867 results on '"Geisler, Carsten"'
Search Results
202. MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells
- Author
-
Boding, Lasse, primary, Hansen, Ann K., additional, Meroni, Germana, additional, Levring, Trine B., additional, Woetmann, Anders, additional, Ødum, Niels, additional, Bonefeld, Charlotte M., additional, and Geisler, Carsten, additional
- Published
- 2015
- Full Text
- View/download PDF
203. Fine-tuning of T-cell development by the CD3γ di-leucine-based TCR-sorting motif
- Author
-
Lauritsen, Jens Peter H., primary, Boding, Lasse, additional, Buus, Terkild B., additional, Kongsbak, Martin, additional, Levring, Trine B., additional, Rode, Anna K. O., additional, Bonefeld, Charlotte Menné, additional, and Geisler, Carsten, additional
- Published
- 2015
- Full Text
- View/download PDF
204. Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma
- Author
-
Lauenborg, Britt, primary, Christensen, Louise, additional, Ralfkiaer, Ulrik, additional, Kopp, Katharina L., additional, Jønson, Lars, additional, Dabelsteen, Sally, additional, Bonefeld, Charlotte M., additional, Geisler, Carsten, additional, Gjerdrum, Lise Mette R., additional, Zhang, Qian, additional, Wasik, Mariusz A., additional, Ralfkiaer, Elisabeth, additional, Ødum, Niels, additional, and Woetmann, Anders, additional
- Published
- 2015
- Full Text
- View/download PDF
205. Ectopic expression of a novel CD22 splice-variant regulates survival and proliferation in malignant T cells from cutaneous T cell lymphoma (CTCL) patients
- Author
-
Bagdonaite, Ieva, primary, Wandall, Hans H., additional, Litvinov, Ivan V., additional, Nastasi, Claudia, additional, Becker, Jürgen C., additional, Dabelsteen, Sally, additional, Geisler, Carsten, additional, Bonefeld, Charlotte M., additional, Zhang, Qian, additional, Wasik, Mariusz A., additional, Zhou, Youwen, additional, Sasseville, Denis, additional, Ødum, Niels, additional, and Woetmann, Anders, additional
- Published
- 2015
- Full Text
- View/download PDF
206. Nickel acts as an adjuvant during cobalt sensitization
- Author
-
Bonefeld, Charlotte Menné, primary, Nielsen, Morten Milek, additional, Vennegaard, Marie T., additional, Johansen, Jeanne Duus, additional, Geisler, Carsten, additional, and Thyssen, Jacob P., additional
- Published
- 2015
- Full Text
- View/download PDF
207. Vitamin D-binding protein controls T cell responses to vitamin D
- Author
-
Kongsbak, Martin, von Essen, Marina Rode, Levring, Trine Bøegh, Schjerling, Peter, Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte Menné, Geisler, Carsten, Kongsbak, Martin, von Essen, Marina Rode, Levring, Trine Bøegh, Schjerling, Peter, Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte Menné, and Geisler, Carsten
- Abstract
BACKGROUND: In vitro studies have shown that the active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), can regulate differentiation of CD4+ T cells by inhibiting Th1 and Th17 cell differentiation and promoting Th2 and Treg cell differentiation. However, the serum concentration of 1,25(OH)2D3 is far below the effective concentration of 1,25(OH)2D3 found in in vitro studies, and it has been suggested that 1,25(OH)2D3 must be produced locally from the inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to affect ongoing immune responses in vivo. Although it has been reported that activated T cells express the 25(OH)D-1α-hydroxylase CYP27B1 that converts 25(OH)D3 to 1,25(OH)2D3, it is still controversial whether activated T cells have the capacity to produce sufficient amounts of 1,25(OH)2D3 to affect vitamin D-responsive genes. Furthermore, it is not known how the vitamin D-binding protein (DBP) found in high concentrations in serum affects T cell responses to 25(OH)D3.RESULTS: We found that activated T cells express CYP27B1 and have the capacity to produce sufficient 1,25(OH)2D3 to affect vitamin D-responsive genes when cultured with physiological concentrations of 25(OH)D3 in serum-free medium. However, if the medium was supplemented with serum or purified DBP, DBP strictly inhibited the production of 1,25(OH)2D3 and 25(OH)D3-induced T cell responses. In contrast, DBP did not inhibit the effect of exogenous 1,25(OH)2D3. Actin, arachidonic acid and albumin did not affect the sequestration of 25(OH)D3 by DBP, whereas carbonylation of DBP did.CONCLUSIONS: Activated T cells express CYP27B1 and can convert 25(OH)D3 to 1,25(OH)2D3 in sufficiently high concentrations to affect vitamin D-responsive genes when cultured in serum-free medium. However, DBP sequesters 25(OH)D3 and inhibits the production of 1,25(OH)2D3 in T cells. To fully exploit the immune-regulatory potential of vitamin D, future studies of the mechanisms that enable the immune sy
