Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease.
Cell
; 172(3): 564-577.e13, 2018 01 25.
Article
em En
| MEDLINE
| ID: mdl-29275858
ABSTRACT
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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Siálicos
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Doenças Autoimunes
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Imunoglobulina G
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Processamento de Proteína Pós-Traducional
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Imunoterapia
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article