T. Fernandez
Universidad de Málaga, Biología celular, genética y fisiología, Faculty Member
- FIMABIS, Enfermedades Alérgicas a Fármacos y Alérgenos, Faculty Memberadd
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The immunological mechanisms involved in drug hypersensitivity reactions (DHRs) are complex and, despite important advances, multiple aspects remain poorly understood. These not fully-known aspects are mainly related to the factors that... more
The immunological mechanisms involved in drug hypersensitivity reactions (DHRs) are complex and, despite important advances, multiple aspects remain poorly understood. These not fully-known aspects are mainly related to the factors that drive towards either a tolerant or a hypersensitivity response, and specifically regarding the role of B and T cells. In this review, we focus on recent findings on this knowledge area within the last two years. We highlight new evidences of covalent and non-covalent interactions of drug antigen with proteins, as well as the very first characterisation of naturally processed flucloxacillin-haptenated human leukocyte antigen (HLA) ligands. Moreover, we have analysed new insights into the identification of risk factors associated with the development of DHRs, such as the role of oxidative metabolism of drugs in the activation of the immune system and the discovery of new associations between DHRs and HLA variants. Finally, evidence of IgG-mediated anaphylaxis in humans and the involvement of specific subpopulations of effector cells associated with different clinical entities are also topics explored in this review. All these recent findings are relevant for the underlying pathology mechanisms and advance the field towards a more precise diagnosis, management, and treatment approach for DHRs.
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Lymphocyte transformation test (LTT) has been widely used to evaluate non‐immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug... more
Lymphocyte transformation test (LTT) has been widely used to evaluate non‐immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow‐cytometry‐based methods can help apply these improvements. We aimed to assess the added value of using drug‐primed‐DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs.
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Background Drug hypersensitivity reactions (DHRs) occurring less than 6 h after the drug intake are named immediate reactions. They include allergic reactions, and pseudo-allergic or non-allergic reactions, and despite their similar... more
Background Drug hypersensitivity reactions (DHRs) occurring less than 6 h after the drug intake are named immediate reactions. They include allergic reactions, and pseudo-allergic or non-allergic reactions, and despite their similar clinical manifestations, the underlying mechanism is different. Its identification is essential for their management. In IgE-mediated-DHRs, the best biomarker is drug-specific IgE, which can be determined by in vivo and in vitro tests. Identifying the culprit drug is critical for the design of avoidance strategies and the recommendation of safe alternatives for future treatments.Recent findings It has been suggested the existence of other mechanisms beyond IgE and related with the drug interaction with MRGPRX2 or IgG receptors, or mediated by their effect on some enzymes. However, the lack of a clear biomarker for characterizing them, together with the difficulty of predicting cross-reactivity, makes the management of non-allergic reactions very complex.Desensitization is standard intervention in allergic patients who need the drug. It is successful in IgE-mediated DHRs but its value on non-IgE-mediated DHRs is not well-known.Summary Further research is needed to identify the mechanism involved in DHRs considering that IgE and non-allergic reactions cannot be mutually exclusive and can happen simultaneously, increasing their severity. It is crucial the identification of biomarkers in non-allergic reactions.
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Research Interests: Immunology and Medicine
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Betalactam (BL) antibiotics are the drugs most frequently involved in IgE-mediated reactions. The culprit BL varies according to consumption patterns, with amoxicillin (AX) more prevalent in Southern Europe and penicillin V in... more
Betalactam (BL) antibiotics are the drugs most frequently involved in IgE-mediated reactions. The culprit BL varies according to consumption patterns, with amoxicillin (AX) more prevalent in Southern Europe and penicillin V in Scandinavian countries. Nowadays, the combination of AX and clavulanic acid (CLV) is the most highly consumed BL containing medicine worldwide. Both BLs, AX and CLV, can independently be involved in reactions, which poses a diagnostic challenge. In patients with immediate allergic reactions to AX, two patterns of responses have been described, those responding to benzylpenicillin (cross-reactors) and those selective to AX. In addition, selective reactions to CLV account for around 30% of allergic reactions to the combination AX-CLV. These patterns of IgE recognition could be related to differences in the haptenation process, in the immunological response, or in the BL involved in the first sensitization. In this regard, patients with selective responses to CLV are generally younger than those allergic to AX or benzylpenicillin. So far, no evidence of cross-reactivity between CLV and other BLs has been reported. This shows the importance of an accurate diagnosis of CLV allergy, as patients with selective reactions to CLV could take other BLs including AX. Diagnosis can be performed in vivo and in vitro, although no immunoassay currently exists. Research regarding the CLV antigenic determinants and protein conjugates is essential to improve diagnosis. BLs need to covalently bind to a carrier protein to be immunogenic. The antigenic determinant of AX is the amoxicilloyl amide, but CLV leads to unstable structures, many of which are unknown. Moreover, the nature of the BL-protein conjugates plays an important role in IgE recognition. This review aims to summarize current knowledge on the immunochemistry, diagnostic approaches as well as chemical and proteomic studies for both AX and CLV.
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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... more
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 determin...
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Maculopapular exanthema (MPE) induced by drugs is a T-cell mediated reaction and effector cells may play an important role in its development. We assessed the effector and cutaneous homing phenotype in peripheral blood cells from allergic... more
Maculopapular exanthema (MPE) induced by drugs is a T-cell mediated reaction and effector cells may play an important role in its development. We assessed the effector and cutaneous homing phenotype in peripheral blood cells from allergic patients after drug stimulation. This study included 10 patients and 10 controls. The effector phenotype (CCR7(-)CD27(+/-)), chemokine receptors (CCR4 and CCR10), and activation (CD25(low)) and regulatory markers (CD25(high)) were measured by flow cytometry in both peripheral blood mononuclear cells (PBMCs) and CD4-T-lymphocytes. Proliferation was determined by 5-(-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) assay and the migratory capacity by a chemotaxis assay using CCL17 and CCL27. Compared to controls, CCR7(-)CD27(-) cells were increased in patients without (p=0.003) and with drug stimulation (p less than 0.001) and had significantly higher proliferation (p=0.010). CCR10 expression was increased in patients after drug stimulation ...
