Biomarkers of immediate drug hypersensitivity Mayorga, Cristobalina; Ariza, Adriana; Muñoz‐Cano, Rosa ...
Allergy,
March 2024, 2024-Mar, 2024-03-00, 20240301, Letnik:
79, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the health systems. This problem increases when taking into account that only a small proportion of patients initially ...labelled as allergic are finally confirmed after an allergological workup. The diverse nature of drugs involved will imply different interactions with the immunological system. Therefore, IDHRs can be produced by a wide array of mechanisms mediated by the drug interaction with specific antibodies or directly on effector target cells. These heterogeneous mechanisms imply an enhanced complexity for an accurate diagnosis and the identification of the phenotype and endotype at early stages of the reaction is of vital importance. Currently, several endophenotypic categories (type I IgE/non‐IgE, cytokine release, Mast‐related G‐protein coupled receptor X2 (MRGPRX2) or Cyclooxygenase‐1 (COX‐1) inhibition and their associated biomarkers have been proposed. A precise knowledge of endotypes will permit to discriminate patients within the same phenotype, which is crucial in order to personalise diagnosis, future treatment and prevention to improve the patient's quality of life.
Background
In up to 70%–80% of patients with a suspected non‐steroidal anti‐inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other ...hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food‐dependent NSAID‐induced hypersensitivity (FDNIH).
Methods
We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID.
Results
199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%.
Conclusion
Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH.
16% of patients with suspicion of acute NSAID hypersensitivity were diagnosed as FDNIH reactions being lipid transfer protein (Pru p 3) the main food allergen involved. With four variables (Pru p 3 or Tri a 19 sensitization, anaphylactic reaction and any NSAID involved different from a pyrazolone), FDNIH is correctly diagnosed in 95.3% of cases (92% of sensitivity, 96% of specificity). These observations support the relevance of individualized assessment of both NSAID hypersensitivity and food allergy in patients with suspected acute NSAID hypersensitivity.
Abbreviations: FDNIH, food‐dependent NSAID‐Induced hypersensitivity; NSAID, non‐steroidal anti‐inflammatory drug
Sphingosine-1-phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly ...through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments.
Anaphylaxis is a severe allergic reaction, rapid in onset, and can lead to fatal consequences if not promptly treated. The incidence of anaphylaxis has risen at an alarming rate in past decades and ...continues to rise. Therefore, there is a general interest in understanding the molecular mechanism that leads to an exacerbated response. The main effector cells are mast cells, commonly triggered by stimuli that involve the IgE-dependent or IgE-independent pathway. These signaling pathways converge in the release of proinflammatory mediators, such as histamine, tryptases, prostaglandins, etc., in minutes. The action and cell targets of these proinflammatory mediators are linked to the pathophysiologic consequences observed in this severe allergic reaction. While many molecules are involved in cellular regulation, the expression and regulation of transcription factors involved in the synthesis of proinflammatory mediators and secretory granule homeostasis are of special interest, due to their ability to control gene expression and change phenotype, and they may be key in the severity of the entire reaction. In this review, we will describe our current understanding of the pathophysiology of human anaphylaxis, focusing on the transcription factors’ contributions to this systemic hypersensitivity reaction. Host mutation in transcription factor expression, or deregulation of their activity in an anaphylaxis context, will be updated. So far, the risk of anaphylaxis is unpredictable thus, increasing our knowledge of the molecular mechanism that leads and regulates mast cell activity will enable us to improve our understanding of how anaphylaxis can be prevented or treated.
Activating mutations in KIT (CD117) have been associated with several diseases, including gastrointestinal stromal tumors and mastocytosis. Rapidly progressing pathologies or drug resistance ...highlight the need for alternative treatment strategies. Previously, we reported that the adaptor molecule SH3 binding protein 2 (SH3BP2 or 3BP2) regulates KIT expression at the transcriptional level and microphthalmia-associated transcription factor (MITF) expression at the post-transcriptional level in human mast cells and gastrointestinal stromal tumor (GIST) cell lines. Lately, we have found that the SH3BP2 pathway regulates MITF through miR-1246 and miR-5100 in GIST. In this study, miR-1246 and miR-5100 were validated by qPCR in the SH3BP2-silenced human mast cell leukemia cell line (HMC-1). MiRNA overexpression reduces MITF and MITF-dependent target expression in HMC-1. The same pattern was observed after MITF silencing. In addition, MITF inhibitor ML329 treatment reduces MITF expression and affects the viability and cell cycle progression in HMC-1. We also examine whether MITF downregulation affected IgE-dependent mast cell degranulation. MiRNA overexpression, MITF silencing, and ML329 treatment reduced IgE-dependent degranulation in LAD2- and CD34
-derived mast cells. These findings suggest MITF may be a potential therapeutic target for allergic reactions and deregulated KIT mast-cell-mediated disorders.
