HLA and Delayed Drug-Induced Hypersensitivity

Abstract

Delayed drug allergy reactions (DDAR) are potentially fatal. Certain human leukocyte antigen (HLA) alleles have been associated with delayed allergy reactions following the administration of particular drugs. Examples are HLA-B*57:01 (abacavir), HLA-B*15:02/HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). Based on the identification of these associations, it may now be possible to prevent certain allergy reactions that were, until recently, considered unpredictable. In this review, we will focus on the pharmacogenetics of the best-studied associations between specific HLA alleles and delayed allergy reactions and describe the pathogenesis models proposed so far. Finally, we will evaluate the genetic screening strategies available and discuss the clinical relevance of a better understanding of the immunogenetics and mechanisms involved in DDAR.

HLA‐B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum–Induced Liver Injury in Humans

“…This evidence indicated that an immune‐mediated idiosyncratic hepatotoxicity was induced by PM. Delayed adverse drug reactions are driven by the inappropriate activation of T cells . The HLA molecules encoded in the MHC region on chromosome 6 are thought to primarily be key proteins that activate T cells .…”

Stevens–Johnson syndrome/toxic epidermal necrolysis and erythema multiforme drug-related hospitalisations in a national administrative database

“…After adjusting for the number of drug packages sold, we also found a high rate of hospitalisations associated with adverse reactions to antineoplastic and immunosuppressive drugs, supporting some underlying immune deregulation associated with malignancies or autoimmune diseases [ 14 ]. While many cases of EM and SCARs have been reported following the use of several of these drugs, the underlying immunological mechanisms are still only partially identified [ 20 , 39 , 40 ]. Some antineoplastic drugs (e.g., EGFR tyrosine kinase inhibitors) interfere with keratinocyte proliferation, differentiation, and migration, and, thus, might facilitate the development of more severe SCARs.…”

“…We compared the frequency of comorbidities potentially associated with an increased risk of SJS/TEN (whether directly or indirectly), namely chronic kidney disease, hypertension, heart failure, diabetes, HIV infection, and liver disease (Additional file 1 : Table S1). Chronic kidney disease is associated with an increased risk of allopurinol-induced SJS/TEN [ 20 ]. As the use of diuretics is also associated with the latter condition [ 21 ], we also assessed conditions whose treatment frequently requires the use of diuretics, namely hypertension, heart failure, and diabetes.…”

Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy

“…The allele and its tag-SNP were also associated with lower lymphocyte levels and overlapped with T cell regulatory annotations, which suggests that the variant may predispose to a T-cell-mediated, delayed type of penicillin allergy. MHC I molecules are expressed by almost all cells and present peptides to cytotoxic CD8+ T cells, whereas MHC II molecules are expressed by antigen-presenting cells to present peptides to CD4+ T helper lymphocytes 31,34 There are several examples of MHC I alleles associated with drug-induced hypersensitivity mediated by CD8+ T cells 34,36,37 The involvement of T cells in delayed hypersensitivity reactions has been shown by isolating drug reactive T cell clones 38 , and cytotoxic CD8+ T cells have been shown to be relevant especially in allergic skin reactions 39–41 . More than twenty years ago, CD8+ T cells reactive to penicillin were isolated from patients with delayed type of hypersensitivity to penicillin 42 .…”