Cell
Volume 172, Issue 3, 25 January 2018, Pages 564-577.e13
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Article
Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease

https://doi.org/10.1016/j.cell.2017.11.041Get rights and content
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Highlights

  • 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

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.

Keywords

Antibody
glycosylation
platelets
sialic acid
autoimmune disease therapy
inflammation

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