Drug Hypersensitivity (Severe Cutaneous Adverse Reaction) Module

Toxicology Pharmacology Immunology Module drug_hypersensitivity_scar 2 disorders Pathograph 5

A conserved treatment-toxicity module representing the T-cell-mediated immune pathway by which culprit drugs trigger severe cutaneous adverse reactions (SCARs), with Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) as the prototype. Unlike the cytotoxic (myelosuppression), metabolic (DILI), and transport-mediated (nephrotoxicity) toxicity modules, the insult here is immunological: a drug or its metabolite is presented in an HLA-restricted manner to drug-specific T cells, which expand and kill keratinocytes via cytotoxic mediators (granulysin, FasL, perforin/granzyme), producing epidermal necrolysis and detachment. The culprit drug varies (allopurinol, aromatic antiepileptics, sulfonamides, abacavir, NSAIDs) and HLA risk alleles gate susceptibility, but the downstream cascade converges. This is a "side effect as mechanism" module: a drug-toxicity entry can declare conformance rather than re-deriving the chain. Related SCAR presentations (DRESS, AGEP) share the T-cell-mediated logic but are not the evidence focus here.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

antigen processing and presentation GO:0019882 INCREASED T cell activation GO:0042110 INCREASED T cell mediated cytotoxicity GO:0001913 INCREASED apoptotic process GO:0006915 INCREASED cell death GO:0008219 INCREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "drug_hypersensitivity_scar#Cytotoxic Mediator Release and Keratinocyte Death"). Conforming nodes should substitute the drug-specific culprit and its HLA risk allele (e.g. HLA-B*58:01/allopurinol, HLA-B*15:02/carbamazepine, HLA-B*57:01/abacavir) while preserving the conserved HLA-restricted presentation → cytotoxic T-cell activation → keratinocyte death → epidermal necrolysis → mucocutaneous failure chain. The key conformance / central-effector target is "drug_hypersensitivity_scar#Cytotoxic Mediator Release and Keratinocyte Death".

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Used By Disorder Entries

Allopurinol-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis via Oxypurinol-HLA class I interaction with HLA-B*58:01 susceptibility → HLA-Restricted Drug Presentation to Drug-Specific T Cells , Drug-specific cytotoxic T-cell activation → Drug-Specific Cytotoxic T-Cell and NK-Cell Activation , Keratinocyte death by cytotoxic mediators → Cytotoxic Mediator Release and Keratinocyte Death , Epidermal necrolysis and detachment → Epidermal Necrolysis and Detachment , Mucocutaneous failure → Mucocutaneous Failure and Systemic Complications

Stevens-Johnson Syndrome via Drug-HLA Direct Interaction → HLA-Restricted Drug Presentation to Drug-Specific T Cells , Drug-Specific Cytotoxic T Cell Activation → Drug-Specific Cytotoxic T-Cell and NK-Cell Activation , Granulysin-Mediated Keratinocyte Apoptosis → Cytotoxic Mediator Release and Keratinocyte Death , Confluent Epidermal Necrosis and Detachment → Epidermal Necrolysis and Detachment

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Pathograph

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Pathophysiology

HLA-Restricted Drug Presentation to Drug-Specific T Cells

trigger

The conserved initiating lesion is immunological recognition of the drug: the drug or its metabolite is presented in an HLA class I-restricted manner to drug-specific T cells (via hapten, p-i, or altered-peptide mechanisms). Risk arises from the combination of drug structure/metabolism, HLA alleles, and the T-cell receptor repertoire — a type IV (delayed) hypersensitivity reaction.

CD8-positive cytotoxic T cell CL:0000625 keratinocyte CL:0000312

antigen processing and presentation GO:0019882 INCREASED

Used by disorders

Allopurinol-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis as Oxypurinol-HLA class I interaction with HLA-B*58:01 susceptibility

Stevens-Johnson Syndrome as Drug-HLA Direct Interaction

Downstream

Drug-Specific Cytotoxic T-Cell and NK-Cell Activation HLA-restricted presentation activates and expands drug-specific cytotoxic lymphocytes.

Drug-Specific Cytotoxic T-Cell and NK-Cell Activation

amplifier

Drug-specific CD8 T cells and natural killer cells are activated and expand, becoming the effector population that targets keratinocytes — the amplifying step linking antigen recognition to tissue injury.

CD8-positive cytotoxic T cell CL:0000625 natural killer cell CL:0000623

T cell activation GO:0042110 INCREASED

Used by disorders

Allopurinol-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis as Drug-specific cytotoxic T-cell activation

Stevens-Johnson Syndrome as Drug-Specific Cytotoxic T Cell Activation

Downstream

Cytotoxic Mediator Release and Keratinocyte Death Activated cytotoxic lymphocytes release mediators that kill keratinocytes.

Cytotoxic Mediator Release and Keratinocyte Death

central effector

Activated cytotoxic lymphocytes release soluble mediators — granulysin, Fas ligand, perforin/granzyme — that drive keratinocyte apoptosis and necroptosis. This is the central effector lesion and the key conformance target; conforming disorder nodes substitute the drug-specific culprit but converge here.

keratinocyte CL:0000312

T cell mediated cytotoxicity GO:0001913 INCREASED apoptotic process GO:0006915 INCREASED

Used by disorders

Allopurinol-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis as Keratinocyte death by cytotoxic mediators

Stevens-Johnson Syndrome as Granulysin-Mediated Keratinocyte Apoptosis

Downstream

Epidermal Necrolysis and Detachment Confluent keratinocyte death produces full-thickness epidermal necrosis.

Epidermal Necrolysis and Detachment

effector

Confluent keratinocyte death produces full-thickness epidermal necrosis that separates the epidermis from the dermis, the histopathologic hallmark of SJS/TEN that manifests as widespread skin and mucosal detachment.

keratinocyte CL:0000312

cell death GO:0008219 INCREASED

Used by disorders

Allopurinol-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis as Epidermal necrolysis and detachment

Stevens-Johnson Syndrome as Confluent Epidermal Necrosis and Detachment

Downstream

Mucocutaneous Failure and Systemic Complications Loss of the epidermal barrier produces life-threatening systemic consequences.

Mucocutaneous Failure and Systemic Complications

consequence

Extensive epidermal and mucosal detachment causes failure of the skin barrier, with fluid loss, infection risk, and multi-organ involvement, producing the high mortality of SJS/TEN — the defining consequence of the module.

keratinocyte CL:0000312

cell death GO:0008219 INCREASED

Used by disorders

Allopurinol-Induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis as Mucocutaneous failure