- Published
- 2014
208. Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin
- Author
-
Dyring-Andersen, B, Geisler, Carsten, Agerbeck, C, Lauritsen, J P H, Gúdjonsdottir, S D, Skov, L, Bonefeld, C M, Dyring-Andersen, B, Geisler, Carsten, Agerbeck, C, Lauritsen, J P H, Gúdjonsdottir, S D, Skov, L, and Bonefeld, C M
- Abstract
BACKGROUND: Psoriasis is a common immune-mediated inflammatory disease that affects the skin and joints. The interleukin (IL)-23/IL-17A axis and IL-22 play key roles in the pathogenesis of psoriasis. IL-23-responsive innate lymphoid cells (ILCs) with a high capacity to produce IL-17 and/or IL-22 have recently been identified and associated with inflammatory bowel diseases. The occurrence and role of ILCs in human skin are poorly understood.OBJECTIVES: To describe the prevalence of the different ILC subpopulations in skin from healthy controls and patients with psoriasis or allergy to nickel.METHODS: Skin biopsies were taken from healthy skin, nonlesional and lesional psoriatic skin, and nickel- and petrolatum-exposed skin from patients with contact allergy to nickel, and lymphocytes were isolated. The cells were stained and characterized by flow cytometry. Cytokine and ligand mRNA expression were measured by quantitative polymerase chain reaction.RESULTS: We found that members of the three groups of ILCs were present in human skin. Remarkably, the number and frequency of RORγt(+) CD56(+) ILC3s, which are known to produce IL-22, were elevated in both nonlesional and lesional skin from patients with psoriasis compared with healthy skin and skin from patients with contact allergy to nickel. Furthermore, skin ILCs expressed high levels of the natural killer receptor NKG2D. NKG2D binds to stress-induced ligands, including major histocompatibility complex class I-related chain A, which we found to be strongly upregulated in lesional skin from patients with psoriasis.CONCLUSION: These results show that ILCs are present in human skin and indicate that RORγt(+) CD56(+) ILC3 may be involved in the pathogenesis of psoriasis.
- Published
- 2014
209. An immune response study of oakmoss absolute and its constituents atranol and chloroatranol
- Author
-
Bonefeld, Charlotte Menné, Nielsen, Morten Milek, Gimenéz-Arnau, Elena, Lang, Matthieu, Vennegaard, Marie Torp, Geisler, Carsten, Johansen, Jeanne Duus, Lepoittevin, Jean-Pierre, Bonefeld, Charlotte Menné, Nielsen, Morten Milek, Gimenéz-Arnau, Elena, Lang, Matthieu, Vennegaard, Marie Torp, Geisler, Carsten, Johansen, Jeanne Duus, and Lepoittevin, Jean-Pierre
- Abstract
BACKGROUND: Atranol and chloroatranol are the main allergens of oakmoss absolute. However, the immune responses induced by these substances are poorly characterized.OBJECTIVES: To characterize immune responses induced by atranol, chloroatranol and oakmoss absolute in mice.METHODS: Mice were sensitized and challenged with various concentrations of atranol, chloroatranol, and oakmoss absolute. The immune responses were analysed as B cell infiltration, T cell proliferation in the draining lymph nodes, and expression of interleukin (IL)-18, IL-1β and tumour necrosis factor-α in skin. The cytotoxicity of atranol and chloroatranol against keratinocytes was determined.RESULTS: Sensitization experiments showed that atranol, chloroatranol and oakmoss induced sensitization when applied in high concentrations. Challenge experiments showed that even low concentrations of atranol and chloroatranol induced sensitization. In parallel, atranol and chloroatranol elicited challenge reactions following sensitization with oakmoss. The magnitude of the immune response to the three allergens increased in the following order: atranol, chloroatranol, and oakmoss. The expression of proinflammatory cytokines was induced by chloroatranol and oakmoss, but not by atranol. Chloroatranol was found to be more cytotoxic than atranol against keratinocytes.CONCLUSIONS: Atranol and chloroatranol can elicit both sensitization and challenge reactions, but the mixture of allergens in oakmoss absolute is more potent than atranol and chloroatranol alone.
