HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

“…The cumulative level of flucloxacillin-protein binding directly correlated with the size of the T-cell response. Their data indicate that flucloxacillinprotein binding is critical for the formation of functional T-cell antigens and subsequent fluxcloxacillin stimulation of CD8 + T-cell clones supported a hapten mechanism of action [65]. However, evidence for a non-hapten mechanism in clones with HLA-B*5701 suggested additional immunopathological pathways, described below.…”

“…Wuillemin et al analysed the flucloxacillin-DILI mechanism based on three key criteria: first, stability/ability of drug binding to APC; second, involvement of proteosomal processing; and third, kinetics of drug stimulation of T-cell clones [65]. This found evidence to suggest that flucloxacillin can stimulate T-cells via both hapten and pi routes.…”

“…However, the properties of T-cell clones derived from this genotype and in vitro protein binding appears to be conserved across these drugs, suggesting that, theoretically at least, there is persistent risk of using these alternatives as therapies in HLA-B*5701 patients. Understanding the molecular mechanisms of flucloxacillin toxicity has provided an explanation as to why this allele confers an additional risk of DILI [65] but no reason has emerged as to why this applies in only a small fraction of people with this genotype leading them to develop fluxcloxacillin-DILI. Additionally, no mechanistic models so far address why flucloxacillin-reactive T-cells cause damage specifically in the liver.…”

Promiscuous T-cell responses to drugs and drug-haptens

“…Nonsense mutations in neighboring codons (G227X and Q232X) have been previously reported as causes of X-linked hyper-IgM syndrome. 6,7 Based on the mutation's absence in control subjects and in Exome Variant Server (EVS; National Heart, Lung, and Blood Institute GO Exome Sequencing Project, Seattle, Wash; http://evs.gs.washington.…”

Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy

“…In investigating flucloxacillin-induced liver injury, one group found that flucloxacillin was presented via the hapten mechanism with multiple HLA types, but was also presented in a non-proteasome dependent and labile manner restricted to HLA-B* 57:01 resulting in immediate CD8+ T cell activation, suggesting that the p-i mechanism is involved in this HLA-B* 57:01 associated drug reaction resulting in liver damage. (52, 53) However, another study found that activation of CD8+ T cells was restricted by HLA-B*57:01 and the closely related HLA-B*58:01 and that activation was processing dependent and correlated with flucloxacillin binding to albumin. (54) In studies of reactions to nevaripine, HLA I associations were found for severe skin manifestations in multiple populations, but HLA II was associated with hepatic events in Caucasians suggesting that different mechanisms of presentation may explain why some drugs induce a variety of different immunologically mediated adverse reactions.…”