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标题：Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs
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作者：Benjamin M. Fiebiger ; Jad Maamary ; Andrew Pincetic 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：18
页码：E2385-E2394
DOI：10.1073/pnas.1505292112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceIgG molecules are capable of inducing pro- and antiinflammatory responses dependent on their fragment crystallizable domain (Fc) glycan composition. Antiinflammatory responses are specifically triggered upon Fc sialylation, which decreases the binding affinity for type I Fc receptors but enhances binding to type II Fc receptors such as SIGN-R1, CD23, or human DC-SIGN. Structural analyses revealed that sialylation induces conformational changes in the Fc portion, which is a prerequisite for the selective binding to type II Fc receptors. Here we generated an Fc variant, F241A, that mimics the conformational state of sialylated Fc. F241A, even when nonsialylated, mediated protection from autoantibody- and T cell-mediated inflammation in a type II Fc receptor-dependent manner. 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 CH2 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 CH2 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 (Treg 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.
关键词：IgG Fc sialylation ; conformational change ; antiinflammatory ; T_reg cells