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Iskalni niz: "avtor" (Matija Rijavec) .

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CD3+CD4-CD8- mucosal T cells are associated with uncontrolled chronic rhinosinusitis with nasal polyps
Peter Korošec, Irena Hočevar-Boltežar, Izidor Kern, Ana Koren, Matija Rijavec, Mira Šilar, Tanja Soklič, 2019

Povzetek: Increased mucosal double-negative (DN) CD3+CD4-CD8- T cells were found for the first time in CRS and were much more abundant in uncontrolled CRSwNP than in well-controlled CRSwNP.
Ključne besede: chronic rhinosinusitis, CD3+ T-cells, CD4- T-cells, CD8- T-cells
DiRROS - Objavljeno: 22.10.2020; Ogledov: 420; Prenosov: 203

Heritable risk for severe anaphylaxis associated with increased [alpha]-tryptase-encoding germline copy number at TPSAB1
Jonathan 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

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
DiRROS - Objavljeno: 11.09.2020; Ogledov: 482; Prenosov: 68

Transcription factors gene expression in chronic rhinosinusitis with and without nasal polyps
Tanja Soklič, Matija Rijavec, Mira Šilar, Ana Koren, Izidor Kern, Irena Hočevar-Boltežar, Peter Korošec, 2019

Povzetek: Background. Chronic rhinosinusitis (CRS) current therapeutic approaches still fail in some patients with severe persistent symptoms and recurrences after surgery. We aimed to evaluate the master transcription factors gene expression levels of T cell subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) that could represent new, up-stream targets for topical DNAzyme treatment. Patients and methods. Twenty-two newly diagnosed CRS patients (14 CRSwNP and 8 CRSsNP) were prospectively biopsied and examined histopathologically. Gene expression levels of T-box transcription factor (T-bet, TBX21), GATA binding protein 3 (GATA3), Retinoic acid-related orphan receptor C (RORC) and Forkhead box P3 (FOXP3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Results. Eosinophilic CRSwNP was characterized by higher level of GATA3 gene expression compared to noneosinophilic CRSwNP, whereas there was no difference in T-bet, RORC and FOXP3 between eosinophilic and noneosinophilic CRSwNP. In CRSsNP, we found simultaneous upregulation of T-bet, GATA3 and RORC gene expression levels in comparison to CRSwNP; meanwhile, there was no difference in FOXP3 gene expression between CRSwNP and CRSsNP. Conclusions. In eosinophilic CRSwNP, we confirmed the type 2 inflammation by elevated GATA3 gene expression level. In CRSsNP, we unexpectedly found simultaneous upregulation of T-bet and GATA3 that is currently unexplained; however, it might originate from activated CD8+ cells, abundant in nasal mucosa of CRSsNP patients. The elevated RORC in CRSsNP could be part of homeostatic nasal immune response that might be better preserved in CRSsNP patients compared to CRSwNP patients. Further data on transcription factors expression rates in CRS phenotypes are needed.
Ključne besede: sinusitis, nasal polyps, Th1 cells, Th2 cells, Th17 cells, transcription factors, chronic rhinosinusitis
DiRROS - Objavljeno: 09.10.2020; Ogledov: 369; Prenosov: 177
.pdf Celotno besedilo (698,54 KB)

Hereditary angioedema due to C1-inhibitor deficiency in Macedonia : clinical characteristics, novel SERPING1 mutations, and genetic factors modifying the clinical phenotype
Vesna Grivčeva-Panovska, Mitja Košnik, Peter Korošec, Slađana Andrejević, Ljerka Karadža-Lapić, Matija Rijavec, 2018

