Autoantibodies, which recognize autoantigens (i.e., self-antigens), serve as both hallmarks and diagnostic markers of autoimmune diseases. Although autoimmune disease mechanisms are complex and involve various humoral and cellular immune responses, some are exclusively dependent on the presence of autoantibodies. Upon binding to their cognate autoantigens, self-reactive antibodies induce effector mechanisms of immunity through complement activation and/or Fc receptor binding. The resulting autoantibody-mediated effector mechanisms lead to chronic inflammation and the eventual tissue damage symptomatic of autoimmune disease. The effector functions mediated by IgG antibodies, whether they recognize self or foreign antigens, are entirely dependent on the presence of an N-linked complex type glycan on Asn297 of the IgG Fc region, which enables the antibody to bind Fc γ receptors (FcγRs) and activate complement, endowing the antibody with immune signaling capabilities. Endoglycosidases (i.e., enzymes that remove glycans from glycoproteins) can remove the glycan molecule linked to Asn297 and render IgG antibodies immunologically inert. Of all the known endoglycosidases, Endoglycosidase S (EndoS) is unique in that it removes only the Asn297-linked glycan from IgG antibodies. Due to its IgG-specific properties, EndoS pretreatment of pathological autoantibodies and/or injection of purified EndoS in animal models of autoimmunity has been shown to protect against or alleviate the symptoms of many autoimmune diseases. Although EndoS is exquisitely specific to IgG antibodies, it has no capacity to discriminate between antibodies with different antigen specificities. Instead, EndoS deglycosylates all IgG antibodies, including those that keep cancer in check, as well as those that are specific to foreign antigens that provide defense from infections. Engineering EndoS such that it recognizes and deglycosylates only autoantibodies, as opposed to all IgG antibodies, is essential for making a truly specific autoimmunity drug. We hypothesize that we can translate EndoS from an autoimmune disease therapeutic of great potential to one of actual clinical utility by constructing fusion proteins of EndoS linked to autoantigens (EndoS-autoAg) that will drive the targeted deglycosylation and inactivation of pathological autoantibodies, while leaving the remainder of the immune system functionally intact. We will provide proof-of-principle for this concept by: (1) optimizing EndoS-autoAg fusion protein properties for specificity and activity in vitro; and (2) investigating EndoS-autoAg fusion protein efficacy and specificity in vivo using a mouse model of autoimmune epidermolysis bullosa acquisita (EBA).