Post-epidemic eosinophilia myalgia syndrome associated with L-Tryptophan
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ABSTRACT: Eosinophilia–myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. The EMS epidemic in 1989 was linked to L-tryptophan consumption originating from a single source. Following the Food and Drug Administration (FDA) ban on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been published since the FDA ban was lifted in 2005. We report the clinical, histopathological and immunogenetic features of a new case of L-tryptophan-associated EMS along with evidence of activated transforming growth factor-ß and interleukin-4 signaling in the lesional skin. 6 samples were analyzed to include EMS patient and two replicates along with three normal controls
Project description:Eosinophilia–myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. The EMS epidemic in 1989 was linked to L-tryptophan consumption originating from a single source. Following the Food and Drug Administration (FDA) ban on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been published since the FDA ban was lifted in 2005. We report the clinical, histopathological and immunogenetic features of a new case of L-tryptophan-associated EMS along with evidence of activated transforming growth factor-ß and interleukin-4 signaling in the lesional skin.
Project description:Background. Endometriosis (EMS) is a chronic, gynecological condition affecting 6-10% of reproductive-age women. While these lesions are benign, ovarian EMS present cancer-like features, and can progress to endometriosis-correlated ovarian cancer (ECOC) through a multistep process. Given the regulatory role of miRNAs in gene expression and biological pathways, we aimed to identify miRNAs associated with the malignant transformation of ovarian EMS, which could serve as a potential diagnostic tool for the early identification of such patients. Methods. Global miRNA profiling was performed in patients with benign ovarian EMS (EMS-b) and patients with ECOC. Differential expression analysis (DEA) of miRNAs between EMS-b, EMS tissues from patients with ECOC (EMS-k) and ECOC tissues was performed. Receiver Operating Characteristic (ROC) curves were built to evaluate the binary classification performance of significant miRNAs. Results. Comparison between EMS-b and EMS-k revealed 13 significantly deregulated miRNAs. Furthermore, when comparing ECOC and EMS-b we observed significant deregulation of 181 miRNAs. ROC analysis revealed a panel of seven upregulated miRNAs with accuracies above 0.7 in identifying EMS-k and EMS-b. Notably, four miRNAs (hsa-miR-200a-3p, hsa-miR-141-3p, hsa-miR-183-5p, hsa-miR-10a-5p) were consistently upregulated in both EMS-k and ECOC tissues. Conclusions. Our study identified a panel of miRNA biomarkers that may serve as potential candidates for the early detection of ECOC in patients previously diagnosed with ovarian EMS.
Project description:Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and viscera. To understand the immunological components of DRESS, we prospectively assessed 40 DRESS patients. The patients were evaluated for phenotype, cytokine secretion, repertoire of CD4+ and CD8+ peripheral blood T lymphocytes and viral reactivation. A subgroup of patients was analyzed using microarrays.
Project description:Endometriosis (EMs) is a common infertility-related disease in women of reproductive age. Impaired endometrial decidualization is one of the most important factors contributing to the embryo implantation failure EMs patients. However, the exact mechanism remains unclear. Previous studies have shown collagen I deposition in the eutopic endometrium of EMs patients, which may lead to impaired endometrial decidualization. The level of collagen I in eutopic endometrium of EMs was analyzed. We performed a proteomic analysis of ectopic endometrial stromal cell-derived extracellular vesicles (EMs-EVs) and extracellular vesicles derived from endometrial stromal cells in the endometrium of control patients (CTL-EVs). An endometrial transcriptional profiles of EMs patients and normal controls in the mid-secretory phase of menstrual cycle was compared. Endometrial stromal cells (ESCs) were stimulated with chloroquine or rapamycin to evaluate the association between autophagy and collagen I. The expression of PKM2 in EMs-EVs and serum extracellular vesicles from EMs patients were examined by western blotting. PKM2 was overexpressed or knockdown in ESCs to investigate the level of autophagy and collagen I. ESCs were treated with ectopic ESC-derived extracellular vesicles with highly expressed PKM2 protein, and the potential molecular mechanisms were further confirmed through western blotting and immunohistochemical analysis. We found that endometrial collagen I expression during the mid-secretory phase was increased in the EMs group. We demonstrated that autophagy is defective in eutopic endometrial stromal cells (ESCs) of EMs patients. In ESCs, pharmacological inhibition of autophagy by chloroquine (CQ) promoted collagen I deposition. Ectopic endometrial stromal cell-derived extracellular vesicles (EMs-EVs) inhibited autophagy of ESCs and promoted collagen I deposition in vivo and in vitro. Mechanistically, EMs-EVs encapsulating PKM2 impair eutopic endometrial autophagy via Akt/mTOR signaling pathway. Together, we demonstrated that EMs-EVs encapsulating PKM2 impaired endometrial autophagy inducing collagen I deposition in EMs, which provided a potential target for therapeutic implications.
