An Update on the Immunological, Metabolic and Genetic Mechanisms in Drug Hypersensitivity Reactions

Drug hypersensitivity reactions (DHRs) represent a major burden on the healthcare system since their diagnostic and management are complex. As they can be influenced by individual genetic background, it is conceivable that the identification of variants in genes potentially involved could be used in genetic testing for the prevention of adverse effects during drug administration. Most genetic studies on severe DHRs have documented HLA alleles as risk factors and some mechanistic models support these associations, which try to shed light on the interaction between drugs and the immune system during lymphocyte presentation. In this sense, drugs are small molecules that behave as haptens, and currently three hypotheses try to explain how they interact with the immune system to induce DHRs: the hapten hypothesis, the direct pharmacological interaction of drugs with immune receptors hypothesis (p-i concept), and the altered self-peptide repertoire hypothesis. The interaction will depend on the nature of the drug and its reactivity, the metabolites generated and the specific HLA alleles. However, there is still a need of a better understanding of the different aspects related to the immunological mechanism, the drug determinants that are finally presented as well as the genetic factors for increasing the risk of suffering DHRs. Most available information on the predictive capacity of genetic testing refers to abacavir hypersensitivity and anticonvulsants-induced severe cutaneous reactions. Better understanding of the underlying mechanisms of DHRs will help us to identify the drugs likely to induce DHRs and to manage patients at risk.