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PBMS cells from SJS/TEN

ABSTRACT: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell—mediated cytotoxicity that does not require direct cellular contact.

ORGANISM(S): Homo sapiens

PROVIDER: GSE13727 | GEO | 2008/12/04

SECONDARY ACCESSION(S): PRJNA114649

REPOSITORIES: GEO

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SJS blister cells

Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell—mediated cytotoxicity that does not require direct cellular contact.

2008-12-04 | GSE13726 | GEO

Transcription profiling of human Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis patients blister cells from skin lesions reveals these consist of cytotoxic T cells annd NK cells

Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis; (TEN) are life-threatening adverse drug reactions characterized; by massive epidermal necrosis, in which the specific danger; signals involved remain unclear. Here we show that blister; cells from skin lesions of SJS-TEN primarily consist of cytotoxic; T lymphocytes (CTLs) and natural killer (NK) cells, and both; blister fluids and cells were cytotoxic. Gene expression profiling; identified granulysin as the most highly expressed cytotoxic; molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids; were two to four orders of magnitude higher than perforin,; granzyme B or soluble Fas ligand concentrations, and depleting; granulysin reduced the cytotoxicity. Granulysin in the blister; fluids was a 15-kDa secretory form, and injection of it into; mouse skin resulted in features mimicking SJS-TEN. Our; findings demonstrate that secretory granulysin is a key molecule; responsible for the disseminated keratinocyte death in SJS-TEN; and highlight a mechanism for CTL- or NK cellâmediated; cytotoxicity that does not require direct cellular contact. Experiment Overall Design: Blood samples were obtained from 5 different patients with SJS/TEN. The peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood samples by Ficoll-Isopaque (Pharmacia Fine Chemicals) density gradient centrifugation. Total RNA from PBMC was isolated using the RNeasy kit (Qiagen). The 28S and 18S ribosomal RNA peak ratios were determined using microfluidics technology (Agilent). RNA was subjected to reverse transcription using the Superscript II kit (Invitrogen), and the cleaned cRNA was then hybridized to an Affymetrix human genome U133 plus 2.0 array.

2009-01-13 | E-GEOD-13727 | biostudies-arrayexpress

Project description:Blister cells and PBMCs from patients with SJS-TEN

| PRJNA110589 | ENA

Homo sapiens

Project description:SJS blister cells

| PRJNA114647 | ENA

CD127+CD94+ innate lymphoid cells expanded in Crohn’s disease patients highly express granulysin and perforin

Project description:Controversy in the identity and distinction of helper ILC1s and NK cells exist due to overlapping markers and the use of different gating strategies by distinct groups. Recently we identified cytotoxic ILC3s characterized by expression of CD94. Here we analyzed the full spectrum of CD127+ ILCs and NK cells in intestinal lamina propria from healthy donors and Crohn’s disease patients and identified two populations of CD127+CD94+ ILCs, designated A and B that could be distinguished on expression of CD117, CD18 and cytotoxic molecules. Population B highly expressed granulysin, a cytotoxic molecule linked to bacterial lysis and/or chemotaxis of monocytes. Granulysin protein was amply secreted by population B cells upon stimulation with IL-15. Activation of population B in the presence of TGF-β strongly reduced the expression of cytotoxic effector molecules of population B. Strikingly, samples from individuals that suffer from active Crohn disease displayed dramatically enhanced frequencies of granulysin expressing effector CD127+CD94+ ILCs compared to non-inflamed controls.

2021-10-13 | GSE173642 | GEO

Homo sapiens

Project description:PBMS cells from SJS/TEN

| PRJNA114649 | ENA

Selection of tumor resistant variants following sustained NK-mediated immune stress

Project description:Resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell-mediated cytotoxicity, resistant variants were selected following long term NK cell selection pressure. We found that these variants are resistant to NK cell-mediated lysis but still sensitive to autologous cytotoxic T lymphocytes or cytotoxic drugs. This resistance seems to be dependent, at least partly, of an alteration of the target cell recognition by NK effector cells, but does not appear to involve any alteration of KIR, DNAM1 or NKG2D ligands expression on resistant cells nor the induction of a protective autophagy. To gain further insight into the molecular mechanisms underlying the acquired tumor resistance to NK cells-mediated cytotoxicity, we have conducted a comprehensive analysis of the variants transcriptome. Comparative analysis identified an expression profile of genes that best distinguished resistant variant from parental sensitive cancer cells with candidate genes putatively involved in NK cell-mediated lysis resistance, but also in adhesion, migration and invasiveness including up-regulated genes such as POT1, L1CAM or ECM1 and down-regulated genes like B7-H6 or UCHL1. Consequently, the selected variants did not only display resistance to NK cell-mediated lysis but also exhibited more aggressive properties. The present studies emphasize that NK cells expand far beyond the simple killing of malignant cells and may be important effectors during cancer immunoediting.This study aims to compare transcriptome of T1_ref cells (2 triplicates samples untreated versus 2 triplicate samples of T1 after cocultured with NK cells).

