Publication:
Hypersensitivity reactions to β-lactams: relevance of hapten-protein conjugates.

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Date

2015

Authors

Ariza, A
Mayorga, C
Fernandez, T D
Barbero, N
Martín-Serrano, A
Pérez-Sala, D
Sánchez-Gómez, F J
Blanca, M
Torres, M J
Montanez, M I

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Esmon Publicidad
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Abstract

Las betalactamas (BL) son los fármacos implicados más frecuentemente en reacciones alérgicas. Se clasifican según su estructura química en penicilinas, cefalosporinas, monobactamas, carbapenems y clavamas. Poseen un anillo betalactámico que, excepto en las monobactamas, está fusionado a un anillo de cinco o seis miembros y, excluyendo las clavamas, tienen 1, 2 o 3 cadenas laterales. Las diferencias en las estructuras químicas resultan en un amplio rango de BLs, que puede ser discriminado por el sistema inmune, con inducción de reacciones clínicas a una BL y tolerancia a otras. El diagnóstico está basado en pruebas cutáneas e in vitro, aunque ambas presentan una baja sensibilidad. Esto podría deberse a que los fármacos o conjugados de fármacos empleados en estos tests que no se reconocen de manera óptima por el sistema inmune. Las BLs son haptenos que necesitan de su unión covalente a proteínas para inducir una respuesta inmunológica. Estos fármacos presentan una elevada capacidad para formar aductos covalentes con proteínas mediante el ataque nucleofílico de grupos aminos de proteínas al anillo BL. Aunque la bencilpenicilina ha sido la mejor estudiada, también se han descrito determinantes alergénicos del resto de BLs. Además, la formación de los aductos BLs-proteína muestra selectividad, así se ha demostrado recientemente para la amoxicilina, que principalmente modifica la albúmina en suero (HSA), la transferrina y las cadenas ligeras y pesadas en suero humano. Dada la complejidad de la alergia a BL, el conocimiento de los mecanismos inmunológicos implicados y la optimización de los métodos diagnósticos requieren de abordajes multidisciplinares teniendo en cuenta tanto la estructura química de los fármacos y de las moléculas portadoras, como las respuestas de los pacientes.
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.

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Journal Article; Research Support, Non-U.S. Gov't; Review;

MeSH Terms

Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins
Medical Subject Headings::Diseases::Immune System Diseases::Hypersensitivity::Drug Hypersensitivity
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Epitopes::Haptens
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Immunologic Tests
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Lactams::beta-Lactams
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents

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Keywords

Betalactams, Carrier, Proteins, IgE, Hapten, Betalactamas, Hapteno, Portador, Proteínas, IgE

Citation

Ariza A, Mayorga C, Fernandez TD, Barbero N, Martín-Serrano A, Pérez-Sala D, et al. Hypersensitivity reactions to β-lactams: relevance of hapten-protein conjugates. J Investig Allergol Clin Immunol. 2015; 25(1):12-25