Effector functions of differentially glycosylated anti-Bet v 1 human IgG subclasses
Pediatric and Adolescent Medicine
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
IgE antibodies (Abs) can mediate allergic reactions, including systemic anaphylaxis, by activating the high affinity Fcepsilon receptor (R) I on mast cells and basophils, leading to release of inflammatory mediators. In contrast, allergen-specific IgG Abs, which are also induced by allergen-specific immunotherapies (AIT), can inhibit IgE-mediated anaphylaxis caused by low levels of allergen through allergen-masking and crosslinking of the Fcepsilon RI with the classical IgG inhibitory receptor Fcgamma RIIb. However, when allergen levels are high, IgG Abs for example to medical drugs also have the potential to mediate anaphylaxis by activating classical activating Fcgamma Rs on different immune cell types. The effector functions of IgG Abs depend on their subclass and the type of Fc Nglycosylation. Agalactosylated (non-galactosylated) IgG Abs are associated with inflammation, whereas galactosylation and terminal sialylation of IgG Abs can suppress inflammation. However, the effects of IgG subclass and Fc glycosylation pattern in allergy remain unclear. The results of this project showed that the IgG subclass and the IgG Fc glycosylation pattern had only a slight effect on extent of inhibition of an IgE-mediated llergic reaction via Fcgamma RIIb. However, we identified that the severity of IgG-mediated systemic anaphylaxis, which required challenge with a higher antigen dose, was IgG subclass- and Fc glycosylation-dependent. Sialylation of IgG Abs reduced their potential to induce an IgG-mediated anaphylaxis. This inhibitory effect was dependent on the C-type lectin receptor SignR1.In conclusion, the IgG Ab subclass distribution and their Fc glycosylation pattern might predict the potential of IgG-mediated allergic reactions against medical drugs or also during AIT, when allergen doses are high. We further analyzed how conventional AIT with birch pollen extract and the adjuvant aluminium hydroxide (alum) affects the IgG subclass and Fc glycosylation pattern of anti-Bet v 1 (Betula verrucosa 1; the major birch pollen allergen) Abs in birch pollen allergic patients. In untreated patients, Bet v 1-specific IgG4 titers were constantly low, while IgE but also IgG1 titers increased during the pollen season. In contrast, during AIT, levels of Bet v 1-specific IgG1 increased in the first 12 months but decreased afterwards, while Bet v 1-specific IgG4 titers persistently increased. However, the Fc glycosylation profile of Bet v 1-specific serum IgG Abs from untreated and AIT-treated patients remained stable and were highly galactosylated and sialylated. Consistent with an inverse relationship between IgG sialylation and inflammatory potential, we found that in vitro de-sialylation of native Bet v 1-specific IgG Abs from the serum of AIT-treated patients strongly increased their ability to activate neutrophils in vitro. These observations suggest that conventional AIT with alum induces sialylated IgG(4) Abs that probably have low potential to induce IgG-mediated allergic reactions, when the allergen dose would be high. However, studies remain required to assess how Fc glycosylation modulates the effector functions of human IgG1 and IgG4 and how new AIT protocols with distinct adjuvants, will influence the human IgG subclass distribution and Fc glycosylation pattern and consequently, the risk of IgG-mediated allergic reactions, when the allergen dose would be high. Taken together, our data suggest that although IgG subclass and glycosylation pattern have relatively little effect on IgG Ab blocking of IgE-mediated anaphylaxis, increased sialylation of IgG(4) Abs should decrease the risk of IgG-induced anaphylaxis in the presence of high allergen doses.
Publications
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Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions. J Allergy Clinic Immunol 2018; 141 (1): 399-402.e8
Epp A, Hobusch J, Bartsch YC, Petry J, Lilienthal G-M, Koeleman CAM, Eschweiler S, Möbs C, Hall A, Morris SC, Petzold D, Engellenner C, Bitterling J, Rahmöller J, Leliavski A, Thurmann R, Collin M, Moremen KW, Strait RT, Blanchard V, Petersen A, Gemoll T, Habermann JK, Petersen F, Nandy A, Kahlert H, Hertl M, Wuhrer M, Pfützner W, Jappe U, Finkelman FD, and Ehlers M
