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Updated: May 25, 2025
Granulocyte-dependent Autoantibody-induced Skin Blistering
Published on: October 12, 2012
Single-cell immunopathology of recurrent acute generalized exanthematous pustulosis associated with vancomycin
Eric M Mukherjee1,2, Andrew Gibson3, Matthew S Krantz1
1Department of Medicine, Center for Drug Safety and Immunology, Vanderbilt University Medical Center, Nashville, Tenn.
Background:
Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction to medication that presents within 72 hours of exposure with erythematous papules and plaques with overlying pustules. The immunopathogenesis and predisposing factors of AGEP are not well characterized.
Objective:
To better understand the genetic risk factors and single-cell immunopathogenesis of AGEP, we longitudinally characterized a patient with recurrent AGEP after an initial episode triggered by vancomycin.
Methods:
A clinical timeline over an 8-year period was paired with skin testing, histopathology, and immunogenetic and other testing at 3 time points. Skin biopsies performed on affected skin (positive vancomycin-delayed intradermal testing [IDT]) and unaffected control skin 8 years after the initial event were subjected to single-cell sequencing to measure gene and protein expression.
Results:
The patient was HLA-A∗32:01 positive, which has been associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms. IDT remained positive over time, despite recurrent reactions without drug exposure. Clinical features and histopathology of IDT-positive skin were consistent with AGEP. Single-cell analysis of affected skin showed polyclonal TH17-like cells with gene expression signatures similar to T-cell response during prevalent infectious diseases.
Conclusions:
This patient exhibited persistent vancomycin-positive IDT despite distinct nondrug episodes of ALEP/AGEP. This suggests that AGEP may be triggered by both antigen-specific and non-antigen-specific factors. AGEP-affected skin showed an inflammatory infiltrate with a TH17-like effector population, which may represent potentially actionable targets for therapeutic intervention. The presence of HLA-A∗32:01, a defined risk factor for vancomycin-induced drug reaction with eosinophilia and systemic symptoms, may indicate a shared predisposition, warranting further study.
Insights
Acute generalized exanthematous pustulosis (AGEP) can be triggered by non-drug factors, suggesting complex immunopathogenesis. Affected skin reveals TH17-like cells, offering potential therapeutic targets for this severe drug reaction.
Area of Science:
- Dermatology
- Immunology
- Pharmacogenomics
Background:
- Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse drug reaction.
- It typically manifests within 72 hours of medication exposure with pustules.
- The underlying immunopathogenesis and risk factors for AGEP remain poorly understood.
Purpose of the Study:
- To investigate the genetic risk factors and single-cell immunopathogenesis of AGEP.
- To longitudinally characterize a patient experiencing recurrent AGEP after vancomycin exposure.
Main Methods:
- Longitudinal clinical data collection over 8 years.
- Skin testing (intradermal testing - IDT) and histopathology performed at multiple time points.
- Single-cell sequencing of skin biopsies from affected and unaffected skin.
Main Results:
- The patient carried the HLA-A∗32:01 allele, a known risk factor for vancomycin-induced hypersensitivity.
- Persistent vancomycin-positive IDT was observed, even during non-drug-triggered AGEP episodes.
- Single-cell analysis revealed a TH17-like inflammatory infiltrate in affected skin.
Conclusions:
- AGEP may be initiated by both drug-specific and non-specific factors.
- The TH17-like effector population in AGEP skin presents potential therapeutic targets.
- The shared genetic predisposition, indicated by HLA-A∗32:01, warrants further investigation in AGEP.
