Kinetics of Abacavir-Induced Remodelling of the Major Histocompatibility Complex Class I Peptide Repertoire

Illing, Patricia T.; Hateren, Andy van; Darley, Rachel; Croft, Nathan P.; Mifsud, Nicole A.; King, Serina; Kostenko, Lyudmila; Bharadwaj, Mandvi; McCluskey, James; Elliott, Tim; Purcell, Anthony W.

doi:10.3389/fimmu.2021.672737

Cited by 9 publications

(3 citation statements)

References 67 publications

(113 reference statements)

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“…4 ). This implies that the activation of CD8 + T cells still occurs based on the effect of abacavir on antigen presentation, consistent with previous studies ( 21 , 22 ). However, abacavir-induced recruitment of inflammatory cells to the skin was reliant on HLA polymorphism-dependent ER stress responses in keratinocytes.…”

Section: Discussionsupporting

confidence: 92%

“…Since we observed an HLA polymorphism-dependent intracellular response to abacavir, we hypothesized that HLA could bind to abacavir intracellularly. Although not yet confirmed, the abacavir parent drug has been predicted to interact with HLA-B*57:01 in the ER ( 21 , 22 ). Consistent with a previous study ( 20 ), we demonstrated the binding of HLA-B*57:01 to abacavir using HeLa cells in which HLA was transiently expressed ( 36 ).…”

Section: Resultsmentioning

confidence: 99%

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HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

Kazaoka,

Fujimori,

Yamada

et al. 2024

PNAS Nexus

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Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity, which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T-cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as IFN-γ, IL-1β, and CCL27, and induced T-lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate. HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-phenylbutyrate. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated abacavir hypersensitivity. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

Kazaoka,

Fujimori,

Yamada

et al. 2024

PNAS Nexus

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“…Previous studies showed that HLA-B*5701 is necessary for the development of abacavir hypersensitivity syndrome (AHS) 9 . Abacavir is able to alter the self-peptide loading into HLA-B*57:01, co-occupy the groove and selectively affect the formation of HLA-B*57:01-peptide complexes thus provoking immune responses 7 , 10 – 12 . Cytotoxic CD8+ T cells drove systemic reactions to abacavir by drug-specific activation which could only be mediated by HLA-B*57:01 and not closely related, non-AHS associated allotypes 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Allopurinol non-covalently facilitates binding of unconventional peptides to HLA-B*58:01

Huan,

Zhuo,

Lee

et al. 2023

Sci Rep

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Allopurinol, widely used in gout treatment, is the most common cause of severe cutaneous adverse drug reactions. The risk of developing such life-threatening reactions is increased particularly for HLA-B*58:01 positive individuals. However the mechanism of action between allopurinol and HLA remains unknown. We demonstrate here that a Lamin A/C peptide KAGQVVTI which is unable to bind HLA-B*58:01 on its own, is enabled to form a stable peptide-HLA complex only in the presence of allopurinol. Crystal structure analysis reveal that allopurinol non-covalently facilitated KAGQVVTI to adopt an unusual binding conformation, whereby the C-terminal isoleucine does not engage as a PΩ that typically fit deeply in the binding F-pocket. A similar observation, though to a lesser degree was seen with oxypurinol. Presentation of unconventional peptides by HLA-B*58:01 aided by allopurinol contributes to our fundamental understanding of drug-HLA interactions. The binding of peptides from endogenously available proteins such as self-protein lamin A/C and viral protein EBNA3B suggest that aberrant loading of unconventional peptides in the presence of allopurinol or oxypurinol may be able to trigger anti-self reactions that can lead to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

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Immunopharmacogenomics: Mechanisms of HLA‐Associated Drug Reactions

Deshpande

Hertzman

Palubinsky

et al. 2021

Clin Pharma and Therapeutics

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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. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug‐induced T‐cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T‐cell‐mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA‐associated drug reactions and the implications for future translation into clinical care.

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Kinetics of Abacavir-Induced Remodelling of the Major Histocompatibility Complex Class I Peptide Repertoire

Cited by 9 publications

References 67 publications

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

Allopurinol non-covalently facilitates binding of unconventional peptides to HLA-B*58:01

Immunopharmacogenomics: Mechanisms of HLA‐Associated Drug Reactions

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