IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis

Abstract

Studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, have shown that B cells markedly influence the course of the disease, although whether their effects are protective or pathological is a matter of debate. EndoS hydrolysis of the IgG glycan has profound effects on IgG effector functions, such as complement activation and Fc receptor binding, suggesting that the enzyme could be used as an immunomodulatory therapeutic agent against IgG-mediated diseases. We demonstrate here that EndoS has a protective effect in myelin oligodendrocyte glycoprotein peptide amino acid 35–55 (MOG35-55)-induced EAE, a chronic neuroinflammatory demyelinating disorder of the central nervous system (CNS) in which humoral immune responses are thought to play only a minor role. EndoS treatment in chronic MOG35-55-EAE did not impair encephalitogenic T cell priming and recruitment into the CNS of mice, consistent with a primary role of EndoS in controlling IgG effector functions. In contrast, reduced EAE severity coincided with poor serum complement activation and deposition within the spinal cord, suggesting that EndoS treatment impairs B cell effector function. These results identify EndoS as a potential therapeutic agent against antibody-mediated CNS autoimmune disorders.

Targeting B cells in the treatment of multiple sclerosis: recent advances and remaining challenges

“…Mechanistically, it is clear that these antibodies alone are not capable of initiating EAE in otherwise naïve animals. However, certain studies suggest that they may facilitate CNS damage and promote progression of ongoing EAE [Benkhoucha et al 2012]. More than 20 years ago, Schluesener and colleagues reported that intravenous administration of a monoclonal antibody against MOG enhanced CNS demyelination and induced fatal relapses in a rodent disease model [Schluesener et al 1987].…”

EndoSd: An IgG Glycan Hydrolyzing Enzyme in Streptococcus Dysgalactiae Subspecies Dysgalactiae

“…Therefore, enzymes with activity on these glycans could be developed as pharmaceuticals against antibody mediated autoimmune diseases. Toward that end, EndoS has been successful as experimental treatment in a number of animal models of antibody mediated autoimmunity, including arthritis, systemic lupus erythematosus, multiple sclerosis, autoimmune kidney disease and autoimmune blistering skin diseases [20,22,[50][51][52][53][54][55][56]. This work, which is based on the functional similarities between EndoSd from SDSD and EndoS from S. pyogenes emphasize the close evolutionary relationship between the species and contributes to a deeper understanding of the biology of immune evasion by bacterial pathogens.…”

Bacterial Modulation of Fc Effector Functions

“…These include arthritis, systemic lupus erythematosus (SLE), autoimmune thrombocytopenia, autoimmune hemolysis, bullous skin disease, autoimmunity of the kidney, and multiple sclerosis. [95][96][97][98][99][100][101][102] Furthermore, it has recently been demonstrated that pathogenic antibodies from neuromyelitis optica can be transformed into potentially therapeutic antibodies by ex vivo treatment with EndoS. 103 Since the discovery of EndoS, several structurally or functionally related enzymes have been identified in other bacterial pathogens.…”