1. Toll-like receptor 1 polymorphism is associated with impaired immune tolerance, dysregulated inflammatory responses to Borrelia burgdorferi, and heightened risk of post-infectious Lyme arthritisMorgan A. Williams, Sergio A. Hernández, Sheila Arvikar, Katherine B. Sulka, Franc Strle, Christopher C. Wells, Tanja Petnicki-Ocwieja, Allen C. Steere, Klemen Strle, 2025, izvirni znanstveni članek Povzetek: Introduction: Clinical presentation of Lyme disease is largely due to host immune response to infection. Previously, we identified a variant (1805GG) in the TLR1 gene, a key immune sensor for Borrelia burgdorferi, which was associated with excessive inflammation and severe disease. Herein we examined the mechanism by which this variant leads to dysregulated immunity. Methods: We found that patients with post-infectious Lyme arthritis, a condition characterized by marked persistent synovitis in joints, have a higher frequency of TLR1-1805GG compared to those whose arthritis resolves with antibiotics. To explore the possibility that this genotype-phenotype association was due to excessive inflammation, we then tested the functional impact of TLR1-1805GG on inflammatory responses and immune tolerance in PBMCs with or without this SNP and in THP-1 cell lines lacking TLR1. Results: In response to B. burgdorferi stimulation, PBMCs with TLR1-1805GG had greater transcriptional upregulation of ~1200 immune-related genes and significantly higher cytokine levels in supernatants compared to cells without this variant. Moreover, repeat B. burgdorferi stimulation, which mimics tolerogenic conditions during the infection, failed to induce innate immune tolerance in PBMCs with TLR1-1805GG, or in THP-1 cells lacking TLR1, resulting in seemingly unabated immune activation consistent with marked inflammation in Lyme arthritis joints. Conclusions: These results suggest that excessive inflammation in patients with TLR1-1805GG variant appears to be due to immune dysregulation and inability to induce immune tolerance. The findings help explain how early events during the infection may contribute to sustained immune activation after antibiotics and point to the role of TLR1 signaling in immune regulation. Ključne besede: Lyme disease, Borrelia burgdorferi, toll-like receptors, innate immune tolerance, inflammation, Lyme arthritis, innate immunology Objavljeno v DiRROS: 16.12.2025; Ogledov: 171; Prenosov: 67
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2. The new occurrence of antiphospholipid syndrome in severe COVID-19 cases with pneumonia and vascular thrombosis could explain the post-COVID syndromeMirjana Zlatković Švenda, Melanija Rašić, Milica Ovuka, Slavica Pavlov Dolijanović, Marija Atanasković Popović, Manca Ogrič, Polona Žigon, Snežna Sodin-Šemrl, Marija Zdravković, Goran Radunović, 2025, izvirni znanstveni članek Povzetek: Introduction: The classification of antiphospholipid syndrome (APS) comprises clinical criteria (vascular thrombosis or obstetric complications throughout life) and laboratory criteria (antiphospholipid antibodies (aPLs) positivity, confirmed at least twice at 12-week interval). Methods: In 100 patients admitted to the hospital with COVID-19 pneumonia, thrombosis and pregnancy complications were recorded during the hospital stay and in personal medical history. They were tested for nine types of aPLs at four time points (admission, deterioration, discharge, and 3-month follow-up): anticardiolipin (aCL), anti-β2-glycoproteinI (anti-β2GPI), and antiphosphatidylserine/prothrombin (aPS/PT) isotypes IgM/IgG/IgA. Results: During hospitalization, aPLs were detected at least once in 51% of patients. All 7% of deceased patients tested negative for aPLs upon admission, and only one patient became aCL IgG positive as his condition worsened. In 83.3% of patients, intrahospital thrombosis was not related to aPLs. One patient with pulmonary artery and cerebral artery thrombosis was given an APS diagnosis (triple aPLs positivity on admission, double on follow-up). Personal anamnesis (PA) for thromboembolism was verified in 10 patients, all of whom tested negative for aPLs at admission; however, transition to aPLs positivity at discharge (as the disease subsided) was seen in 60% of patients: three of six with arterial thrombosis (at follow-up, two did not appear, and one was negativized) and three of four with deep vein thrombosis (one was confirmed at follow-up and diagnosed with APS, one was negativized, and one did not appear). At admission, the majority of the aPLs were of the aCL IgG class (58.8%). Unexpectedly, as the COVID-19 disease decreased, anti-β2GPI IgG antibodies (linked with thromboses) became newly positive at discharge (14.9%), as confirmed at follow-up (20.8%). Conclusion: The