A Novel Role for the IgG Fc Glycan: The Anti-inflammatory Activity of Sialylated IgG Fcs
A Novel Role for the IgG Fc Glycan: The Anti-inflammatory Activity of Sialylated IgG Fcs
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DOI：
10.1007/s10875-010-9405-6
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发表时间：
2010-05-01
影响因子：
9.1
通讯作者：
Ravetch, Jeffrey V.
中科院分区：
文献类型：
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作者：
Anthony, Robert M.;Ravetch, Jeffrey V.
IgG抗体长期以来被认为是体液免疫应答的促炎介质。抗体结合并中和抗原以促进抗体依赖性细胞毒性、抗原的调理作用和吞噬作用的启动。尽管抗体的抗原特异性由抗原结合Fab部分决定，但由抗体引发的效应子功能由Fc（可结晶）结构域触发。这些效应子功能严重依赖于重链的单个N-连接双触角聚糖，其位于铰链区正下方。认为该聚糖将Fc的两条重链维持在与活化Fc γ受体（Fc γ R）相互作用所需的开放构象。然而，聚糖上存在特定糖部分对Fc效应子功能具有深远意义。向聚糖中添加末端唾液酸可降低Fc γ R结合，并通过获得新的结合活性将IgG抗体转化为抗炎介质。我们实验室的研究表明，这些唾液酸化IgG Fc对静脉注射免疫球蛋白的体内活性很重要。唾液酸化Fc不与Fc γ R结合，而是通过凝集素受体SIGN-R1或DC-SIGN启动抗炎级联反应。这导致炎性细胞上抑制性FcR（Fc γ RIIb）的表面表达上调，从而减弱自身抗体引发的炎症。
IgG antibodies have long been recognized as proinflammatory mediators of the humoral immune response. Antibodies bind and neutralize antigens to promote antibody-dependent cytotoxicity, opsonization of antigens, and the initiation of phagocytosis. Whereas the antigen specificity of antibodies is determined by the antigen-binding Fab portion, the effector functions initiated by antibodies are triggered by the Fc (crystallizable) domain. These effector functions are heavily dependent on the single N-linked, biantennary glycan of the heavy chain, which resides just below the hinge region. This glycan is believed to maintain the two heavy chains of the Fc in an open confirmation required for interactions with activating Fc gamma receptors (Fc gamma Rs). However, the presence of specific sugar moieties on the glycan has profound implications on Fc effector functions. The addition of terminal sialic acid to the glycan reduces Fc gamma R binding and converts IgG antibodies to anti-inflammatory mediators through the acquisition of novel binding activities. Studies from our laboratory demonstrated that these sialylated IgG Fcs are important for the in vivo activity of intravenous immunoglobulin. Instead of binding with Fc gamma Rs, sialylated Fcs initiate an anti-inflammatory cascade through the lectin receptor SIGN-R1 or DC-SIGN. This leads to upregulated surface expression of the inhibitory FcR, Fc gamma RIIb, on inflammatory cells, thereby attenuating autoantibody-initiated inflammation.