Characterization of immunoglobulin-ε (IgE) to benefit therapeutic IgE engineering.

Abstract

Several food proteins, e.g. in peanut, can trigger adversely immune responses that lead to severe, even fatal, clinical symptoms. Immunoglobulin-ε (IgE) is the main immunoglobulin isotype associated with such Type-I hypersensitivity. The allergic immune reactions are mediated by IgE and its interactions to the receptor FcεRIα located on mast cells. The cellular activation is triggered by the FcεRIα-bound IgE typically with multivalent antigen binding or occasionally without any presence of known antigens. Disrupting such interactions could intervene the allergic immune responses.Our previous study (doi: 10.1016/j.jaci.2019.03.028) suggested prolonged FcεRIα-IgE interactions led to emergence and over-presentation of the persistent IgE. Such effects were due to long-ranged communications between the IgE V-regions and the FcεRIα-binding site. Additionally, varying structural arrangements of the IgE complementarity-determining regions (CDRs) and framework regions (FWRs) of both the antibody heavy and light chains with influence from the CH-region could orient a single mutation in the VH-CDR2 to abrogate the non-specific binding of superantigen spA or could form inducible structural glutamine stretches that bound nickel Ni2+ without losing the antigen specificity (doi: 10.3389/fimmu.2021.676048). In fact, these work advocate analyzing IgE holistically as a whole, rather than a sum of its parts.In the current work riding on the long-ranged communications between the IgE antigen-binding and FcεRIα-binding regions, we further characterize the impact of the linking Cε2 on the IgE conformational changes upon antigen and/or FcεRIα binding, applied in peanut allergy. These characteristics elucidate the structural mechanisms for allosteric effects observed in the allergen and the FcεRIα binding. This will provide better understanding of initiating steps in the Type-I hypersensitivity as well as the crucial interdomain communications in the whole IgE structure, and hence further complement understanding the role of IgE in allergy pathogenesis.