[Show abstract][Hide abstract] ABSTRACT: Allergic rhinitis is highly prevalent worldwide. Immunotherapy has been shown to control its symptoms, however, up to 30% of patients may not respond. Previous studies of the immunological mechanisms involved in allergen-immunotherapy (AIT) have focused on the humoral and T-cell response and several studies have evaluated some B-cell subpopulations during AIT and their role in immunological tolerance. However, although B and plasma-cell subpopulations are two of the most important cellular subtypes involved in allergic reactions, their relation with AIT efficacy remains unelucidated. The objective was to analyze the effects of immunotherapy on different B and plasma-cell subpopulations and whether these changes correlate with the clinical response to the treatment. Although no changes are found in B-cell subpopulations, responder patients show increased levels of memory B-cells even before the beginning of treatment. Changes in plasma-cell subpopulations are found, mainly in circulating inflammatory plasma-cells that could affect the response to the allergen. Moreover, an early increase of specific-IgG4 and IgG4 secreting-cells was found. All these suggest that the determination of the memory B-cells before the initiation of the treatment, and the quantification of IgG4 and IgG4-secreting-cells in the first months of immunotherapy, could serve as markers for the clinical response to treatment.
[Show abstract][Hide abstract] ABSTRACT: NSAIDs-induced urticaria and/or angioedema (NIUA) is the most frequent entity of hypersensitivity reactions to NSAIDs. The underlying cause is considered to be because of a nonspecific immunological mechanism in which mast cells are key players. We studied the association of nine single nucleotide polymorphisms in five genes involved in mast cell activation (SYK, LAT1, PLCG1, PLA2G4A, and TNFRSF11A) in 450 NIUA patients and 500 controls. We identified several statistically significant associations when stratifying patients by symptoms: PLA2G4A rs12746200 (urticaria vs. controls, Pc=0.005). PLCG1 rs2228246 (angioedema vs. controls; Pc=0.044), and TNFRS11A rs1805034 (urticaria+angioedema vs. controls; Pc=0.041). The frequency of haplotype PLCG1 rs753381-rs2228246 (C-G) in angioedema-NIUA patients was lower than that in controls (Pc=0.040). In addition, the haplotype frequency of TNFRS11A rs1805034-rs35211496 (C-T) was higher among urticaria-NIUA and urticaria+angioedema-NIUA patients than the controls (Pc=0.045 and 0.046). Our results shed light on the involvement of variants in genes related to non-immunological mast cell activation in NIUA.
Pharmacogenetics and Genomics 09/2015; 25(12). DOI:10.1097/FPC.0000000000000179 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the synthesis and characterisation of gold nanoclusters (Au NCs) stabilised by a mixture of zwitterionic and multivalent mannose ligands. Characterisation of this carbohydrated nanosystem confirms its small size (~2 nm), intense red-NIR fluorescence, relatively high affinity to lectin (ConA), and stability in physiological media. Cell studies performed using human monocyte-derived dendritic cells (DCs) show that Au NC uptake efficiency is greatly enhanced by the presence of surface carbohydrate (> 250% compared to non-carbohydrated Au NCs) allowing their detection in cells by fluorescence following incubation with concentrations as low as 1 μg.mL-1. Investigation using electron microscopy and pharmacological inhibitors indicates that Au NC uptake is mediated by multiple endocytic pathways involving the engulfment of Au NCs into endosomes and partial transport to lysosomes. Results show that clathrin and F-actin dependent pathways play major roles in Au NC uptake by DCs regardless of whether or not they are coated with carbohydrates. In contrast, a specific C-lectin inhibitor induces a 60% decrease in DC particle uptake only for the carbohydrate-coated Au NCs. This study demonstrates that the combination of ultra-small gold NCs and functionalisation with multivalent mannose ligands results in greatly enhanced human DC targeting, presumably due to increased diffusion and target cell binding, respectively.
