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- Presentation
Immune Pathogenesis and Genetic Risk Factors Distinguishing Low-Risk Exanthems from Severe Cutaneous Adverse Reactions
Description
The speaker reviewed the immune mechanisms and genetic factors that distinguish low-risk morbilliform drug eruptions from severe cutaneous adverse reactions (SCAR) such as DRESS, SJS/TEN, and AGEP. He explained that these are type IV, T-cell–mediated hypersensitivity reactions, and described how drugs can trigger them through hapten formation, pharmacologic interaction, or altered peptide presentation. Two major studies were highlighted: one using single-cell and TCR sequencing showed that SJS/TEN is driven by recruited circulating cytotoxic CD8 T cells with low Treg activity, while morbilliform eruptions are more skin-limited and enriched for resident memory T cells and Treg signatures; another using spatial proteomics found distinct pathway patterns, including strong interferon/oxidative stress and keratinocyte STAT1 activation in TEN, and viral-reactivation signatures in DRESS. The talk then addressed why the same drugs can cause different phenotypes, emphasizing HLA risk alleles, but also noting that HLA alone has limited predictive value and that other genes such as ERAP and CYP enzymes contribute. Finally, the speaker described work showing immune checkpoint inhibitors independently and synergistically increase the risk of SJS/TEN, supporting a two-hit model in which they amplify susceptibility to other high-risk drugs.
View moreConclusions
- Low-risk morbilliform eruptions and severe cutaneous adverse reactions are both type IV, T-cell-mediated drug hypersensitivity reactions, but they arise from distinct immune programs.
- Morbilliform drug eruptions appear to be more skin-limited and driven largely by resident memory T cells with a more Treg-rich regulatory environment.
- SJS/TEN is characterized by recruitment and expansion of circulating cytotoxic T cells, strong cytotoxic effector activity, and markedly reduced Treg signaling.
- DRESS sits between these entities as a more systemic delayed hypersensitivity reaction with recruited cytotoxic T cells and immune dysregulation.
- JAK/STAT activation is present across severe drug reactions, but it is broader and includes keratinocyte involvement in SJS/TEN, helping explain its greater tissue destruction.
- Distinct HLA alleles confer drug-specific susceptibility, but HLA alone does not fully predict who will develop a reaction or which phenotype will occur.
- Additional genetic factors such as drug metabolism genes and peptide-processing genes like CYP2C9 and ERAP1 modify risk beyond HLA.
- The same drug can produce different phenotypes because outcome depends on the interaction of HLA restriction, TCR/peptide recognition, clonality, and immune context.
- Immune checkpoint inhibitors act as independent and synergistic risk amplifiers for SJS/TEN by lowering the activation threshold for drug-specific T-cell responses.
- Overall, clinical phenotype is shaped by the combination of genetic susceptibility and immune exposures rather than by a single mechanism or allele alone.
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