[PDF][PDF] Engineered sialylation of pathogenic antibodies in vivo attenuates autoimmune disease

JD Pagan, M Kitaoka, RM Anthony - Cell, 2018 - cell.com
JD Pagan, M Kitaoka, RM Anthony
Cell, 2018cell.com
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 …
Summary
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.
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