Novel Pharmacology Following Heteromerization of the Angiotensin II Type 2 Receptor and the Bradykinin Type 2 Receptor.

The angiotensin type 2 (AT) receptor and the bradykinin type 2 (B) receptor are G protein-coupled receptors (GPCRs) that have major roles in the cardiovascular system. The two receptors are known to functionally interact at various levels, and there is some evidence that the observed crosstalk may occur as a result of heteromerization. We investigated evidence for heteromerization of the AT receptor and the B receptor in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)-proximity based assays, including the Receptor Heteromer Investigation Technology (Receptor-HIT) and the NanoBRET ligand-binding assay.

Visual Genomics Analysis Studio as a Tool to Analyze Multiomic Data.

Type B adverse drug reactions (ADRs) are iatrogenic immune-mediated syndromes with mechanistic etiologies that remain incompletely understood. Some of the most severe ADRs, including delayed drug hypersensitivity reactions, are T-cell mediated, restricted by specific human leukocyte antigen risk alleles and sometimes by public or oligoclonal T-cell receptors (TCRs), central to the immunopathogenesis of tissue-damaging response. However, the specific cellular signatures of effector, regulatory, and accessory immune populations that mediate disease, define reaction phenotype, and determine severity have not been defined.

Immunopharmacogenomics: Mechanisms of HLA-Associated Drug Reactions.

The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell-mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy.

Role of pharmacogenomics in T-cell hypersensitivity drug reactions.

Purpose Of Review: An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions.

Recent Findings: Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B∗13:01 with co-trimoxazole-induced SCAR, and HLA-A∗32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide prior to HLA loading, are now associated with protection from abacavir-hypersensitivity in HLA-B∗57:01+ patients, and single-cell sequencing has defined the skin-restricted expansion of a single, public and drug-reactive dominant TCR across patients with HLA-B∗15:02-restricted carbamazepine-induced SJS/TEN.

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions.

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation.