General mechanism for modulating immunoglobulin effector function

被引：182

作者：

Sondermann, Peter ^{[1
]}

Pincetic, Andrew ^{[2
]}

Maamary, Jad ^{[2
]}

Lammens, Katja ^{[3
]}

Ravetch, Jeffrey V. ^{[2
]}

机构：

[1] SuppreMol GmbH, D-82152 Martinsried, Germany

[2] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA

[3] Univ Munich, Gene Ctr, D-81377 Munich, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 24期

基金：

美国国家卫生研究院;

关键词：

conformational change; sialylated IgG Fc; FC-EPSILON-RI; HUMAN-IGG-FC; ANTIINFLAMMATORY ACTIVITY; DC-SIGN; CRYSTAL-STRUCTURE; CD23; GLYCOSYLATION; BINDING; FRAGMENT; REVEALS;

D O I：

10.1073/pnas.1307864110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：9868 / 9872

页数：5

共 28 条

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