Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease

Cell. 2018 Jan 25;172(3):564-577.e13. doi: 10.1016/j.cell.2017.11.041. Epub 2017 Dec 21.


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; autoimmune disease therapy; glycosylation; inflammation; platelets; sialic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / therapy
  • Cells, Cultured
  • Female
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism*
  • Immunotherapy / methods*
  • Mice
  • Mice, Inbred C57BL
  • Protein Processing, Post-Translational*
  • Sialic Acids / metabolism*
  • Sialyltransferases / genetics
  • Sialyltransferases / metabolism


  • Immunoglobulin G
  • Sialic Acids
  • Sialyltransferases