- Published
- 2014
210. IL-1β-Dependent Activation of Dendritic Epidermal T Cells in Contact Hypersensitivity
- Author
-
Nielsen, Morten M, Lovato, Paola, Macleod, Amanda S, Witherden, Deborah A, Skov, Lone, Dyring-Andersen, Beatrice, Dabelsteen, Sally, Woetmann, Anders, Odum, Niels, Havran, Wendy L, Geisler, Carsten, Bonefeld, Charlotte M, Nielsen, Morten M, Lovato, Paola, Macleod, Amanda S, Witherden, Deborah A, Skov, Lone, Dyring-Andersen, Beatrice, Dabelsteen, Sally, Woetmann, Anders, Odum, Niels, Havran, Wendy L, Geisler, Carsten, and Bonefeld, Charlotte M
- Abstract
Substances that penetrate the skin surface can act as allergens and induce a T cell-mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4(+) T cells. However, it is now known that several cell types, including γδ T cells, can produce IL-17. In this study, we determine the role of γδ T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitrofluorobenzene (DNFB) is used as allergen, we found that γδ T cells are important players in CHS. Thus, more IL-17-producing DETCs appear in the skin following exposure to DNFB in wild-type mice, and DNFB-induced ear swelling is reduced by ∼50% in TCRδ(-/-) mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by ∼50% in IL-17(-/-) mice. We show that DNFB triggers DETC activation and IL-1β production in the skin and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1β produce IL-17. Importantly, we demonstrate that the IL-1R antagonist anakinra significantly reduces CHS responses, as measured by decreased ear swelling, inhibition of local DETC activation, and a reduction in the number of IL-17(+) γδ T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during CHS, suggesting a key role for DETCs in CHS.
- Published
- 2014
211. Immune responses to hair dyes containing toluene-2,5-diamine
- Author
-
Schmidt, J D, Johansen, J D, Nielsen, M M, Zimersson, E, Svedman, C, Bruze, M, Engkilde, K, Poulsen, S S, Geisler, Carsten, Bonefeld, C M, Schmidt, J D, Johansen, J D, Nielsen, M M, Zimersson, E, Svedman, C, Bruze, M, Engkilde, K, Poulsen, S S, Geisler, Carsten, and Bonefeld, C M
- Abstract
BACKGROUND: Toluene-2,5-diamine (PTD) is the most frequently used dye in oxidative hair dyes on the Scandinavian market. However, little is known about immune responses to PTD-containing oxidative hair dyes.OBJECTIVES: To study immune responses induced by PTD-containing hair dyes in mice.METHODS: Immune responses against two different permanent hair dye products containing 1·60% (w/w) and 0·48% (w/w) PTD within the colour gel, and various concentrations of pure PTD were studied. The local inflammatory response was measured by ear swelling and cell infiltration, and T- and B-cell infiltration and proliferation was determined in the draining lymph nodes.RESULTS: Concentration-dependent immune responses were seen to PTD both in the skin and draining lymph nodes. The hair dye containing 1·60% PTD induced strong local inflammation and caused T- and B-cell infiltration and proliferation as well as an increased number of regulatory T cells in the draining lymph nodes. In contrast, the hair dye containing 0·48% PTD induced skin inflammation but only minor responses in the draining lymph nodes.CONCLUSIONS: Consumer-available PTD-containing permanent hair dyes can be potent immune activators inducing both pro- and anti-inflammatory responses. The outcome of the response is dependent on allergen dose, amount of additional allergens and exposure regime.
