Effector functions of differentially glycosylated anti-Bet v 1 human IgG subclasses

• Applicant: Professor Dr. Marc Ehlers
• Subject Area: Rheumatology ; Pediatric and Adolescent Medicine ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 257739680

Allergy to birch pollen is characterized by the development of IgE and IgG antibodies (Abs) against the major allergen Bet v 1. Successful allergen-specific immunotherapy (SIT; hyposensibilization) to combat birch pollen allergy is often associated with a large increase in Bet v 1-reactive serum IgG Abs, mainly IgG1 and IgG4. The common idea about the function of these anti-Bet v 1 IgG Abs is that they capture the allergen and inhibit its binding to the pro-inflammatory IgE bound to mast cells. However, it has recently been shown that the Fc N-glycosylation pattern of IgG Abs determines their pro- or anti-inflammatory effector functions: agalactosylated (non-galactosylated and non-sialylated; G0) IgG Abs are pro-inflammatory and galactosylated plus sialylated IgG Abs are anti-inflammatory.In this context, we have shown that sialylated IgG Abs are induced after successful tolerance induction with protein antigens in mice and after SIT in humans, suggesting that sialylated allergen-specific IgG Abs are involved in this SIT-dependent tolerance induction. Further results indicated that sialylated, but not G0, anti-ovalbumin (OVA) murine monoclonal IgG1 Abs, can reduce allergic airway inflammation in an OVA-dependent mouse model. Furthermore, these studies indicated that immune complexes containing antigen-specific sialylated IgG Abs are able to inhibit dendritic cell maturation and therefore priming of pro-inflammatory T cells.In this study, we want to clone and produce differentially glycosylated monoclonal humanized and real human anti-Bet v 1 IgG1 and IgG4 Abs to investigate their inhibitory potential in human immune cell culture assays and, in parallel with differentially glycosylated murine anti-Bet v 1 IgG1 Abs, in a Bet v 1-dependent mouse allergy model. In this mouse model, we also want to characterize the receptor complexes of the differentially glycosylated IgG Abs.Additionally, we want to analyze the Fc glycosylation patterns of human anti-Bet v 1 serum IgG Abs before, during and after subcutaneous SIT.Overall, we want to identify the optimal Fc glycosylated allergen-specific human IgG subclass to inhibit allergic reactions and characterize its functional role. This will be important for the validation of successful SIT, the possible development of Abs for passive immunization and the optimization of individualized SIT protocols.

• DFG Programme: Research Grants