Heritable risk for anaphylaxis associated with the increased germline copy number of α-tryptase-encoding sequences at TPSAB1

Anaphylaxis is a severe, systemic hypersensitivity reaction that is rapid in onset. It is characterized by life-threatening airway, breathing, and/or circulatory problems usually accompanied with skin and mucosal changes. We recently identified (together with the NIH/NSAID), a novel genetic cause for allergic inflammation and immune dysregulation, a common germline genetic trait resulting from increased ?-tryptase–encoding sequences at TPSAB1 gene associated with severe anaphylaxis (Lyons, J.J., Chovanec, J., O'Connell, MP,… Korošec, P. 2021, J Allergy Clin Immunol). This project will contribute to further characterization of this inherited genetic variant, which leads to severe allergic inflammation and anaphylaxis. We will dissect TPSAB1 copy number pathogenesis according to the anaphylactic reactions in children, different triggers of anaphylaxis (food, Hymenoptera venom, and medications), clinical signs and symptoms, potentially near-fatal outcome of anaphylaxis and the natural course of anaphylaxis in adults. Finally, we will functionally characterize blood-derived mast cells from selected anaphylactic subjects with duplication or triplication of ?-tryptase–encoding copies at TPSAB1. In this last, functional part of the project, we are hypothesizing that a functional putative mast cell contributing anaphylactic mechanism may exist among individuals with increased ?-tryptase–encoding sequences, reflecting a gene dose-dependent mast cell hyperresponsiveness. A role for tryptases in anaphylaxis is relevant to recent efforts toward developing a targeted mAb that neutralizes tryptase proteolytic activity and limits anaphylaxis severity in a humanized mouse model. Our data might suggest that patient outcomes in clinical trials targeting tryptases for neutralization or inhibition may be significantly affected by tryptase genetic variation and that tryptase genotyping may help identify individuals in whom these personalized therapies may be of most benefit.