Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 18, Pages E2385-E2394Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1505292112
Keywords
IgG Fc sialylation; conformational change; antiinflammatory; T-reg cells
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Funding
- Merck Sharp Dohme
- Deutsche Forschungsgemeinschaft [FI 2035/1-1]
- Ludwig Fellowship Program
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The antiinflammatory activity of intravenous immunoglobulin (IVIG) is dependent on the presence of sialic acid in the core IgG fragment crystallizable domain (Fc) glycan, resulting in increased conformational flexibility of the C(H)2 domain with corresponding modulation of Fc receptor (FcR) binding specificity from type I to type II receptors. Sialylated IgG Fc (sFc) increases the activation threshold of innate effector cells to immune complexes by stimulating the up-regulation of the inhibitory receptor Fc gamma RIIB. We have found that the structural alterations induced by sialylation can be mimicked by specific amino acid modifications to the C(H)2 domain. An IgG Fc variant with a point mutation at position 241 (F -> A) exhibits antiinflammatory activity even in the absence of sialylation. F241A and sFc protect mice from arthritis in the K/BxN-induced model and, in the T cell-mediated experimental autoimmune encephalomyelitis (EAE) mouse model, suppress disease by specifically activating regulatory T cells (T-reg cells). Protection by these antiinflammatory Fcs in both antibody- and T cell-mediated autoimmune diseases required type II FcRs and the induction of IL-33. These results further clarify the mechanism of action of IVIG in both antibody- and T cell-mediated inflammatory diseases and demonstrate that Fc variants that mimic the structural alterations induced by sialylation, such as F241A, can be promising therapeutic candidates for the treatment of various autoimmune disorders.
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