A Temporal Model of Human IgE and IgG Antibody Function.
A Temporal Model of Human IgE and IgG Antibody Function.
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DOI：
10.3389/fimmu.2013.00235
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发表时间：
2013
影响因子：
7.3
通讯作者：
Jackson KJ
中科院分区：
文献类型：
--
作者：
Collins AM;Jackson KJ
由V(D)J基因重排产生的人类抗体库的多样性因九个恒定区基因而得以扩展，这些基因赋予抗体复杂多样的效应功能。高通量测序在V(D)J基因重排研究中的应用使我们对抗体结合库的理解近期有了重大进展。相比之下，我们对抗体功能的理解变化不大，四种不同的IgG亚类的存在仍然充满神秘。来自小鼠模型以及人类VDJ体细胞点突变研究的近期观察结果表明，生发中心细胞出现的时间可能因类别转换而有所不同。这应该会导致同种型之间亲和力的可预测差异。这些差异以及同种型固定补体和结合Fc受体的不同能力，可能有助于在免疫应答过程中协调体液防御。因此，我们提出了一个人类IgE和IgG功能的时间模型，在该模型中，IgE的早期出现使哨兵肥大细胞致敏，而转换为IgG3则将FcγR介导的功能招募到早期应答中。然后IgG1作为抗原清除的主要效应分子出现，随后IgG2与IgG1竞争以产生免疫复合物，从而减缓炎症驱动。持续存在的抗原可能最终刺激高亲和力的IgG4，它胜过其他同种型，并可通过抑制性FcγRIIB终止IgG1/FcγR介导的激活。通过这种方式，不同亚类、不同浓度且有时功能相反的IgG抗体提供了内聚的保护性免疫功能。
The diversity of the human antibody repertoire that is generated by V(D)J gene rearrangement is extended by nine constant region genes that give antibodies their complex array of effector functions. The application of high throughput sequencing to the study of V(D)J gene rearrangements has led to significant recent advances in our understanding of the antigen-binding repertoire. In contrast, our understanding of antibody function has changed little, and mystery still surrounds the existence of four distinctive IgG subclasses. Recent observations from murine models and from human studies of VDJ somatic point mutations suggest that the timing of emergence of cells from the germinal center may vary as a consequence of class switching. This should lead to predictable differences in affinity between isotypes. These differences, and varying abilities of the isotypes to fix complement and bind FcRs, could help coordinate the humoral defenses over the time course of a response. We therefore propose a Temporal Model of human IgE and IgG function in which early emergence of IgE sensitizes sentinel mast cells while switching to IgG3 recruits FcγR-mediated functions to the early response. IgG1 then emerges as the major effector of antigen clearance, and subsequently IgG2 competes with IgG1 to produce immune complexes that slow the inflammatory drive. Persisting antigen may finally stimulate high affinity IgG4 that outcompetes other isotypes and can terminate IgG1/FcγR-mediated activation via the inhibitory FcγRIIB. In this way, IgG antibodies of different subclasses, at different concentrations and with sometimes opposing functions deliver cohesive, protective immune function.
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