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Hypersensitivity drug reactions (HDRs) vary over time in frequency, drugs involved, and clinical entities. Specific reactions are mediated by IgE, other antibody isotypes (IgG or IgM), and T cells. Nonspecific HDRs include those caused by... more
Hypersensitivity drug reactions (HDRs) vary over time in frequency, drugs involved, and clinical entities. Specific reactions are mediated by IgE, other antibody isotypes (IgG or IgM), and T cells. Nonspecific HDRs include those caused by nonsteroidal anti-inflammatory drugs (NSAIDs). beta-Lactams--the most important of which are amoxicillin and clavulanic acid--are involved in specific immunological mechanisms. Fluoroquinolones (mainly moxifloxacin, followed by ciprofloxacin and levofloxacin) can also induce HDRs mediated by IgE and T cells. In the case of radio contrast media, immediate reactions have decreased, while nonimmediate reactions, mediated by T cells, have increased. There has been a substantial rise in hypersensitivity reactions to antibiotics and latex in perioperative allergic reactions to anesthetics. NSAIDs are the most frequent drugs involved in HDRs. Five well-defined clinical entities, the most common of which is NSAID-induced urticaria/angioedema, have been pro...
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Summary Adverse drug reactions with an immunological basis (ADRIB) may involve activation of other concomitant, non-specific mechanisms, amplifying the specific response and contributing to the severity and duration. One concomitant... more
Summary Adverse drug reactions with an immunological basis (ADRIB) may involve activation of other concomitant, non-specific mechanisms, amplifying the specific response and contributing to the severity and duration. One concomitant mechanism could be the generation of reactive oxygen species (ROS) and/or their detoxification by anti-oxidants, including anti-oxidant enzymes. We analysed the activity of the anti-oxidant enzymes Cu/Zn-superoxide dismutase (SOD), catalase (CAT) and cellular glutathione peroxidase (GPX), as well as certain markers of oxidative damage (thiobarbituric acid reactive substances (TBARS) and carbonyl content) in peripheral blood mononuclear cells from patients with non-immediate ADRIB using spectrophotometric methods and the anti-oxidant enzymes expression by quantitative real-time reverse transcription–polymerase chain reaction. SOD activity and expression were increased in all types of non-immediate reactions (urticaria, maculopapular exanthema and toxic ep...
Research Interests: Immunology, Oxidative Stress, Adolescent, Antioxidants, Humans, and 15 moreReactive Oxygen Species, Female, Male, Catalase, Glutathione Peroxidase, Spectrophotometry, Superoxide Dismutase, Lipid peroxidation, Aged, Middle Aged, Adult, Urticaria, Hypersensitivity Delayed, reverse transcriptase polymerase chain reaction, and Drug hypersensitivity
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No consensus exists on the diagnostic approach for immediate hypersensitivity reactions (IHR) to radiocontrast media (RCM). We analyzed the diagnostic value of a skin test (ST), drug provocation test (DPT) and basophil activation test... more
No consensus exists on the diagnostic approach for immediate hypersensitivity reactions (IHR) to radiocontrast media (RCM). We analyzed the diagnostic value of a skin test (ST), drug provocation test (DPT) and basophil activation test (BAT) in patients with symptoms compatible with IHR to RCM. Ninety patients with symptoms suggestive of IHR to RCM were evaluated. ST with a panel of RCM was performed, and if negative, DPT was carried out with the culprit RCM. If ST or DPT were positive, tolerance was assessed with an alternative RCM and BAT was carried out with the same panel used for ST. Eight (8.9%) cases were confirmed as having IHR, 5 (62.5%) by ST and 3 (37.5%) by DPT. Five from those confirmed as IHR (62.5%) had a positive BAT. Hypersensitivity to RCM was confirmed in 9%, by ST or DPT. BAT proved a valuable method for diagnosis.
Research Interests: Immunology, Medicine, Allergy, Humans, Female, and 7 moreMale, Allergens, Aged, Middle Aged, Adult, Radiopharmaceuticals, and Contrast Media
Hypersensitivity drug reactions (HDRs) represent a large and important health problem, affecting many patients and leading to a variety of clinical entities, some of which can be life-threatening. The culprit drugs include commonly used... more
Hypersensitivity drug reactions (HDRs) represent a large and important health problem, affecting many patients and leading to a variety of clinical entities, some of which can be life-threatening. The culprit drugs include commonly used medications including antibiotics and NSAIDs. Nontherapeutical agents, such as contrast media, are also involved. Because the pathophysiological mechanisms are not well known and the current diagnostic procedures are somewhat insufficient, new approaches are needed for understanding the complexity of HDRs. Histochemical and molecular biology studies have enabled us to classify these reactions more precisely. Pharmacogenetics has led to the identification of several genes, involved mainly in T-cell-dependent responses, with a number of markers being replicated in different studies. These markers are now being considered as potential targets for reducing the number of HDRs. Transcriptomic approaches have also been used to investigate HDRs by identifying genes that show different patterns of expression in a number of clinical entities. This information can be of value for further elucidation of the mechanisms involved. Although first studies were performed using RT-PCR analysis to monitor the acute phase of the reaction, nowadays high-density expression platforms represent a more integrative way for providing a complete view of gene expression. By combining a detailed and precise clinical description with information obtained by these approaches, we will obtain a better understanding and management of patients with HDRs.
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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... more
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 circula...