ABSTRACT
Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype and function of pathogenic T cells across the spectrum of severity requires investigation. 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, SJS/TEN and DRESS, and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling and scRNAseq + CITEseq + TCRseq supported in SJS/TEN clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin, along with expanded and non-expanded cytotoxic CD8+ skin TRM. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRM as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRM were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced regulatory T cell (Treg) signature compared to MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin like SJS/TEN, yet a pro-Treg signature like MDE. These findings have important implications for fundamental skin immunology and clinical care.
Subject(s)
Eccrine Porocarcinoma/diagnosis , Eccrine Porocarcinoma/therapy , Mohs Surgery , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/therapy , Sweat Gland Neoplasms/diagnosis , Sweat Gland Neoplasms/therapy , Axilla , Biopsy, Fine-Needle , Eccrine Porocarcinoma/radiotherapy , Eccrine Porocarcinoma/secondary , Eccrine Porocarcinoma/surgery , Female , Humans , Lymph Node Excision , Lymphatic Metastasis , Middle Aged , Multimodal Imaging , Neoplasm Recurrence, Local/pathology , Positron-Emission Tomography , Prognosis , Radiotherapy, Adjuvant , Sweat Gland Neoplasms/pathology , Sweat Gland Neoplasms/radiotherapy , Sweat Gland Neoplasms/surgery , Time Factors , Tomography, X-Ray ComputedABSTRACT
Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol compound, is derived from natural products such as the skin of red grapes, blueberries and cranberries. Resveratrol not only exhibits antioxidant, cardioprotection, and anti-aging properties, but can also inhibit cancer cell growth and induce apoptosis. It has been shown that resveratrol inhibits the activation of Nf-κB and subsequently down regulates the expression of Nf-κB regulated genes such as interleukin-2 and Bcl-2, leading to cell cycle arrest and increased apoptosis in multiple myeloma cells. In the skin, resveratrol has been reported to sensitize keratinocytes to UVA induced apoptosis. However, the effect of resveratrol on opening of the mitochondrial permeability transition pore has not been previously examined. Our data show that UVA (14 J/cm(2)) along with resveratrol causes massive oxidative stress in mitochondria. As a consequence of oxidative stress, the mitochondrial membrane potential decreases which results in opening of the mitochondrial pores ultimately leading to apoptosis in human keratinocytes. These results may have clinical implications for development of future chemotherapeutic treatment for tumors of the skin.
