Immune pathomechanism and classification of drug hypersensitivity

Abstract

Drug hypersensitivity reactions (DHR) are based on distinct mechanisms and are clinically heterogeneous. Taking into account that also off-target activities of drugs may lead to stimulations of immune or inflammatory cells, three forms of DHR were discriminated: the allergic-immune mechanism relies on the covalent binding of drugs/ chemicals to proteins, which thereby form new antigens, to which a humoural and/or cellular immune response can develop. In IgE-mediated drug allergies, a possible tolerance mechanism to the drug during sensitization and the need of a covalent hapten-carrier link for initiation, but not for elicitation of IgE-mediated reactions is discussed. The p-i ("pharmacological interaction with immune receptor") concept represents an off-target activity of drugs with immune receptors (HLA or TCR), which can result in unorthodox, alloimmune-like stimulations of T cells. Some of these p-i stimulations occur only in carriers of certain HLA alleles and can result in clinically severe reactions. The third form of DHR ("pseudo-allergy") is represented by drug interactions with receptors or enzymes of inflammatory cells, which may lead to their direct activation or enhanced levels of inflammatory products. Specific IgE or T cells are not involved. This classification is based on the action of drugs and is clinically useful, as it can explain differences in sensitizations, unusual clinical symptoms, dependence on drug concentrations, predictability and immunological and pharmacological cross-reactivities in DHR. K E Y W O R D Sallergic/immune hypersensitivity, classification, drug hypersensitivity, p-i concept, pseudoallergic drug reactions

Progress in understanding hypersensitivity reactions to nonsteroidal anti‐inflammatory drugs

“…CRs have been the most studied models in NSAIDs hypersensitivity despite SHRs also playing an important role . Considering the rapid onset of symptoms, the lack of cross‐reactivity with other NSAIDs and the clinical entities, SNIUAA is thought to be mediated by specific IgE antibodies . Due to their low molecular weight, NSAIDs or their metabolites need to conjugate with proteins to initiate a reaction, which requires a previous exposition (sensitization) to the culprit.…”

Recent developments and highlights in drug hypersensitivity

“…The diagnostic procedure depends on the drug involved and the type of DHR, IR or NIR . Precise definitions and provision of background, in a standardized available questionnaire, are helpful to correctly classify DHRs . Although in NSAID hypersensitivity, the current classification needs a revision including new entities as blended reactions …”

“…Basing on the immune pathomechanisms, DHRs have recently been classified into (a) allergic, which follow the hapten hypothesis and can be mediated by IgE and IgG antibodies or T cells; (b) pharmacological interaction (p‐I), in which the drug can bind directly to HLA or TCR; and (c) pseudoallergic, in which the drug binds directly to receptors or interacts with enzymes of effector cells, without immune mechanisms (Figure ).…”

“…p‐I reactions are considered NIR since symptoms appear only after specific T‐cell expansion and migration into tissue . Latest advances in their mechanisms have focused on finding new associations with specific HLA alleles .…”

Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

“…DHRs constitute an important health problem, affecting more than 7% of the population, for whom drugs, such as beta‐lactam antibiotics and nonsteroidal anti‐inflammatory drugs, are essential for treatment of common diseases . Based on the clinical characteristics of DHRs, different phenotypes have been identified, although the lack in understanding the underlying mechanisms of many DHRs has hampered the definition of endotypes and identification of biomarkers …”