Scope
LTP‐syndrome is characterized by sensitization (IgE) to multiple non‐specific lipid transfer proteins (nsLTPs) with a variable clinical outcome. The treatment is primarily based on offending ...food avoidance. However, the determination of Pru p 3‐specific IgE is currently the main diagnostic tool to assess sensitization to nsLTPs. Herein, the study evaluates improvement of LTP‐syndrome diagnosis and clinical management using a new IgE multiplex‐immunoblot assay with a high diversity of food nsLTPs.
Methods and results
An EUROLINE‐LTP strip with 28 recombinant nsLTPs from 18 allergenic sources is designed. In total the study investigates 38 patients with LTP‐syndrome and compares results from the nsLTPs (LTP‐strip) with the respective food extracts of Prick‐by‐prick (PbP) testing. The agreement exceeds 70% for most nsLTPs, e.g., Pru p 3 (100%), Mal d 3 (97%), Pru av 3 (89%), Pha v 3 isoforms (87%/84%), Ara h 9 (82%), Cor a 8 (82%), and Jug r 3 (82%). The functionality and allergenic relevance of nine recombinant nsLTPs are proven by Basophil activation testing (BAT).
Conclusions
The new IgE multiplex‐immunoblot nsLTP assay shows a good diagnostic performance allowing culprit food assessment. Negative results from LTP‐strip may indicate potentially tolerable foods, improving diet intervention and patients’ quality of life.
The multiparameter‐immunoblot assay containing a high diversity of plant‐food‐nsLTPs shows a good diagnostic performance compared to Prick‐by‐Prick, representing an opportunity to improve the LTP‐syndrome allergological work‐up and clinical management. True positive tests allow culprit food assessment while true negatives may provide potentially tolerable foods, improving diet intervention and patient quality of life.
Adenosine is a nucleoside involved in the pathogenesis of allergic diseases. Its effects are mediated through its binding to G protein-coupled receptors: A1, A2a, A2b and A3. The receptors differ in ...the type of G protein they recruit, in the effect on adenylyl cyclase (AC) activity and the downstream signaling pathway triggered. Adenosine can produce both an enhancement and an inhibition of mast cell degranulation, indicating that adenosine effects on these receptors is controversial and remains to be clarified. Depending on the study model, A1, A2b, and A3 receptors have shown anti- or pro-inflammatory activity. However, most studies reported an anti-inflammatory activity of A2a receptor. The precise knowledge of the adenosine mechanism of action may allow to develop more efficient therapies for allergic diseases by using selective agonist and antagonist against specific receptor subtypes.
Anaphylaxis is an acute and life-threatening systemic reaction. Many triggers have been described, including food, drug, and hymenoptera allergens, which are the most frequently involved. The ...mechanisms described in anaphylactic reactions are complex and implicate a diversity of pathways. Some of these mechanisms may be key to the development of the anaphylactic reaction, while others may only modify its severity. Although specific IgE, mast cells, and basophils are considered the principal players in anaphylaxis, alternative mechanisms have been proposed in non-IgE anaphylactic reactions. Neutrophils, macrophages, as well as basophils, have been involved, as have IgG-dependent, complement and contact system activation. A range of cationic substances can induce antibody-independent mast cells activation through MRGPRX2 receptor. Cofactors and augmenting factors may explain why, in some patients, food allergen exposure can cause anaphylaxis, while in other clinical scenario it can be tolerated or elicits a mild reaction. With the influence of these factors, food allergic reactions may be induced at lower doses of allergen and/or become more severe. Exercise, alcohol, estrogens, and some drugs such as Non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, β-blockers, and lipid-lowering drugs are the main factors described, though their mechanisms and signaling pathways are poorly understood.
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