent inflammation (ADI). ADI is important to provide proper immune responses upon infection with various types of pathogens, but can also have adverse effects when activated excessively or undesirably. Because of its inflammatory potential, ADI is tightly controlled and critically depends on the fulfillment of four criteria: (1) the formation of immune complexes, (2) the availability of a co-stimulus (provided by other receptors such as TLRs), (3) the intrinsic properties of the antibody (isotype, subclass, and glycosylation), and (4) the location of the antibody-immune complexes. Understanding these ADI “safety switches”, which combined determine when and where ADI is activated in the human body gives insight in how our immune system is regulated but also how over activation of ADI causes disease. This thesis also described how ADI could be activated or inhibited therapeutically, to promote host defense or to counteract chronic or excessive inflammation.