[Show abstract][Hide abstract] ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide and are responsible for several types of drug hypersensitivity reactions (DHRs) in all age groups. The 2 major groups of DHRs to NSAIDs are those induced by immunological mechanisms (selective reactions) and those where inflammatory mediators are released through activation of the prostaglandin-leukotriene pathway without specific immunological recognition (cross-intolerance). In the present review, we focus on cross-intolerance reactions, which are the most frequent DHRs and are becoming a topic of major interest in children and adolescents. Paracetamol and ibuprofen are the drugs that most frequently cause DHRs in children; other NSAIDs are responsible for reactions in adolescents. In vivo and in vitro tests are of limited diagnostic value, with some exceptions for the less common selective reactions. In cross-intolerance, the clinical history and controlled administration are in many instances the only way to establish a diagnosis and look for alternatives. The clinical history is diagnostic when consistent symptoms occur repeatedly after exposure to NSAIDs with different chemical structures. Cutaneous and respiratory symptoms often co-occur in young children. The natural history of these reactions in children is unknown, and some patients can develop tolerance over time. Atopy remains a major risk factor for cross-intolerant reactions. The increasing interest in hypersensitivity to NSAIDs with improvements in patient phenotyping and the information provided by pharmacogenetics will improve our understanding and management of these reactions in the near future.
Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología 08/2015; 25(4):259-69. · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metamizole is a NSAID that has been banned in several countries because of its toxicity. It is often involved in selective hypersensitivity reactions and most hypersensitivity patients develop anaphylaxis. Metamizole is rapidly metabolized, and metabolic profiles are related to genetic factors. We analyzed whether genetic determinants of metamizole metabolism influence the risk of developing hypersensitivity in 265 patients diagnosed with hypersensitivity to metamizole and 362 healthy individuals who tolerated metamizole. Slow acetylation is associated with an increased risk of developing selective hypersensitivity to metamizole [odds ratio for slow alleles=2.17 (95% confidence interval=1.44-3.27); P=0.00016], and particularly anaphylaxis [odds ratio=4.77 (95% confidence interval=2.28-9.98); P=0.000006], with a significant gene-dose effect. The association was not identified in patients with cross-hypersensitivity. Cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) genotypes did not influence risk association. Our findings raise the hypothesis of genetically determined metabolic variability as a risk factor for developing anaphylaxis with metamizole.
Pharmacogenetics and Genomics 06/2015; 25(9). DOI:10.1097/FPC.0000000000000157 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peanut allergens are common triggers of food allergy. Analyses of sensitization patterns, relationships with other allergens, clinical symptoms and variation with age are needed. We studied sensitization to Ara h 2, Ara h 9 and Pru p 3 in a peanut allergic children/adolescents, and the relationship with peach and pollen.
Peanut allergic patients aged between 1 and 20 years old were classified into two groups: A) allergic to peanut only, and B) allergic to peach and peanut. The IgE response was measured to Ara h 2, Ara h 9 and Pru p 3.
Of 964 subjects evaluated, 28% were allergic to peanut. From this group 68% were also sensitized to pollen. Urticaria was the most frequent entity followed by anaphylaxis and OAS. Fifty-eight percent had Ara h 2 and/or Ara h 9 specific IgE. More than half reported symptoms with peanut alone (Group A); 35% to peanut and peach (Group B). We observed significant differences in sex, age, onset of symptoms and sensitization to Artemisia between groups. IgE response to Ara h 2 was more frequent in Group A; Ara h 9 and Pru p 3 in Group B. We observed a decrease in sensitization to Ara h 2 and an increase to Ara h 9 and Pru p 3 with increasing age.
Peanut allergy is frequent in subjects with allergy to plant-foods, with Ara h 2 and Ara h 9 being two important allergens. In younger patients Ara h 2 predominates over Ara h 9. The reverse was observed in older patients.
