Deutsche Forschungsgemeinschaft, Cluster of Excellence "Inflammation at Interfaces" [EXC 306/1, EXC 306/2]; Swedish Research Council [2010-57X-20240]; Foundation of Ake Wiberg; Foundation of Alfred Osterlund; Foundation of King Gustaf V's 80 years fund; Foundation of Hansa Medical AB; Medical College of Xiamen University ; Endo-beta-N-acetylglucosaminidase (EndoS) has been shown to act as a potent pathogen-derived immunomodulatory molecule in autoimmune diseases. Here we investigated how EndoS treatment reduces the pathogenicity of rabbit anti-mCOL7 IgG using different experimental models of epidermolysis bullosa acquisita (EBA). Our results show that the EndoS treatment does not interfere with the binding of the antibody to the antigen but reduces immune complex (IC)-mediated neutrophil activation by impairing the binding of the IC to Fc gamma R on neutrophils. On the basis of this newly identified EndoS-mediated mechanism we hope to develop new strategies in the treatment of the disease.