Project description:This study aimed to screen candidate genes regulating EMs using a combination of whole transcriptome and proteomics analyses and provide a theoretical basis for further study of the pathogenesis of EMs.
Project description:Lesional skin biopsies were taken from patients with active, untreated lupus skin disease (chronic discoid lupus erythematosus, CDLE, n=6; subacute cutaneous lupus erythematosus, SCLE, n=5). Healthy control specimens (HC) were obtained from healthy skin of 5 patients undergoing plastic surgery. In every case, two 4mm punch biopsies were taken. One was flash-frozen in liquid nitrogen and afterwards processed for mRNA isolation. The second biopsy was fixed in 5% formalin solution overnight, and was proceeded for histological investigation.The one-color Agilent 60-mer oligo microarray (Agilent, Santa Clara, CA) was used for gene expression analyses. Statistical analyses were performed using the Agilent Feature Extraction Software⢠and the Rosetta Resolver⢠gene expression data analysis system. The presented gene list (Table S1) includes normalized sample/ control log10-ratios (expression > 2-fold enhanced, p<0.01).
Project description:Many tumors escape by activating multiple cellular pathways that induce immunosuppression. One pivotal immune-suppressive mechanism is the production of tryptophan metabolites along the kynurenine pathway by IFNγ-induced IDO1 enzyme production 4-8. Phase III clinical trials using chemical inhibition of IDO1 in combination with PD1 pathway blockade, however, failed to improve melanoma treatment 9-12. This points at an incomplete understanding of the role of IDO1 and the consequent tryptophan degradation on mRNA translation and cancer progression. Here, we investigated the effects of prolonged IFNγ treatment on mRNA translation in melanoma cells by ribosome profiling. Surprisingly, we observed a massive accumulation of ribosomes ~20 amino acids downstream of tryptophan codons (termed here as W-Bumps) along with their expected stalling at the tryptophan codon itself. This indicated ribosomal bypass of the tryptophan codons in the absence of tryptophan. Detailed examination of W-Bumps position and its corresponding peptide sequences pinpointed towards ribosomal frameshifting events and their effects in the ribosome exit tunnel. In particular, W-Bumps strength was associated with the disorderedness level of potential out-of-frame peptides predicted downstream of tryptophan codons. Indeed, reporter assays demonstrated the induction of ribosomal frameshifting, and the generation of trans-frame proteins and their presentation at the cell surface after IFNγ treatment. Proteomics and immunopeptidomics analyses verified the production of IFNγ-induced trans-frame and out-of-frame aberrant peptides and their presentation on HLA class I molecules. Priming of naïve T cells from healthy donors with aberrant peptides resulted in identification of reactive, peptide-specific T cells. Altogether, our results suggest that IFNγ-induced IDO1-mediated tryptophan depletion plays a role in the immune recognition of melanoma cells by contributing to the diversity of the peptidome landscape, and by inducing the presentation of aberrant peptides.
Project description:Granulosa cells are essential to the growth, development, and maturation of oocytes and follicles. In patients with EMs-related infertility, follicle maturation disorders, poor oocyte quality may be closely related to GCs in the follicle. However, the molecular biological mechanism of GCs in EMs-related infertility has not been reported. Therefore, we tried to explore the possible causes of EMs-related infertility through the study of ovarian GCs in patients with EMs-related infertility and tubal factor infertility.
Project description:Extensive tumor inflammation, reflected by high levels of infiltrating T-cells and Interferon gamma (IFNγ) signaling, is thought to improve checkpoint immunotherapy response. However, many tumors escape by activating multiple cellular pathways that induce immunosuppression. One pivotal immune-suppressive mechanism is the production of Tryptophan metabolites along the kynurenine pathway by IFNγ-induced IDO1 enzyme production. However, phase III clinical trials using chemical inhibition of IDO1 in combination with PD1 pathway blockade failed to improve melanoma treatment, suggesting incomplete understanding of the role of IDO1 and the consequent Tryptophan degradation on mRNA translation and cancer progression. Here, we investigated the effects of prolonged IFNγ treatment on mRNA translation in melanoma cells by ribosome profiling. Our results suggest that IFNγ-induced IDO1-mediated Tryptophan depletion may play a key role in the immune recognition of melanoma cells, by inducing the production and presentation of aberrant peptides.