incidence of APS in our cohort was 2.0%, whereas in the general population, it ranges from 0.001% to 0.002%. The incidence might have increased even more if the four aPLs-positive patients with intrahospital thrombosis/history of thrombosis had attended follow-up. Recommendation: All patients with severe COVID-19 or post-COVID syndrome should be evaluated for current/previous thrombosis and tested for aPLs at least twice: at admission to the hospital and at discharge, then retested 3 months later in positive cases in order to be given the appropriate therapy. Ključne besede: COVID-19, SARS-CoV2, anti-phosphatidylserine-prothrombin (aPS/PT) antibodies, anti-β2-glycoprotein I (anti-β2GPI) antibodies, anticardiolipin (aCL) antibodies, antiphospholipid antibodies (aPLs), antiphospholipid syndrome, immunology, post-COVID syndrome, vascular thrombosis Objavljeno v DiRROS: 01.12.2025; Ogledov: 206; Prenosov: 95
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3. Risk factors for severe sting reactions and side effects during venom immunotherapyGunter Sturm, Eva Schadelbauer, Giorgia Marta, Patrizia Bonadonna, Mitja Košnik, 2025, pregledni znanstveni članek Povzetek: Understanding the risk factors leading to severe systemic sting reactions (SSRs) is crucial for initiating venom immunotherapy (VIT) and for educating affected individuals and their families. Some of these risk factors are well established, some are no longer considered risk factors, and some remain controversial. Well-established risk factors for severe SSRs include clonal mast cell disease, high baseline serum tryptase, and advanced age. The absence of skin symptoms and the rapid onset of symptoms are indicators of severe SSRs. Recent publications indicate that antihypertensive treatment and stings in the head and neck area are not risk factors for severe SSRs. VIT is the only available treatment that can potentially prevent further anaphylactic reactions. Although rare and generally manageable, individuals undergoing VIT may experience systemic adverse events (sAEs). More sAEs are expected in patients undergoing bee VIT compared with vespid VIT. The role of elevated baseline serum tryptase as a risk factor for sAEs remains debated, but if it is a factor, the risk is increased by only about 1.5-fold. Rapid updosing protocols, depending on the specific regimen, can also be associated with more sAEs. Severe initial SSRs, antihypertensive medication, high skin test reactivity, and high specific IgE levels are not risk factors for sAEs. Ključne besede: immunology, anaphylaxis, Hymenoptera venom allergy, risk factors, severe systemic sting reactions, side effects, venom immunotherapy Objavljeno v DiRROS: 02.07.2025; Ogledov: 509; Prenosov: 398
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4. Hereditary α-tryptasemia is associated with anaphylaxis to antibiotics and monoclonal antibodiesPeter Korošec, Jonathan J. Lyons, Manca Svetina, Monika Koudová, Martina Bittóová, Mihaela Zidarn, Lenka Sedláčková, Matija Rijavec, Peter Kopač, 2025, izvirni znanstveni članek Povzetek: Background
Hereditary α-tryptasemia, a genetic trait caused by increased α-tryptase copy number, is associated with idiopathic and venom anaphylaxis.
Objective
We aimed to determine the impact of tryptase genotypes on drug-induced anaphylaxis.
Methods
A prospective discovery cohort of 99 patients from a referral center in Slovenia with acute anaphylaxis to drugs underwent tryptase genotyping by droplet digital PCR. For validation, we included a cohort of 26 patients from the Czech Republic. Associated inciting agents and the severity of the reactions were subsequently examined.
Results
Hereditary α-tryptasemia was associated with drug-induced anaphylaxis with a prevalence of 13% (n = 13 of 99) in the discovery cohort and 15% in the validation cohort (n = 4 of 26). Hereditary α-tryptasemia was identified in every individual with elevated basal serum tryptase levels (11.6-21.9 ng/mL; n = 14) within both cohorts of patients. Hereditary α-tryptasemia was more prevalent in individuals with antibiotic- or mAb-induced anaphylaxis in both the discovery and validation cohorts (n = 13 of 51; 26%) compared to those with anaphylaxis resulting from neuromuscular blocking agents, nonsteroidal anti-inflammatory drugs, contrast, chlorhexidine, or other drugs (n = 5 of 74; 7%; P = .02; odds ratio = 4.1; 95% CI, 1.3-11.1). Overall, we found fewer individuals with no ⍺-tryptase than in the general population, and there was a trend for subjects with more ⍺-tryptase copies to have more severe reactions. Thus, among subjects with three ⍺-tryptase copies, the prevalence of severe anaphylaxis was 73%, compared with 59% with one to two ⍺-tryptase copies and 58% for subjects without ⍺-tryptase.