2020-11-02 | E-MTAB-8777 | biostudies-arrayexpress

Differential gene expression in the Lacrimal gland during development and onset of xerostomia in Sjogren's syndrome-like disease of the C57BL/6.NOD-Aec1Aec2 mouse.

Project description:Recently, we reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the NOD mouse capable of conferring Sjogren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying onset of stomatitis sicca (xerostomia) in this C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study utilizing genomic microarray technology. The present study was designed to define the changing gene expression profiles within the Lacrimal glands of C57BL/6.NOD-Aec1Aec2 mice at five time points representing a pre-disease stage (4 weeks), the early pre-clinical stage (8 weeks), the initial influx of leukocytes into the Lacrimal glands (12 weeks), the early clinical phase of autoimmunity (16 weeks), and the early onset of clinical SjS-like disease characterized by secretory dysfunction (20 weeks). The C57BL/6.NOD-Aec1Aec2 mouse is a model of primary SjS in which the Idd3 region of chromosome 3 and the Idd5 region of chromosome 1 derived from the NOD mouse were bred into the non-autoimmune C57BL/6 mouse, resulting in a SjS-like disease susceptibility that mimics both the pathophysiological characteristics and reduced secretory responses observed with NOD mice during development and onset of disease. This SjS-susceptible strain was designated C57BL/6.NOD-Aec1Aec2, where Aec1 corresponds to Idd3 (of chromosome 3) and Aec2 corresponds to Idd5 (of chromosome 1).

2013-06-25 | E-GEOD-48139 | biostudies-arrayexpress

Salivary gland during development and onset of xerostomia in murine model of SjM-CM-6gren's syndrome-like disease

Project description:Differential gene expression in the salivary gland during development and onset of xerostomia in SjM-CM-6grenM-bM-^@M-^Ys syndrome-like disease of the C57BL/6.NOD-Aec1Aec2 mouse. Recently, we reported the development of the C57BL/6.NOD-Aec1Aec2 mouse that carries two genetic intervals derived from the NOD mouse capable of conferring SjM-CM-6grenM-bM-^@M-^Ys syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. In an attempt to define the molecular bases underlying onset of stomatitis sicca (xerostomia) in this C57BL/6.NOD-Aec1Aec2 mouse model, we have carried out a study utilizing microarray technology. The present study was designed to define the changing gene expression profiles within the salivary glands of C57BL/6.NOD-Aec1Aec2 mice at five time points representing a pre-disease stage (4 weeks), the early pre-clinical stage (8 weeks), the initial influx of leukocytes into the salivary glands (12 weeks), the early clinical phase of autoimmunity (16 weeks), and the early onset of clinical SjSlike disease characterized by secretory dysfunction (20 weeks). The C57BL/6.NOD-Aec1Aec2 mouse is a model of primary SjS in which the Idd3 region of chromosome 3 and the Idd5 region of chromosome 1 derived from the NOD mouse were bred into the non-autoimmune C57BL/6 mouse, resulting in a SjS-like disease susceptibility that mimics both the pathophysiological characteristics and reduced secretory responses observed with NOD mice during development and onset of disease. This SjS-susceptible strain was designated C57BL/6.NOD-Aec1Aec2, where Aec1 corresponds to Idd3 (of chromosome 3) and Aec2 corresponds to Idd5 (of chromosome 1).

2009-04-11 | E-GEOD-15640 | biostudies-arrayexpress

Treatment of human K562 chronic myelogenous leukemia cells with NK3.3-derived extracellular vesicles

Project description:Our study investigates the features and anti-tumor function of extracellular vesicles (EVs) isolated from our well described NK cell line - NK3.3 - the only published clonal, normal human cell line to date. Natural killer (NK) cells, critical for proper immune function, destroy tumor cells primarily through the release of granules containing potent cytolytic molecules. NK cells also release these molecules within membrane-bound exosomes and microvesicles collectively known as EVs. We show that NK3.3 EVs contain the cytolytic molecules perforin, granzymes A and B, and granulysin, and an array of common EV proteins. We previously showed that the E3 ubiquitin ligase identified by our laboratory, natural killer lytic-associated molecule (NKLAM/RNF19b), is localized to NK granules and is essential for maximal NK killing; our current study shows NKLAM situated within the NK3.3 EV membrane. We demonstrate that treatment of an array of hematopoietic and non-hematopoietic tumor cell lines with NK3.3 EVs inhibits proliferation and induces apoptosis and cell death while leaving normal cells unaffected. The anti-tumor effects of NK3.3EVs were evaluated via proteomic analysis of K562 leukemia cells treated with NK3.3-derived EVs compared to treatment with non-cytotoxic HEK293 cell-derived EVs or PBS. The results of this analysis suggest strong inhibitory regulation of cell cycle- and cell survival-associated proteins. Taken together, our study suggests that NK3.3 EVs have the potential to be effective immunotherapeutic agents.

2021-09-07 | PXD027221 | Pride

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