Investigating the regulatory mechanisms of allergen-specific IgG4 production

Abstract

Food allergy (FA) is driven by an abnormal type 2 immune response, where allergen-specific IgE antibodies trigger granulocyte activation and allergic reactions. FA affects millions in Canada and is the leading cause of fatal anaphylaxis in Ontario, with no current cure available. Treatments like allergen immunotherapy (AIT) and monoclonal antibodies (Omalizumab and Dupilumab) aim to reduce symptoms but are not curative and require ongoing treatment. Emerging research suggests that IgG4 antibodies, which increase with chronic allergen exposure and AIT, play a protective role by competing with IgE to prevent granulocyte activation and subsequent allergic symptoms, though the underlying mechanisms remain to be fully elucidated. In this study, we present the development and optimization of tools to explore the role of IgG4 in allergic responses. Utilizing CRISPR-Cas9 technology, we demonstrate the ability to genetically engineer B cell receptors to express allergen-specific antibodies in vitro. Additionally, we developed a robust naïve human B cell culture platform to investigate the impact of various cytokines on IgG4 class-switching. Our findings highlight the critical roles of cytokines such as IL-21 and IL-10 in promoting IgG4 production, while IL-4 appears to be non-essential. These novel tools and platforms shall enable a deeper exploration of the mediators driving IgG4 production in the context of food allergy, ultimately advancing our understanding of the disease and facilitating the development of transformative treatments.