1. Targeting of the IL-5 pathway in severe asthma reduces mast cell progenitorsAbigail P. Alvarado-Vazquez, Erika Mendez-Enriquez, Maya Salomonsson, Peter Kopač, Ana Koren, Urška Bidovec, Sabina Škrgat, Oscar E. Simonson, Valentyina Yasinska, Peter Korošec, 2025, izvirni znanstveni članek Ključne besede: asthma, benralizumab, IL-5, mepolizumab, mast cells, mast cell progenitors
Objavljeno v DiRROS: 15.04.2026; Ogledov: 45; Prenosov: 31
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2. Cold-induced anaphylaxis : new insights into clinical and genetic characteristicsMojca Bizjak, Peter Korošec, Mitja Košnik, Julij Šelb, Urška Bidovec, Manca Svetina, Samo Zver, Dejan Dinevski, Matija Rijavec, 2025, izvirni znanstveni članek Povzetek: The pathogenesis of cold urticaria (ColdU) and cold-induced anaphylaxis (ColdA) remains poorly understood, and ColdA is underrepresented in anaphylaxis literature. Laboratory features to guide management are largely unknown. This study evaluated basal serum tryptase (BST) and total immunoglobulin E (IgE) levels in ColdU and ColdA, their associations with clinical features, and the utility of testing for the KIT p.D816V variant in blood leukocytes and hereditary a-tryptasemia (HaT).
Ključne besede: anaphylaxis, cold urticaria, hereditary α-tryptasemia, KIT p.D816V, mast cell, total IgE, tryptase
Objavljeno v DiRROS: 21.05.2025; Ogledov: 897; Prenosov: 438
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3. Autoimmune mast cell activation test as a diagnostic tool in chronic spontaneous urticariaAna Koren, Luka Dejanović, Matija Rijavec, Peter Kopač, Mojca Bizjak, Mihaela Zidarn, Mitja Košnik, Peter Korošec, 2024, izvirni znanstveni članek Povzetek: first_pagesettingsOrder Article Reprints
Open AccessArticle
Autoimmune Mast Cell Activation Test as a Diagnostic Tool in Chronic Spontaneous Urticaria
by Ana Koren 1,*ORCID,Luka Dejanović 1ORCID,Matija Rijavec 1,2ORCID,Peter Kopač 1,3ORCID,Mojca Bizjak 1ORCID,Mihaela Zidarn 1,3,Mitja Košnik 1,3ORCID andPeter Korošec 1,4
1
University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia
2
Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
3
Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
4
Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(17), 9281; https://doi.org/10.3390/ijms25179281
Submission received: 25 July 2024 / Revised: 23 August 2024 / Accepted: 25 August 2024 / Published: 27 August 2024
(This article belongs to the Special Issue Progression of Allergy and Immune Response)
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Abstract
Chronic spontaneous urticaria (CSU) is associated with skin mast cell activation, and its triggering mechanisms are not completely elucidated. Evidence suggests an autoimmune component of CSU. Our aim was to assess the usefulness of an autoimmune mast cell activation test (aiMAT) for diagnosing and differentiating CSU into different subtypes. We enrolled 43 patients with active, uncontrolled CSU before starting treatment with omalizumab and 15 controls. Patients were evaluated based on omalizumab response. aiMATs were performed using non-IgE-sensitized (NS) or myeloma IgE-sensitized (S) LAD2 cells, which were then stimulated with CSU/control sera (25 µL and 10 µL). The expression of CD63 was assessed with flow cytometry. CD63 response on NS-LAD2 was significantly increased in CSU patients compared to controls after the stimulation with 25 µL CSU/control sera (p = 0.0007) and with 10 µL CSU/control sera (p = 0.0001). The ROC curve analysis demonstrated an area under the curve (AUC) of 0.82. The cutoff for autoimmune-non-IgE-sensitized-MAT was 40.3% CD63+ LAD2, which resulted in 73.3% sensitivity and 81.4% specificity. CD63 response on S-LAD2 was significantly increased in CSU patients compared to controls after the stimulation with 25 µL CSU/control sera (p = 0.03). The ROC curve analysis demonstrated an AUC of 0.66. The cutoff for the autoimmune-myeloma IgE-sensitized-MAT was 58.4% CD63+ cells, which resulted in 62.8% sensitivity and 66.7% specificity. Overall, 36 out of 43 (84%) patients responded to omalizumab, and 7 (16%) were nonresponders. We found no differences between LAD2 CD63 response and response to omalizumab. In conclusion, aiMAT could represent a new diagnostic tool in CSU. Additional studies are needed to evaluate the potential benefits during omalizumab therapy.