Conclusions
Risk for anaphylaxis to antibiotics and biologics is associated with inherited differences in α-tryptase–encoding copies at Tryptase α/β1 . Ključne besede: immunology, drug allergy, anaphylaxis, antibiotics, monoclonal antibodies, α-tryptase, hereditary α-tryptasemia Objavljeno v DiRROS: 18.06.2025; Ogledov: 528; Prenosov: 276
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5. Patients with detectable KIT p.D816V in peripheral blood are at high risk for adverse systemic events during venom immunotherapy and treatment failureAjda Demšar Luzar, Jakob Otorepec, Mitja Košnik, Peter Kopač, Julij Šelb, Peter Korošec, Matija Rijavec, 2024, izvirni znanstveni članek Ključne besede: immunology, allergy to poison Hymenoptera, peripheral leukocytes, venom immunotherapy Objavljeno v DiRROS: 19.02.2025; Ogledov: 776; Prenosov: 464
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6. Patch testing with the European baseline series and 10 added allergens : single centre study of 748 patientsMojca Bizjak, Katja Adamič, Nisera Bajrović, Renato Eržen, Maja Jošt, Peter Kopač, Mitja Košnik, Nika Lalek, Mihaela Zidarn, Dejan Dinevski, 2022, izvirni znanstveni članek Povzetek: Background. The European baseline series (EBS) of contact allergens is subject to change. An allergen is considered for inclusion when routine patch testing of patients with suspected contact dermatitis results in ≥ 0.5% prevalence rate. Objectives. We aimed to determine the frequency of sensitizations to 30 EBS allergens and 10 locally added allergens. Additionally, we assessed the strength and evolution of reactions to all tested allergens and co-reactivity of additional allergens. Methods. Patch testing with our baseline series of 40 allergens was done in 748 consecutive adults. Tests were applied to the upper back and removed by patients after 48 hours. Readings were done on day 3 (D3) and D6 or D7 (D6/7). Positive reactions fulfilled the criteria of at least one plus (+) reaction. Retrospective analysis was done. Results. Eight allergens not listed in the EBS had ≥ 0.5% prevalence rate (i.e., cocamidopropyl betaine, thiomersal, disperse blue mix 106/124, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, propylene glycol, Compositae mix II, and dexamethasone-21-phosphate), and 16.6% of positive reactions would have been missed without D6/7 readings. Conclusion. We propose further studies to evaluate whether cocamidopropyl betaine, disperse blue mix 106/124, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, and Compositae mix II need to be added to the EBS. Ključne besede: allergy and immunology -- diagnosis, hypersensitivity -- diagnosis, skin tests, clinical epidemiology, baseline series, contact sensitization, patch tests, simultaneous reactivity Objavljeno v DiRROS: 24.06.2022; Ogledov: 1634; Prenosov: 667
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7. Treatment outcome clustering patterns correspond to discrete asthma phenotypes in childrenIvana Banić, Mario Lovrić, Gerald Cuder, Roman Kern, Matija Rijavec, Peter Korošec, Mirjana Kljajić-Turkalj, 2021, izvirni znanstveni članek Povzetek: Despite widely and regularly used therapy asthma in children is not fully controlled. Recognizing the complexity of asthma phenotypes and endotypes imposed the concept of precision medicine in asthma treatment. By applying machine learning algorithms assessed with respect to their accuracy in predicting treatment outcome, we have successfully identified 4 distinct clusters in a pediatric asthma cohort with specific treatment outcome patterns according to changes in lung function (FEV1 and MEF50), airway inflammation (FENO) and disease control likely affected by discrete phenotypes at initial disease presentation, differing in the type and level of inflammation, age of onset, comorbidities, certain genetic and other physiologic traits. The smallest and the largest of the 4 clusters- 1 (N = 58) and 3 (N = 138) had better treatment outcomes compared to clusters 2 and 4 and were characterized by more prominent atopic markers and a predominant allelic (A allele) effect for rs37973 in the GLCCI1 gene previously associated with positive treatment outcomes in asthmatics. These patients also had a relatively later onset of disease (6 + yrs). Clusters 2 (N = 87) and 4 (N = 64) had poorer treatment success, but varied in the type of inflammation (predominantly neutrophilic for cluster 4 and likely mixed-type for cluster 2), comorbidities (obesity for cluster 2), level of systemic inflammation (highest hsCRP for cluster 2) and platelet count (lowest for cluster 4). The results of this study emphasize the issues in asthma management due to the overgeneralized approach to the disease, not taking into account specific disease phenotypes. Ključne besede: asthma, allergy and immunology, pediatrics, machine learning, treatment outcome, phenotypes, childhood asthma, clustering Objavljeno v DiRROS: 16.08.2021; Ogledov: 2064; Prenosov: 1329
