20.500.12556/DiRROS-12414
Heritable risk for severe anaphylaxis associated with increased [alpha]-tryptase-encoding germline copy number at TPSAB1
Background: An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association. Objective: Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans. Methods: Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system. Results: Hereditary [alpha]-tryptasemia (H[alpha]T)--a genetic trait caused by increased [alpha]-tryptase-encoding Tryptase-[alpha]/[beta]1 (TPSAB1) copy number resulting in elevated BST level--was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). H[alpha]T was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant H[alpha]T was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not [alpha]- or [beta]-tryptase homotetramers. Conclusions: Risk for severe anaphylaxis in humans is associated with inherited differences in [alpha]-tryptase-encoding copies at TPSAB1.
mastocytosis
venoms
hypersensitivity
anaphylaxis - diagnosis
mast cells
idiopathic anaphylaxis
mast cell activation
hereditary alpha-tryptasemia
mastocitoza
živalski strupi
preobčutljivost
anafilaksija - diagnostika
mastociti
idiopatska anafilaksija
aktivacija mastocitov
hereditarna alfa-triptazemija
true
false
true
Elsevier
Angleški jezik
Ni določen
© 2020 Published by Elsevier Inc.
Neznano
2020-09-11 14:12:50
2020-09-11 14:12:51
2022-08-18 03:37:18
0000-00-00 00:00:00
2020
0
ZDA
0
Nasl. z nasl. zaslona;
Soavtorji iz Slovenije: Julij Šelb, Matija Rijavec, Peter Korošec;
Opis vira z dne 9. 9. 2020;
str. 1-11
iss.
Vol. 146
2020
0000-00-00
PostprintKoncna
VTisku
NiDoloceno
0000-00-00
0000-00-00
0000-00-00
616-097
1097-6825
10.1016/j.jaci.2020.06.035
27755011
3614228
https://www.jacionline.org/article/S0091-6749(20)31029-0/fulltext
1
https://dirros.openscience.si/Dokument.php?lang=slv&id=14972
Univerzitetna klinika za pljučne bolezni in alergijo Golnik
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