Logo image
Back
Single cell approaches to define the pathogenic immune cells that mediate drug hypersensitivity
Journal article   Peer reviewed

Single cell approaches to define the pathogenic immune cells that mediate drug hypersensitivity

K.D. White, K.C. Konvinse, M.A. Pilkinton, A. Redwood, J.A. Trubiano, J.G. Peter, R. Lehloenya, W-H Chung, S-L Hung, R-Y Pan, …
Journal of Allergy and Clinical Immunology, Vol.141(2), AB88
2018
DOI: https://doi.org/10.1016/j.jaci.2017.12.282
url
Link to Published Version *Subscription may be requiredView

Abstract

Rationale Striking class I HLA risk associations and CD8+ T cell dependency have been described for both Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) and abacavir hypersensitivity (AHS). However, distinct clinical phenotypes and positive predictive values (55% for HLA-B*57:01 restricted AHS and <8% for all HLA risk alleles and SJS/TEN) highlight key mechanistic differences. Methods Single cell technologies including T-cell receptor αβ sequencing, multi-parameter flow cytometry, full transcriptome RNA-seq, and mass cytometry were used to define the clonality and molecular signatures of pathogenic drug-specific T cells from paired PBMC, blister fluid, and acute, recovery, and patch test positive skin in SJS/TEN and AHS (n=25). Results Dominant CD8+ T-cell clonotypes of effector memory phenotype (CCR7-) with variable expression of skin homing/residence markers (CLA, CD103) were seen in SJS/TEN skin and blister fluid and were present at much lower frequency in both acute and drug-stimulated recovery peripheral blood. A public TCR was dominant in blister fluid of HLA-B*15:02 restricted carbamazepine-SJS/TEN. For allopurinol SJS/TEN, a dominant clonotype was identified in HLA-B*58:01+ blister fluid and a novel HLA class I restriction was identified with striking T-cell clonality (>97%) in blister fluid and skin. In contrast, for AHS, abacavir responsive CD8+ T cells with shared TCR clonotypes were isolated from the peripheral blood and positive patch tests that were polyclonal. Conclusions Single cell approaches that define the signatures of drug-specific T cells in the skin and peripheral blood highlight mechanistic differences between HLA class I restricted drug hypersensitivity syndromes and will help drive the development of targeted therapeutics and screening approaches.

Details

Metrics

93 Record Views

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types
Domestic collaboration
International collaboration
Citation topics
No Topic Assigned
No Topic Assigned
No Topic Assigned
Web Of Science research areas
Allergy
Immunology
ESI research areas
Immunology
Logo image