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8. Hymenoptera venom immunotherapy : immune mechanisms of induced protection and toleranceAjda Demšar Luzar, Peter Korošec, Mitja Košnik, Mihaela Zidarn, Matija Rijavec, 2021, pregledni znanstveni članek Povzetek: Hymenoptera venom allergy is one of the most severe allergic diseases, with a considerable prevalence of anaphylactic reaction, making it potentially lethal. In this review, we provide an overview of the current knowledge and recent findings in understanding induced immune mechanisms during different phases of venom immunotherapy. We focus on protection mechanisms that occur early, during the build-up phase, and on the immune tolerance, which occurs later, during and after Hymenoptera venom immunotherapy. The short-term protection seems to be established by the early desensitization of mast cells and basophils, which plays a crucial role in preventing anaphylaxis during the build-up phase of treatment. The early generation of blocking IgG antibodies seems to be one of the main reasons for the lower activation of effector cells. Long-term tolerance is reached after at least three years of venom immunotherapy. A decrease in basophil responsiveness correlates with tolerated sting challenge. Furthermore, the persistent decline in IgE levels and, by monitoring the cytokine profiles, a shift from a Th2 to Th1 immune response, can be observed. In addition, the generation of regulatory T and B cells has proven to be essential for inducing allergen tolerance. Most studies on the mechanisms and effectiveness data have been obtained during venom immunotherapy (VIT). Despite the high success rate of VIT, allergen tolerance may not persist for a prolonged time. There is not much known about immune mechanisms that assure longterm tolerance post-therapy. Ključne besede: allergy and immunology, hypersensitivity, immunotherapy, immune tolerance, venoms, Hymenoptera, Hymenoptera venom, short-term protection, long-term tolerance Objavljeno v DiRROS: 16.08.2021; Ogledov: 2907; Prenosov: 768
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9. Immunological outcomes of allergen-specific immunotherapy in food allergyAnne-Marie Malby Schoos, Dominique Bullens, Bo Lund Chawes, Joana Costa, Liselot De Vlieger, Audrey DunnGalvin, Michelle M. Epstein, Johan Garssen, Christiane Hilger, Karen Knipping, Mihaela Zidarn, 2020, izvirni znanstveni članek Povzetek: IgE-mediated food allergies are caused by adverse immunologic responses to food proteins. Allergic reactions may present locally in different tissues such as skin, gastrointestinal and respiratory tract and may result is systemic life-threatening reactions. During the last decades, the prevalence of food allergies has significantly increased throughout the world, and considerable efforts have been made to develop curative therapies. Food allergen immunotherapy is a promising therapeutic approach for food allergies that is based on the administration of increasing doses of culprit food extracts, or purified, and sometime modified food allergens. Different routes of administration for food allergen immunotherapy including oral, sublingual, epicutaneous and subcutaneous regimens are being evaluated. Although a wealth of data from clinical food allergen immunotherapy trials has been obtained, a lack of consistency in assessed clinical and immunological outcome measures presents a major hurdle for evaluating these new treatments. Coordinated efforts are needed to establish standardized outcome measures to be applied in food allergy immunotherapy studies, allowing for better harmonization of data and setting the standards for the future research. Several immunological parameters have been measured in food allergen immunotherapy, including allergen-specific immunoglobulin levels, basophil activation, cytokines, and other soluble biomarkers, T cell and B cell responses and skin prick tests. In this review we discuss different immunological parameters and assess their applicability as potential outcome measures for food allergen immunotherapy that may be included in such a standardized set of outcome measures. Ključne besede: food hypersensitivity, food intolerance, immunotherapy, immunology, food allergy, food allergens, oral immunotherapy Objavljeno v DiRROS: 15.02.2021; Ogledov: 2522; Prenosov: 1868
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10. Important and specific role for basophils in acute allergic reactionsPeter Korošec, Bernhard F. Gibbs, Matija Rijavec, Adnan Custovic, Paul J. Turner, 2018, pregledni znanstveni članek 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 Objavljeno v DiRROS: 14.12.2020; Ogledov: 2585; Prenosov: 1495
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