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Project J3-3072

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

Research project ARRS
Code: J3-3072
Period 1.10.2021 - 30.9.2024
Head: Assoc Prof Peter Korošec, BSc (Biol), PhD
ARRS classification: Medicine/Human reproduction

Organisations:  University Clinic of Respiratory and Allergic Diseases Golnik;  University medical centre Ljubljana 

Researchers.


Description of the project

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 α-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 α-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 α-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.

Project timeline

Project work packages and their realization

Work package (WP)

Tasks

Milestones &Deliverables

Work distribution

 

 

WP1

Adult anaphylaxis cohort for genotyping of TPSAB1 from University Clinic Golnik

&

healthy adult volunteers

WP1A

Clinical characterization of cohort: different triggers of anaphylaxis, clinical signs and symptoms, the near-fatal outcome of anaphylaxis, and natural course




Detailed cohort data








University Clinic Golnik




WP1B

Genotyping of TPSAB1

(β/β, α/β, α/α, αα/β, αα/α, αα/αα, ααα/β and ααα/α)


TPSAB1 genotypes

WP1C

Analysis, publications, clinical implementations


Manuscripts, guidelines






WP2

Pediatric anaphylaxis cohort for genotyping of TPSAB1 from University Children’s Hospital Ljubljana


WP2A

Recruitment of children with anaphylaxis



Recruited pediatric cohort





University Children’s Hospital Ljubljana





WP2B

Clinical characterization of cohort: different triggers of anaphylaxis, clinical signs and symptoms, the near-fatal outcome of anaphylaxis, and natural course




Detailed cohort data

WP2C

Genotyping of TPSAB1

(β/β, α/β, α/α, αα/β, αα/α, αα/αα, ααα/β and ααα/α)

 

TPSAB1 genotypes


University Clinic Golnik

WP2D

Analysis, publications, clinical implementations


Manuscripts, guidelines

University Children’s Hospital Ljubljana

 

 

 

WP3

Functional characterization of blood-derived mast cells from subjects with duplication or triplication of α-tryptase–encoding copies at TPSAB1

WP3A

Generation of primary mast cells from peripheral blood from subjects with selected duplication or triplication of α-tryptase–encoding copies at TPSAB1 &

healthy adult volunteers



Mast cells from peripheral blood precursors

 




University Clinic Golnik




WP3B 

Functional characterization utilizing passive sensitization, expressions of CD63 activation marker and secretion of CCL2, PGD2, β-hexosaminidase, and heterotetrameric α/β -tryptase


Confirming or rejecting hyperresponsiveness

hypothesis, Manuscripts