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

• Applicant: Professor Dr. Marc Ehlers
• Subject Area: Clinical Immunology and Allergology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398859914

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.

• DFG Programme: Research Grants