Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease

• Published in: Cell Vol. 172; no. 3; pp. 564 - 577.e13
• Main Authors: Pagan, Jose D., Kitaoka, Maya, Anthony, Robert M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2018
• Subjects: Animals; Antibody; autoimmune disease therapy; Autoimmune Diseases - immunology; Autoimmune Diseases - therapy; Cells, Cultured; Female; Glycosylation; HEK293 Cells; Humans; Immunoglobulin G - immunology; Immunoglobulin G - metabolism; Immunotherapy - methods; inflammation; Mice; Mice, Inbred C57BL; platelets; Protein Processing, Post-Translational; sialic acid; Sialic Acids - metabolism; Sialyltransferases - genetics; Sialyltransferases - metabolism; glycosylation; autoimmune disease therapy; Antibody; sialic acid; inflammation; platelets
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.11.041

Self-reactive IgGs contribute to the pathology of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Paradoxically, IgGs are used to treat inflammatory diseases in the form of high-dose intravenous immunoglobulin (IVIG). Distinct glycoforms on the IgG crystallizable fragment (Fc) dictate these divergent functions. IgG anti-inflammatory activity is attributed to sialylation of the Fc glycan. We therefore sought to convert endogenous IgG to anti-inflammatory mediators in vivo by engineering solubilized glycosyltransferases that attach galactose or sialic acid. When both enzymes were administered in a prophylactic or therapeutic fashion, autoimmune inflammation was markedly attenuated in vivo. The enzymes worked through a similar pathway to IVIG, requiring DC-SIGN, STAT6 signaling, and FcγRIIB. Importantly, sialylation was highly specific to pathogenic IgG at the site of inflammation, driven by local platelet release of nucleotide-sugar donors. These results underscore the therapeutic potential of glycoengineering in vivo. [Display omitted] •Glycosyltransferase fusions convert endogenous IgG into anti-inflammatory IgG•Platelets enable site-specific sialylation by releasing sugar-nucleotide donors•Inhibitory FcγRIIB, STAT6, and type II FcγRs are required for anti-inflammatory activity Endogenous pathogenic antibodies can be enzymatically converted into anti-inflammatory mediators in inflamed tissues, revealing a new strategy to treat autoimmune diseases.