General mechanism for modulating immunoglobulin effector function
General mechanism for modulating immunoglobulin effector function
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DOI：
10.1073/pnas.1307864110
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发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Ravetch, Jeffrey V.
中科院分区：
文献类型：
--
作者：
Sondermann, Peter;Pincetic, Andrew;Ravetch, Jeffrey V.
免疫球蛋白通过Fc激活的可变区特异性偶联识别和清除微生物病原体和毒素。这些致炎活性受到调节，从而通过调节Fc连接的多糖的组成来避免不受控制的炎症的致病后遗症。唾液酸化后，Fcγ受体的亲和力降低，而与其他细胞受体的亲和力增加，如树突状细胞特异性细胞间黏附分子-3抓取非整合素(DC-SIGN)/CD23。我们证明唾液酸化诱导了C-Gamma 2结构域的显著变化，并提出了一个模型来解释观察到的配体特异性和生物活性的变化。通过与Ig E与其进化上相关的Fc受体形成的相关复合体的类比，我们得出结论：这一机制对抗体触发的免疫反应具有普遍的调节作用，其特征是抗体Fc片段的“开放”激活构象与“封闭”抗炎状态之间的转变。这种常见的机制已经成为病原体的靶点，以避免宿主防御，并为过敏性和自身免疫性疾病的治疗干预提供了靶点。
Immunoglobulins recognize and clear microbial pathogens and toxins through the coupling of variable region specificity to Fc-triggered cellular activation. These proinflammatory activities are regulated, thus avoiding the pathogenic sequelae of uncontrolled inflammation by modulating the composition of the Fc-linked glycan. Upon sialylation, the affinities for Fc gamma receptors are reduced, whereas those for alternative cellular receptors, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)/CD23, are increased. We demonstrate that sialylation induces significant structural alterations in the C gamma 2 domain and propose a model that explains the observed changes in ligand specificity and biological activity. By analogy to related complexes formed by IgE and its evolutionarily related Fc receptors, we conclude that this mechanism is general for the modulation of antibody-triggered immune responses, characterized by a shift between an "open" activating conformation and a "closed" anti-inflammatory state of antibody Fc fragments. This common mechanism has been targeted by pathogens to avoid host defense and offers targets for therapeutic intervention in allergic and autoimmune disorders.