Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs
Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs
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DOI：
10.1073/pnas.1505292112
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发表时间：
2015-05-05
影响因子：
11.1
通讯作者：
Ravetch, Jeffrey V.
中科院分区：
文献类型：
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作者：
Fiebiger, Benjamin M.;Maamary, Jad;Ravetch, Jeffrey V.
静脉注射免疫球蛋白（IVIG）的抗炎活性依赖于核心IgG片段结晶结构域（Fc）聚糖中唾液酸的存在，从而增加C(H)2结构域的构象灵活性，并相应地调节Fc受体（FcR）从I型到II型受体的结合特异性。唾液化IgG Fc （sFc）通过刺激抑制受体Fc γ RIIB的上调，提高先天效应细胞对免疫复合物的激活阈值。我们发现唾液化引起的结构改变可以通过对C(H)2结构域的特定氨基酸修饰来模拟。在241位（F -> a）发生点突变的IgG Fc变体即使在没有唾液化的情况下也表现出抗炎活性。在K/ bxn诱导的模型中，F241A和sFc保护小鼠免受关节炎的影响，在T细胞介导的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中，F241A和sFc通过特异性激活调节性T细胞（T-reg细胞）来抑制疾病。这些抗炎Fcs在抗体和T细胞介导的自身免疫性疾病中的保护作用需要II型fcr和IL-33的诱导。这些结果进一步阐明了IVIG在抗体和T细胞介导的炎症性疾病中的作用机制，并证明了模仿唾液化诱导的结构改变的Fc变体，如F241A，可能是治疗各种自身免疫性疾病的有希望的治疗候选物。
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.