Drug-Related Side Effects and Adverse Reactions study with OTHER data on dbGaP (14 participants)

phs003344 — Investigating Delayed-Onset Drug Hypersensitivity Reactions Prospectively

<p>Delayed-type drug hypersensitivity reactions (dtDHR) are significant causes of morbidity and mortality, but the origin, phenotype and function of pathogenic T cells across the spectrum of severity are unknown. Research has been hampered by several barriers. We leveraged recent technical advancements to study skin-resident memory T cells (TRM) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). As part of the overarching study, we used single cell RNA sequencing (scRNA-seq) with CITE sequencing and TCR sequencing on prospectively collected skin and blood samples from patients with SJS/TEN and MDE patients. We compared this to healthy controls obtained from discarded skin from surgeries and discarded blood collars from a blood donation center. These data are included here in dbGaP database. The overarching study also performed bulk transcriptional profiling and microscopic analysis of clinical skin samples, as well as a mouse model of MDE (<a href="https://pubmed.ncbi.nlm.nih.gov/39042477/">PMID: 39042477</a>). Together, the data supported clonal expansion and recruitment of cytotoxic CD8+ T cells (identified using the mean normalized expression of <a href="https://www.ncbi.nlm.nih.gov/gene/4818">NKG7</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/10578">GNLY</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/3001">GZMA</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/3002">GZMB</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/5551">PRF1</a>) from circulation into skin, along with both expanded and non-expanded cytotoxic CD8+ skin TRM in SJS/TEN whereas MDE displayed a cytotoxic T cell profile without expansion or recruitment of cytotoxic CD8+ T cells from circulation implicating TRM as the potential cause of disease. Concurrently, MDE displayed a pro-Treg signature, highlighted by <a href="https://www.ncbi.nlm.nih.gov/gene/1237">CCR8</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/7293">TNFRSF4</a> (OX40), which promotes Treg survival compared to SJS/TEN.</p>