Povzetek: Objective: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by swellings. We aimed to characterize on a clinical and molecular basis C1-INH-HAE patients in the Republic of Macedonia. Results: All 15 patients from six unrelated families were diagnosed with C1-INHHAE type I, with a mean age of symptom onset of 11 years and an average delay of diagnosis of 7 years. Patients reported on average 31 angioedema attacks/year, with a median clinical severity score (CSS) of 7. We identified three known mutations, and two mutations (c.813_818delCAACAA and c.1488T>G) were reported for the first time. To address the genotype-phenotype association, a pooled analysis including 78 C1-INH-HAE south-eastern European patients was performed, with additional analysis of F12-46C/T and KLKB1- 428G/A polymorphisms. We demonstrated that patients with nonsense and frameshift mutations, large deletions/insertions, splicing defects, and mutations at Arg444 exhibited an increased CSS compared with missense mutations, excluding mutations at Arg444. In addition, the CC F12-46C/T polymorphism was suggestive of earlier disease onset. Discussion: Genetic analysis helped identify the molecular basis of C1-INH-HAE given that causative mutations in SERPING1 were detected in all patients, including an infant before the appearance of clinical symptoms. We identified two novel mutations and further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and CC F12-46C/T predisposes patients to earlier disease onset.
Ključne besede: hereditary angioedemas -- genetics -- Macedonia, C1 inhibitor, SERPING1 gene, C1 inhibitor, SERPING1 gene
DiRROS - Objavljeno: 30.11.2020; Ogledov: 242; Prenosov: 50

Important and specific role for basophils in acute allergic reactions
Peter Korošec, Bernhard F. Gibbs, Matija Rijavec, Adnan Custovic, Paul J. Turner, 2018

Povzetek: IgE-mediated allergic reactions involve the activation of effector cells, predominantly through the high-affinity IgE receptor (FceRI) on mast cells and basophils. Although the mast cell is considered the major effector cell during acute allergic reactions, more recent studies indicate a potentially important and specific role for basophils and their migration which occurs rapidly upon allergen challenge in humans undergoing anaphylaxis. We review the evidence for a role of basophils in contributing to clinical symptoms of anaphylaxis, and discuss the possibility that basophil trafficking during anaphylaxis might be a pathogenic (to target organs) or protective (preventing degranulation in circulation) response. Finally, we examine the potential role of basophils in asthma exacerbations. Understanding the factors that regulate basophil trafficking and activation might lead to new diagnostic and therapeutic strategies in anaphylaxis and asthma.
Ključne besede: allergy and immunology, basophils, anaphylaxis
DiRROS - Objavljeno: 14.12.2020; Ogledov: 231; Prenosov: 115
.pdf Celotno besedilo (511,01 KB)

Hereditary angioedema due to C1-inhibitor deficiency in pediatric patients in Croatia : first national study, diagnostic and prophylactic challenges
Ljerka Karadža-Lapić, Marko Barešić, Renata Vrsalović, Irena Ivković-Jureković, Saša Sršen, Ingrid Prkačin, Matija Rijavec, Draško Cikojević, 2019

Povzetek: Hereditary angioedema (HAE) is a rare autosomal dominant disease with deficiency (type I) or dysfunction (type II) of C1 inhibitor, caused by mutations in the C1-INH gene, characterized by recurrent submucosal or subcutaneous edemas including skin swelling, abdominal pain and life-threatening episodes of upper airway obstruction. The aim of this study was to investigate healthcare experiences in children with HAE due to C1 inhibitor deficiency (C1-INH-HAE) in Croatia in order to estimate the number of affected children and to recommend management protocols for diagnosis, short-term prophylaxis and acute treatment. Patients were recruited during a 4-year period at five hospitals in Croatia. Complement testing was performed in patients with a positive family history. This pilot study revealed nine pediatric patients positive for C1-INH- HAE type I, aged 1-16 years, four of them asymptomatic. Before the age of one year, C1-INH levels may be lower than in adults; it is advisable to confirm C1-INH-HAE after the age of one year. Plasma-derived C1- INH is recommended as acute and short-term prophylactic treatment. Recombinant C1-INH and icatibant are licensed for the acute treatment of pediatric patients. In Croatia, HAE is still underdiagnosed in pediatric population.
Ključne besede: hereditary angioedemas -- genetics -- Croatia, inborn genetic diseases -- Croatia, pediatrics -- Croatia, C1 inhibitor, SERPING1 gene, children
DiRROS - Objavljeno: 16.12.2020; Ogledov: 267; Prenosov: 206
.pdf Celotno besedilo (477,81 KB)

GLCCI1 polymorphism rs37973 and asthma treatment response to inhaled corticosteroids
Matija Rijavec, Mateja Žavbi, Anton Lopert, Matjaž Fležar, Peter Korošec, 2018

