Potential and mutual interference of differently N-glycosylated murine and humane IgG and IgA subclass antibodies during IgG-mediated anaphylaxis

不同 N-糖基化的鼠类和人 IgG 和 IgA 亚类抗体在 IgG 介导的过敏反应过程中的潜在干扰和相互干扰

• 批准号: 398859914
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398859914?language=en
• 关键词: Potential; mutual; interference; differently; glycosylated

IgE antibodies (Abs) can mediate allergic reactions, including systemic anaphylaxis, by activating FcεRI on e.g. mast cells, leading to release of histamine. Allergen-specific IgG Abs, which are also induced by allergen-specific immunotherapies (AITs), can inhibit IgE-mediated anaphylaxis through allergen masking and crosslinking of FcεRI with the classical IgG inhibitory receptor FcyRIIb.However, when allergen levels are high, IgG Abs induced in untreated and AIT-treated allergic patients, as well as to medical drugs (Biologica), also have the potential to mediate anaphylaxis by stimulating classical activating FcyRs on different immune cell types.Effector functions of IgG Abs depend on their subclass and type of Fc N-glycosylation. Agalactosylated IgG Abs are associated with pro-inflammatory effector functions, whereas galactosylated plus terminal sialylated IgG Abs act less or even anti-inflammatory. Differently glycosylated IgG Abs interact not only with classical FcyRs but, depending on the terminal sugar motive, also with C-type lectin receptors. IgA has several Fc N-glycosylation sides, but their influence on the effector function is unclear.We could show that- immunizations of mice with protein antigens and distinct adjuvants induce different IgG subclasses and Fc N-glycosylation patterns und that these distinct IgG compositions have different potentials to induce IgG-mediated anaphylaxis (Oefner et al, JACI 2012; Hess et al, JCI 2013; Epp et al, JACI 2017).- accordingly, the IgG-mediated anaphylaxis highly depends on the IgG subclass and their type of Fc N-glycosylation; sialylation reduces the anaphylactic potential of particular IgG1 (which functionally resembles human IgG4) and of IgG2b (but hardly of IgG2a, which functionally resembles human IgG1) through the C-type lectin receptor SignR1 (Epp et al, 2017).- in addition, sialylated murine IgG1 and IgA inhibits an anaphylaxis induced with agalactosylated IgG2b.- in patients a conventional AIT with birch pollen extract and the adjuvant Alum induces first IgG1 and then IgG4 Abs that are sialylated and show anti-inflammatory functions (Epp et al, 2017).Here, we further want to analyze the potential and mutual interference of differently glycosylated murine and human IgG and IgA subclass Abs by using our mouse modeI of IgG-mediated anaphylaxis also with humanized mice. We want e.g. to investigate- on which cells SignR1 is responsible for the inhibitory effect of the sialic acid; here we will also investigate the role of platelets whose activation has recently been described to be the first step in IgG-mediated anaphylaxis.- whether sialylation of human IgG4 also stronger inhibits its anaphylactic potential than that of human IgG1.- whether sialylated human IgG4 and IgA can also inhibit a human IgG1-induced anaphylaxis and how.These studies will help to better predict the risk of an allergic reaction and the success of AIT protocols in future.

IgE抗体（Abs）可通过激活肥大细胞（如肥大细胞）上的FcεRI，导致组胺释放，介导过敏反应，包括全身性过敏反应。同样由过敏原特异性免疫疗法（AITs）诱导的过敏原特异性IgG抗体，可以通过过敏原掩膜和FcεRI与经典IgG抑制受体FcyRIIb交联来抑制ige介导的过敏反应。然而，当过敏原水平较高时，未经治疗和ait治疗的过敏患者以及药物诱导的IgG抗体也有可能通过刺激不同免疫细胞类型的经典激活FcyRs来介导过敏反应。IgG抗体的效应功能取决于其亚类和Fc n -糖基化类型。无半乳糖化IgG抗体具有促炎作用，而半乳糖化加末端唾液化IgG抗体的抗炎作用较小，甚至抗炎作用较小。不同糖基化的IgG抗体不仅与经典的fcyr相互作用，而且根据末端糖动机，还与c型凝集素受体相互作用。IgA有几个Fc n -糖基化侧，但它们对效应器功能的影响尚不清楚。我们可以证明，用蛋白抗原和不同佐剂免疫小鼠可诱导不同的IgG亚类和Fc n -糖基化模式，并且这些不同的IgG组成具有诱导IgG介导的过敏反应的不同潜力（Oefner等人，JACI 2012； Hess等人，JCI 2013； Epp等人，JACI 2017）。-因此，IgG介导的过敏反应高度依赖于IgG亚类及其Fc n -糖基化类型；唾液酰化通过c型凝集素受体SignR1降低了特定IgG1（功能上类似于人的IgG4）和IgG2b（但几乎没有IgG2a，功能上类似于人的IgG1）的过敏电位（Epp等，2017）。-此外，唾液化小鼠IgG1和IgA抑制无半乳糖化IgG2b诱导的过敏反应。-在患者中，使用桦树花粉提取物和佐剂明矾进行常规AIT，首先诱导IgG1，然后诱导IgG4抗体，这些抗体被唾液化并具有抗炎功能（Epp等人，2017）。在这里，我们想进一步分析不同糖基化的小鼠和人IgG和IgA亚类抗体的潜力和相互干扰，通过使用我们的小鼠模型和人源化小鼠IgG介导的过敏反应。例如，我们想要调查-哪些细胞上的信号r1负责唾液酸的抑制作用；在这里，我们还将研究血小板的作用，血小板的激活最近被描述为igg介导的过敏反应的第一步。-人IgG4唾液酰化是否也比人IgG1更强地抑制其过敏潜能。唾液化的人IgG4和IgA是否也能抑制人igg1诱导的过敏反应，以及如何抑制。这些研究将有助于更好地预测过敏反应的风险和未来AIT方案的成功。