Novel Concepts of Altered Immunoglobulin G Galactosylation in Autoimmune Diseases.
Novel Concepts of Altered Immunoglobulin G Galactosylation in Autoimmune Diseases.
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DOI：
10.3389/fimmu.2018.00553
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发表时间：
2018
影响因子：
7.3
通讯作者：
Vidarsson G
中科院分区：
文献类型：
--
作者：
Dekkers G;Rispens T;Vidarsson G
免疫球蛋白 G (IgG) 中保守的 N297 聚糖的组成已被证明可通过补体系统的 C1q 和免疫细胞上的 Fc gamma 受体 (FcγR) 影响抗体效应器功能。 IgG-糖型总体水平的变化，例如在许多自身免疫性疾病中观察到的总 IgG 半乳糖基化降低，与疾病严重程度的升高有关。因此，无半乳糖化 IgG 被许多人视为促炎性的。然而，有些违反直觉的是，几个研究小组已证明半乳糖基化会降低对 FcγRIII 的亲和力并减少 C1q 结合和下游激活，这似乎与这种提议的促炎性质不一致。在这篇综述中，我们讨论了发现 IgG 半乳糖基化/糖基化改变的情况。我们基于这些观察结果和当前的生化证据提出了一种新模型，其中在总 IgG 中发现的 IgG 半乳糖基化水平影响自身抗体通过 C1q 或 FcγR 实现免疫激活所需的阈值。尽管该模型需要实验验证，但它得到了一些临床观察的支持，并协调了文献中的明显差异，并提出了 IgG 介导的自身免疫性疾病的一般机制。
The composition of the conserved N297 glycan in immunoglobulin G (IgG) has been shown to affect antibody effector functions via C1q of the complement system and Fc gamma receptors (FcγR) on immune cells. Changes in the general levels of IgG-glycoforms, such as lowered total IgG galactosylation observed in many autoimmune diseases have been associated with elevated disease severity. Agalactosyslated IgG has therefore been regarded and classified by many as pro-inflammatory. However, and somewhat counterintuitively, agalactosylation has been shown by several groups to decrease affinity for FcγRIII and decrease C1q binding and downstream activation, which seems at odds with this proposed pro-inflammatory nature. In this review, we discuss these circumstances where altered IgG galactosylation/glycosylation is found. We propose a novel model based on these observations and current biochemical evidence, where the levels of IgG galactosylation found in the total bulk IgG affect the threshold required to achieve immune activation by autoantibodies through either C1q or FcγR. Although this model needs experimental verification, it is supported by several clinical observations and reconciles apparent discrepancies in the literature, and suggests a general mechanism in IgG-mediated autoimmune diseases.