Povzetek: Background. Asthma treatment response is highly variable and pharmacogenetic markers that predict treatment response would be one step closer to personalized treatment. GWAS studies have shown that polymorphisms GLCCI1 could be associated with asthma treatment response to inhaled corticosteroids (ICS). Materials and methods. We genotyped rs37973 of GLCCI1 in 208 adult asthma patients treated with ICS. Change in % predicted FEV1 was analysed after short-term (3 months) and after long-term (at least 3 years) treatment. Treatment success was defined as good when FEV1 decreased less than 30 ml/year. Results. After 3 months of treatment, change of % predicted FEV1 was higher in patients with GG genotype than in patients with AG+AA genotype, and this genotype dependent difference was only evident in non-smokers. Similar results were found after at least 3 years of treatment when all patients were analysed, in non-smokers and patients with atopy. Even though, no differences in treatment success (good vs. poor response) were observed when analysing the entire group of patients, genotype dependent treatment success was highly influenced by smoking and atopy. GG genotype was overrepresented in non-smokers and patients with atopy with good response. Conclusions. Rs37973 was associated with short- and long-term treatment response; however, there was a great influence of smoking and atopy on pharmacogenetic association. Furthermore, we found GG genotype to be associated with better treatment response, what is contrary to results found in GWAS.
Ključne besede: asthma -- diagnosis -- therapy, pharmacogenetics, genetic polymorphism, smoking, inhaled corticosteroids, atopy, GLCCI1, FEV1, rs37973
DiRROS - Objavljeno: 16.12.2020; Ogledov: 206; Prenosov: 90

Chemokines during anaphylaxis : the importance of CCL2 and CCL2-dependent chemotactic activity for basophils
Romana Vantur, Maruša Rihar, Ana Koren, Matija Rijavec, Peter Kopač, Urška Bidovec, Renato Eržen, Peter Korošec, 2020

Povzetek: Background: The role of chemokines in anaphylaxis is unclear. Methods: We prospectively recruited 49 patients presenting to the emergency department with an acute episode of anaphylaxis and 28 healthy subjects. We measured serum levels of the chemokines CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL21, CCL22, CCL24, and CCL26, tryptase, the absolute number of circulating basophils, monocytes, lymphocytes, and PMNs, and whole blood FCER1A, CPA3 and HDC gene expression at two time points: during the anaphylactic episode and in convalescent samples collected approximately 3 months later. We then investigated the in vitro chemotactic activity of chemokines induced during anaphylaxis for the in vitro migration of the corresponding cells. Results: Only CCL2 chemokine levels were signifcantly increased in anaphylaxis samples (median 514 pg/ml) compared to convalescent samples (284 pg/ml, P<0.0001) and healthy subjects (279 pg/ml, P<0.0001); there was no signifcant diference in any of the other chemokines. There was a signifcant positive correlation between the rates of increase of serum CCL2 (median [range]: 106.0% [-44.7% to 557.4%]) and tryptase (133.8% [-6.6% to 893.4%]; r=0.68, P<0.0001) and between the acute concentration of serum CCL2 and the acute concentration of serum tryptase (r=0.77, P<0.0001). The number of circulating basophils, but not other blood cells, signifcantly decreased during anaphylaxis (median 5.0 vs. 19.1 cells/[micro]l in convalescent samples; P<0.0001); a decrease in whole-blood gene expression of basophil markers (PKljučne besede: anaphylaxis, chemokines, tryptases, basophils, chemotaxis, CCL2, cell migration
DiRROS - Objavljeno: 18.01.2021; Ogledov: 227; Prenosov: 124
.pdf Celotno besedilo (2,04 MB)

T2-high asthma, classified by sputum mRNA expression of IL4, IL5, and IL13, is characterized by eosinophilia and severe phenotype
Matija Rijavec, Tomaž Krumpestar, Sabina Škrgat, Izidor Kern, Peter Korošec, 2021