Ključne besede: mast cell activation test, LAD2, chronic spontaneous urticaria, omalizumab, CD63 expression
Objavljeno v DiRROS: 06.03.2025; Ogledov: 833; Prenosov: 594
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4. High burden of clonal mast cell disorders and hereditary ▫$α-tryptasemia$▫ in patients who need Hymenoptera venom immunotherapyPeter Korošec, Gunter Sturm, Jonathan J. Lyons, Tinkara Pirc Marolt, Manca Svetina, Mitja Košnik, Mihaela Zidarn, Mark Kačar, Nina Frelih, Nika Lalek, Ajda Demšar Luzar, Samo Zver, Matevž Škerget, Ewa Czarnobilska, Wojciech Dyga, Sanja Popović-Grle, Miroslav Samaržija, Lisa Arzt-Gradwohl, Urban Čerpes, Grzegorz Porebski, Branko Pevec, Eva Schadelbauer, Peter Kopač, Julij Šelb, Matija Rijavec, 2024, izvirni znanstveni članek Povzetek: Background
In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT.
Methods
1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms.
Results
285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3–4 vs. 11% [n = 78 of 709] with Grade 1–2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3–4 vs. 0.001% [n = 78] in Grade 1–2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01).
Conclusions
By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.
Ključne besede: anaphylaxis, hereditary α-tryptasemia, hypersensitivity, immunotherapy, mast cell, mastocytosis, venom
Objavljeno v DiRROS: 17.06.2024; Ogledov: 1469; Prenosov: 903
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5. Severe cold urticaria can point to an underlying clonal mast cell disorderMojca Bizjak, Marcus Maurer, Mitja Košnik, Dorothea Terhorst, Samo Zver, Thomas Burmeister, Frank Siebenhaar, 2021, drugi znanstveni članki Ključne besede: urticaria, cold urticaria, wheals, clonal mast cell disorder
Objavljeno v DiRROS: 10.05.2021; Ogledov: 2632; Prenosov: 901
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7. Mast cell activation test in the diagnosis of allergic disease and anaphylaxisRajia Bahri, Adnan Custovic, Peter Korošec, Marina Tsoumani, Martin Barron, Jiakai Wu, Rebekah Sayers, Alf Weimann, Monica Ruiz-Garcia, Nandinee Patel, Mira Šilar, 2018, izvirni znanstveni članek Povzetek: Background. Food allergy is an increasing public health issue and the commonest cause of life-threatening anaphylactic reactions. Conventional allergy tests assess for the presence of allergen-specific IgE, significantly overestimating the rate of true clinical allergy resulting in over-diagnosis and adverse impact on health-related quality of life. Objective. To undertake initial validation and assessment of a novel diagnostic tool, the mast cell activation test (MAT). Methods. Primary human mast cells (hMCs) were generated from peripheral blood precursors, and sensitized using patient sera and then incubated with allergen. Mast cell degranulation was assessed by flow cytometry and mediator release. We compared the diagnostic performance of MAT to existing diagnostic tools to assess in a cohort of peanut-sensitized individuals undergoing double-blind, placebo-controlled challenge. Results. hMCs sensitized with sera from peanut, grass pollen and hymenoptera- (wasp venom) allergic patients demonstrated allergen-specific and dose-dependent degranulation by both expression of surface activation markers (CD63 and CD107a) and functional assays (prostaglandins D2 and ß-hexosaminidase release). In this cohort of peanut-sensitized individuals, MAT was found to have superior discrimination performance compared to other testing modalities including component-resolved diagnostics and basophil activation test. Using functional principle component analysis, we identified 5 clusters or patterns of reactivity in the resulting dose-response curves, which at preliminary analysis corresponded to the reaction phenotypes seen at challenge. Conclusion. MAT is a robust tool which may confer superior diagnostic performance compared to existing allergy diagnostics, and may be useful to explore differences in effector cell function between basophils and mast cells during allergic reactions.
Ključne besede: allergy and immunology -- diagnosis, anaphylaxis, immunologic tests, mast cells, food hypersensitivity, basophil activation test, BAT, mast cell activation test
Objavljeno v DiRROS: 30.11.2020; Ogledov: 4496; Prenosov: 2828
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8. Heritable risk for severe anaphylaxis associated with increased [alpha]-tryptase-encoding germline copy number at TPSAB1Jonathan J. Lyons, Jack Chovanec, Michael P. O'Connell, Yihui Liu, Julij Šelb, Roberta Zanotti, Yun Bai, Jiwon Kim, Quang T. Le, Tom DiMaggio, Matija Rijavec, Peter Korošec, 2020, izvirni znanstveni članek Povzetek: 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.
Ključne besede: mastocytosis, venoms, hypersensitivity, anaphylaxis - diagnosis, mast cells, idiopathic anaphylaxis, mast cell activation, hereditary alpha-tryptasemia
Objavljeno v DiRROS: 11.09.2020; Ogledov: 4772; Prenosov: 882
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