Urlaub D, Zhao S, Blank N, et al. - In a series of in vitro experiments, using peripheral blood mononuclear cells (PBMCs), B cell depletion, natural killer (NK) cell degranulation, and the expression of CD69 and CD16 on NK cells were measured to examine whether NK cells may play a part in rituximab’s mechanism of action in granulomatosis with polyangiitis (GPA, a non-malignant, life-threatening systemic inflammatory disease). Through immobilized rituximab, NK cells from GPA patients were activated. Moreover, soluble rituximab activated NK cells revealed the presence of B cells. Reduction in the NK cells degranulated and expressed the activation marker CD69 while CD16 expression was noted. This activation of NK cells by soluble rituximab was followed by a decrease of B cells. In comparison with rituximab, the next-generation anti-CD20 antibody obinutuzumab showed a more robust impact on both the decrease of B cells and the activation of NK cells. Subsequently, rituximab resulted in the activation of NK cells in vivo, given that B cells were not depleted because of former rituximab infusions. Thus, in GPA, B cell-bound rituximab activates NK cells. While NK cells, hence, took part in rituximab’s mechanism of action in humans, their potential could be more effectively misused, like by Fc engineering of therapeutic antibodies.