SSP, seed storage proteins; LTP, lipid transfer proteins; SPT, skin prick test; PR-10, pathogenesis related-10; double-blind-placebo-controlled food challenge (DBPCFC); OAS, oral allergy syndrome. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Drug-induced anaphylaxis can be a life-threatening condition occurring after drug intake by any route, including non-therapeutic exposure due to accidental contact. The most common culprit drugs are non-steroidal anti-inflammatory drugs and beta-lactam antibiotics. Other antibiotics, such as quinolones, are also becoming important elicitors. In the hospital setting, neuromuscular blocking agents and contrast media play an important role. In addition to specific immunological mechanisms (IgE-mediated), other non-immunological mechanisms may participate, including the generation of vasoactive mediators through the arachidonic acid metabolic pathway, direct stimulation of mast cells and the activation of other inflammatory cascades. Diagnosis of drug-induced anaphylaxis includes skin testing, in vitro testing in some instances, and very often requires drug provocation to search for alternatives or in some cases for diagnosis confirmation. Often, the diagnosis must be performed in the context of confounding agents. Factors contributing to the degree of severity include previous diseases (e.g. cardiovascular disease) and the intake of other drugs such as beta-blockers. In circumstances where the culprit drug must be administered, patients should be desensitised if possible. This may be carried out for drug-induced anaphylaxis caused by both immunological and non-immunological reactions, such as cross-intolerance to NSAIDs.
[Show abstract][Hide abstract] ABSTRACT: Although specific immunotherapy is the only aetiological treatment for allergic disorders, the underlying mechanisms are not fully understood. Specific immunotherapy induces changes in lymphocyte Th subsets from Th2 to Th1/Treg. Whether differences in immunological patterns underlie patient response to immunotherapy, has not yet been established.
We studied the immunological changes occurring during a 1-year-period of Dermatophagoides pteronyssinus (DP) immunotherapy and their relation with clinical outcome.
We included 34 patients with DP allergy that received sub-cutaneous immunotherapy (SCIT) for 1 year. Following treatment, patients were classified as responders or non-responders. Fourteen allergic subjects that did not receive SCIT were included as controls. Peripheral blood was obtained at 0, 1, 3, 6 and 12 months, and cultured with nDer p 1. Phenotypic changes, cytokine production and basophil response were analysed by flow cytometry; transcription factors were measured by mRNA quantification. Serum immunoglobulin levels were also measured.
After one year of SCIT, 82% of cases showed improved symptoms (responders). Although increases of sIgG4 were observed, BAT reactivity was not modified in these patients. Increases of TBET/FOXP3 as well as nDer p 1-specific Th1/Treg frequencies were also observed, alongside a decrease in Th2, Th9 and Th17. These changes corresponded to changes in cytokine levels.
Patients who respond well to DP-SCIT show immunological differences compared to non-responders. In responders, basal differences include a lower frequency of Th1 and higher frequencies of Th2, Th9 and Th17 cells. After one year of treatment an increased production of sIgG4 was observed in responders, along with a change in Th2 response toward Th1/Treg. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: β-Lactams (BL) are the drugs most frequently involved in allergic reactions. They are classified according to their chemical structure as penicillins, cephalosporins, monobactams, carbapenems, and clavams. All BL antibiotics have a BL ring that is fused to a 5-member or 6-member ring (except in monobactams) and has 1, 2 or 3 side chains (except in clavams). Differences in chemical structure mean that a wide range of BLs are recognized by the immune system, and patients may experience clinical reactions to one BL while tolerating others. Diagnosis is based on skin and in vitro testing, although both display low sensitivity, possibly because they are based on drugs or drug conjugates that are not optimally recognized by the immune system. BLs are haptens that need to bind to proteins covalently to elicit an immune response. These drugs have a high capacity to form covalent adducts with proteins through nucleophilic attack of amino groups in proteins on the BL ring. Allergenic determinants have been described for all BLs, although benzylpenicillin is the most widely studied. Moreover, formation of BL-protein adducts is selective, as we recently demonstrated for amoxicillin, which mainly modifies albumin, transferrin, and immunoglobulin heavy and light chains in human serum. Given the complexity of BL allergy, understanding the immunological mechanisms involved and optimization of diagnostic methods require multidisciplinary approaches that take into account the chemical structures of the drugs and the carrier molecules, as well as the patient immune response.
Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología 04/2015; 25(1):12-25. · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cyclooxygenases (COX-1 and COX-2) are key enzymes in several physiopathological processes. Many adverse drugs reactions to NSAIDs are attributable to COX-inhibition. The genes coding for these enzymes (PTGS1 and PTGS2) are highly variable, and variations in these genes may underlie the risk of developing, or the clinical evolution of, several diseases and adverse drug reactions. We analyze major variations in the PTGS1 and PTGS2 genes, allele frequencies, functional consequences and population genetics. The most salient clinical associations of PTGS gene variations are related to colorectal cancer and stroke. In many studies, the SNPs interact with NSAIDs use, dietary or environmental factors. We provide an up-to-date catalog of PTGS clinical associations based on case-control studies and genome-wide association studies, and future research suggestions.
[Show abstract][Hide abstract] ABSTRACT: Genetic predictors of beta-lactam (BL) allergy are mostly related to Immunoglobulin E (IgE) synthesis and atopy. Despite this context, little attention has been devoted to genes of IgE/FcɛRI pathway, such as galectin-3, a β-galactoside-binding lectin, which binds to IgE. We evaluated the association of LGALS3 polymorphisms with BL allergy in 395 Spanish and 198 Italian cases, compared with 310- and 339-matched controls, respectively. The rs11125 predicted BL allergy with an odds ratio of 4.0 in Spanish population (P<0.0001). This association was replicated with an odds ratio of 5.1 in Italian population (P<0.0001); rs11125 predicted also increased serum level of total IgE in Spanish controls. These data are consistent with the predicted deleterious influence of Gln>His substitution produced by rs11125 on galactose-binding activity of galectin-3. In conclusion, LGALS3 is the strongest genetic predictor of BL allergy reported so far. This association reflects the influence of genes of IgE/FcɛRI pathway in this pathology.The Pharmacogenomics Journal advance online publication, 14 April 2015; doi:10.1038/tpj.2015.24.
The Pharmacogenomics Journal 04/2015; DOI:10.1038/tpj.2015.24 · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
An increasing number of patients show immediate selective hypersensitivity reactions to clavulanic acid (CLV), and amoxicillin (AX), probably due to their increased prescription. The maintenance of this response should be established.Objective
To assess that the immediate hypersensitivity selective response to AX or to CLV is maintained after repeated administration of Penicillin G (PG)/Penicillin V (PV) and AX.Methods
Patients with proven immediate hypersensitivity to AX (Group A) or CLV (Group B) were included. Diagnosis was performed using skin tests with major and minor determinants of PG (PPL/MDM), AX and CLV and by drug provocation test (DPT) if required. Selectivity was established by confirming tolerance to PG/PV (Group A) and to PG/PV and AX (Group B). The maintenance of the selective response was verified by repeating DPT, 15 days after the initial investigation, with the same procedure.ResultsOf 51 patients, 78% belonged to Group A and 22% to Group B. Most had anaphylaxis. In Group A, 72% were skin test positive; 28% required DPT. In Group B, 63% were skin tests positive; 37% required DPT. Only two AX selective cases developed positive responses after re-provocation with PG/PV. No cases selective for CLV developed a positive response to PG, PV or AX.DiscussionThe selective response to AX appears consistent and a response to penicillin determinants only develops in a minority of cases. For the case of CLV, the selective response appears not to be modified by exposure to penicillin determinants, meaning that patients with CLV allergy can take penicillin derivatives safely.This article is protected by copyright. All rights reserved.