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）可以通过在例如肥大细胞，导致组胺释放。 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 classic IgG inhibitory receptor FcyRIIb.However, when allergen levels are High, IgG Abs induced in untreated and AIT-treated allergic patients, as以及医学药物（生物学），还具有通过刺激不同免疫细胞类型的经典激活FCYR来介导过敏反应的潜力。IGGABS的效应功能取决于它们的子类和FC N-糖基化的类型。 Agalactosylated IgG ABS与促炎效应子功能有关，而半乳糖基化和末端溶解的IgG ABS的作用更少甚至抗炎。不同的糖基化IgG ABS不仅与经典的FCYR相互作用，而且还取决于末端糖运动，也与C型杠杆受体相互作用。 IgA has several Fc N-glycosylation sides, but their influence on the effector function is unclear.We could show that-immmunizations of mice with protein antigens and distinct adjusters 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;囊lyal化会降低特定IgG1（功能在功能上与人IgG4）和IgG2b（但几乎没有IgG2a）（但在功能上与人IgG1相似的IgG2b）的过敏反潜在通过C-Type Lever受体Signr1（Epp et and cyp epp et a igpe and igg1）（EPP等人，2017年）。在患者中，伴有桦木花粉提取物的常规AIT和调整校友在患者中使用AgaLactosyly的IgG2b.-影响第一的IgG1，然后影响IgG4 ABS，然后呈溶性降低并显示出抗炎症功能的IgG4 ABS（Epp等，2017）（EPP等，2017）。 IgG介导的过敏反应也与人源性小鼠一样。我们想要，例如研究哪个细胞Signr1负责唾液酸的抑制作用； here we will also investigate the role of platelets whose activation has recently They were described to be the first step in IgG-mediated anaphylaxis.- whether sialylation of human IgG4 also strongly 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.这些研究将有助于更好地预测未来的过敏反应的风险和AIT方案的成功。