Effect of interleukin-6 on IgG antibody glycosylation

IL-6对IgG抗体糖基化的影响

• 批准号: 400912066
• 负责人: Professor Dr. Marc Ehlers
• 金额: --
• 依托单位: Institut für Ernährungsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/400912066?language=en
• 关键词: Effect; interleukin; IgG; antibody; glycosylation

IL-6 is crucial for mounting protective T cell-dependent (TD) IgG antibody (Ab) responses but also for development of IgG-mediated autoimmune pathologies. IL-6 acts at various stages of an immune response, including the interaction between dendritic cells and CD4+ T cells and later in the germinal center (GC) reaction during Ab affinity maturation and generation of IgG subclass memory B cells and plasma cells (PCs).However, accumulating evidence suggest that not only the IgG subclass but also the structure of an N-linked glycan attached to the Fc domain of IgG Abs modulates IgG effector functions. Non-(a)galactosylated IgG Abs are associated with inflammatory actions e.g. in rheumatoid arthritis (RA) patients, whereas galactosylated plus terminal sialylated IgG Abs have reduced inflammatory potential and may suppress immune reactions.We recently showed in mice that the inflammatory environment determines the type of antigen-specific IgG glycosylation during the GC reaction by programming the CD4+ T follicular helper cell response that regulates the expression level of the corresponding glycosyltransferases in IgG+ GC B cells and PCs.However, it remains unclear what cytokine milieu is necessary for setting the GC environment for setting the IgG glycosylation pattern. Preliminary data suggest that IL-6 deficient mice fail to induce agalactosylated IgG Abs in response to strong inflammatory immunizations.We therefore hypothesise that IL-6 plays an essential role during cellular interactions prior to, and/or during, the GC reaction to set the inflammatory IgG glycosylation pattern. However, how IL-6 influences IgG glycosylation is unclear, also because IL-6 can act via three signaling routes:I) Classical-signaling describes binding of IL-6 to membrane-bound IL-6R and then to the membrane-bound signaling subunit gp130 on the same cell.II) Trans-signaling describes binding of IL-6 to soluble IL-6R, which allows activation of cells that only express gp130.III) The recently described trans-presentation describes binding of IL-6 produced e.g. by dendritic cells to IL-6R on the same cell for activating gp130 on another cell (e.g. CD4+ T cell).In this project, we will explore through which cells and signaling route(s) IL-6 modulates IgG glycosylation. We will study the effect of IL-6 on T follicular helper cell differentiation and glycosyltransferases expression in IgG+ GC B cells and PCs generated upon TD immunization by using an array of conditional knockout and transgenic mice. Finally, we will study a therapeutic effect of IL-6 interference on IgG glycosylation by blocking IL-6 signaling in autoimmune mouse models and RA patients.Together, we expect that this study would provide better understanding of the mechanisms behind differential programming of IgG glycosylation during GC-dependent responses and define a therapeutic potential of modulating IL-6 signaling to reprogram pathogenic IgG glycosylation for treating autoimmune disorders.

IL-6对建立保护性T细胞依赖性（TD） IgG抗体（Ab）反应至关重要，但也对IgG介导的自身免疫病理的发展至关重要。IL-6在免疫反应的各个阶段起作用，包括树突状细胞和CD4+ T细胞之间的相互作用，以及后来在Ab亲和成熟过程中的生发中心（GC）反应和IgG亚类记忆B细胞和浆细胞（PCs）的产生。然而，越来越多的证据表明，不仅是IgG亚类，而且附着在IgG抗体Fc结构域的n -链聚糖的结构也能调节IgG的效应功能。非(a)半乳糖化IgG抗体与炎症反应有关，例如在类风湿关节炎（RA）患者中，而半乳糖化加上末端唾液化的IgG抗体具有降低炎症潜能并可能抑制免疫反应。我们最近在小鼠实验中发现，炎症环境通过编程CD4+ T滤泡辅助细胞反应来决定GC反应中抗原特异性IgG糖基化的类型，该反应调节IgG+ GC B细胞和pc中相应糖基转移酶的表达水平。然而，目前尚不清楚什么细胞因子环境是设置GC环境设置IgG糖基化模式所必需的。初步数据表明，IL-6缺陷小鼠在强炎症免疫反应中不能诱导无半乳糖化IgG抗体。因此，我们假设IL-6在GC反应之前和/或期间的细胞相互作用中发挥重要作用，以设置炎症性IgG糖基化模式。然而，IL-6如何影响IgG糖基化尚不清楚，也因为IL-6可以通过三种信号通路起作用：1)经典信号通路描述IL-6与膜结合的IL-6R结合，然后与同一细胞上的膜结合信号亚基gp130结合。II)反式信号传导描述了IL-6与可溶性IL-6R的结合，这允许只表达gp130的细胞活化。III)最近描述的递呈描述了IL-6的结合，例如由树突状细胞与同一细胞上的IL-6R结合，以激活另一个细胞（例如CD4+ T细胞）上的gp130。在这个项目中，我们将探索通过哪些细胞和信号通路IL-6调节IgG糖基化。我们将通过一系列条件敲除和转基因小鼠研究IL-6对T滤泡辅助细胞分化和糖基转移酶表达的影响。最后，我们将在自身免疫性小鼠模型和RA患者中研究IL-6干扰通过阻断IL-6信号通路对IgG糖基化的治疗作用。总之，我们期望这项研究能够更好地理解gc依赖性应答中IgG糖基化差异编程背后的机制，并确定调节IL-6信号来重编程致病性IgG糖基化以治疗自身免疫性疾病的治疗潜力。