Povzetek: Asthma is a common chronic disease, with different underlying inflammatory mechanisms. Identification of asthma endotypes, which reflect a variable response to different treatments, is important for more precise asthma management. T2 asthma is characterized by airway inflammation driven by T2 cytokines including interleukins IL-4, IL-5, and IL-13. This study aimed to determine whether induced sputum samples can be used for gene expression profiling of T2-high asthma classified by IL4, IL5, and IL13 expression. Induced sputum samples were obtained from 44 subjects, among them 36 asthmatic patients and eight controls, and mRNA expression levels of IL4, IL5, and IL13 were quantified by RT-qPCR. Overall, gene expression levels of IL4, IL5, and IL13 were significantly increased in asthmatic patients' samples compared to controls and there was a high positive correlation between expressions of all three genes. T2 gene mean was calculated by combining the expression levels of all three genes (IL4, IL5, and IL13) and according to T2 gene mean expression in controls, we set a T2-high/T2-low cutoff value. Twenty-four (67%) asthmatic patients had T2-high endotype and those patients had significantly higher eosinophil blood and sputum counts. Furthermore, T2-high endotype was characterized as a more severe, difficult-to-treat asthma, and often uncontrolled despite the use of inhaled and/or oral corticosteroids. Therefore, the majority of those patients (15 [63%] of 24) needed adjunct biological therapy to control their asthma symptoms/exacerbations. In conclusion, we found that interleukins IL4, IL5, and IL13 transcripts could be effectively detected in sputum from asthmatic patients. Implementation of T2 gene mean can be used as sputum molecular biomarker to categorize patients into T2-high endotype, characterized by eosinophilia and severe, difficult-to-treat asthma, and often with a need for biological treatment.
Ključne besede: asthma, gene expression, interleukin-4, interleukin-5, interleukin-13, severe asthma, endotype, IL-4, IL-5, IL-13, biologic treatment
DiRROS - Objavljeno: 02.02.2021; Ogledov: 180; Prenosov: 51
.pdf Celotno besedilo (1,31 MB)

Routine KIT p.D816V screening identifies clonal mast cell disease in Hymenoptera allergic patients regularly missed using baseline tryptase levels alone
Peter Korošec, Jonathan J. Lyons, Mitja Košnik, Samo Zver, Vladka Čurin-Šerbec, Yihui Liu, Young Hwan Park, Ajda Demšar, Nisera Bajrović, Matevž Škerget, Peter Kopač, Mihaela Zidarn, Renato Eržen, Matija Rijavec, Julij Šelb, 2021

Povzetek: Background. Clonal mast cell disorders and elevated BST of unknown cause(s) are associated with severe Hymenoptera venom-triggered anaphylaxis (HVA). However, some individuals with clonal disease have normal BST (<11.4 ng/mL). Objective. To evaluate whether screening for KIT p.D816V in the blood is a useful clinical tool to risk-stratify patients with venom allergy. Methods. We prospectively recruited 374 patients with Hymenoptera allergy and no overt signs of mastocytosis referred to our center in the years 2018-19. KIT p.D816V was determined in the peripheral blood with qPCR and tryptase genotyping was performed by droplet-digital PCR. Results. 351 patients (93.9%) had normal levels of BST and KIT p.D816V was detected in 8% of patients (28/351), predominantly in patients with the most severe Mueller grade IV anaphylaxis (18.2%[24/132] vs 1.8%[4/88 in grade III; 0/131 in other grades] in lower grades; P<0.001). In grade IV patients with normal BST, KIT p.D816V was associated with more severe symptoms including a significantly higher frequency of loss of consciousness (58.3%[14/24] vs 34.3%[37/108]; P=0.03) and absence of skin symptoms (41.7%[10/24] vs 15.7%[17/108]; P=0.004). Among patients with normal BST, KIT p.D816V (OR [95%CI]: 10.25[3.75-36.14]; P<0.0001) was the major risk factor associated with severe HVA. Hereditary [alpha]-tryptasemia (H[alpha]T), due to increased germline copies of TPSAB1 encoding [alpha]-tryptase was the most common cause (65.2%; 15/23) of elevated BST in patients with HVA and together with KIT p.D816V accounted for 90% (20/23) of BST elevations in HVA patients. Conclusion. These results indicate that routine KIT p.D816V screening identifies clonal disease in high-risk HVA patients regularly missed using BST alone.
Ključne besede: anaphylaxis, venoms, hypersensitivity, hereditary alpha-tryptasemia
DiRROS - Objavljeno: 31.03.2021; Ogledov: 95; Prenosov: 41

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