- Published
- 2014
212. MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma
- Author
-
Ralfkiaer, Ulrik, Lindahl, Lise M, Litman, Thomas, Gjerdrum, Lise-Mette, Ahler, Charlotte Busch, Gniadecki, Robert, Marstrand, Troels, Fredholm, Simon, Iversen, Lars, Wasik, Mariusz A, Bonefeld, Charlotte M, Geisler, Carsten, Krejsgaard, Thorbjørn, Glue, Christian, Røpke, Mads Almose, Woetmann, Anders, Skov, Lone, Grønbæk, Kirsten, Odum, Niels, Ralfkiaer, Ulrik, Lindahl, Lise M, Litman, Thomas, Gjerdrum, Lise-Mette, Ahler, Charlotte Busch, Gniadecki, Robert, Marstrand, Troels, Fredholm, Simon, Iversen, Lars, Wasik, Mariusz A, Bonefeld, Charlotte M, Geisler, Carsten, Krejsgaard, Thorbjørn, Glue, Christian, Røpke, Mads Almose, Woetmann, Anders, Skov, Lone, Grønbæk, Kirsten, and Odum, Niels
- Abstract
Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphoma (CTCL). MF is characterized by chronic inflammation dominated by cluster of differentiation 4-positive (CD4(+)) T-cells and T helper 2 cytokines, and as the malignant T-cell clone is initially elusive, early diagnosis is often impossible. MF usually takes an indolent course, but for unknown reasons may turn into an aggressive disease with a poor prognosis. Herein, we used a global quantitative real-time polymerase chain reaction platform to study microRNA (miR) expression in patients with early MF (n=13), more advanced CTCL (n=42), and atopic dermatitis (AD, n=20). Thirty-eight miRs were differentially expressed (≥2-fold) in early MF vs. AD and 36 in early MF vs. more advanced disease. miRs that distinguish early MF from AD included both up-regulated (miR-155, miR-146a, 146b-5p, miR-342-3p, let-7i*) and down-regulated (miR-203, miR-205) miRs previously implicated in advanced CTCL. When comparing early MF to more advanced CTCL, additional miRs were significantly up-regulated including miRs which are part of the oncogenic miR-17/92, 106b/25 and 106a/363 clusters. In 16 patients for whom detailed follow-up data were available, 72 miRs were found differentially expressed between patients with progressive vs. those with non-progressive disease, again including miRs with a known relevance for lymphomagenesis, e.g. miR-155, miR-21, let-7i, miR-16, miR-142-3p, miR-146b-5p, miR-92a, miR-93 and miR-106a. In conclusion, we showed that early MF and AD display very different miR profiles despite their clinical, histological, and immunological similarities. During progression, an additional set of miRs becomes deregulated, suggesting their role in disease progression. These data suggest that miR profiling in CTCL may be a key to improving both diagnosis and risk prediction.
- Published
- 2014
213. STAT3 activation and infiltration of eosinophil granulocytes in mycosis fungoides
- Author
-
Fredholm, Simon, Gjerdrum, Lise Mette R, Willerslev-Olsen, Andreas, Petersen, David L, Nielsen, Inger Ø, Kauczok, Claudia-S, Wobser, Marion, Ralfkiaer, Ulrik, Bonefeld, Charlotte M, Wasik, Mariusz A, Krejsgaard, Thorbjørn, Geisler, Carsten, Ralfkiaer, Elisabeth, Gniadecki, Robert, Andersen, Anders Woetmann, Odum, Niels, Fredholm, Simon, Gjerdrum, Lise Mette R, Willerslev-Olsen, Andreas, Petersen, David L, Nielsen, Inger Ø, Kauczok, Claudia-S, Wobser, Marion, Ralfkiaer, Ulrik, Bonefeld, Charlotte M, Wasik, Mariusz A, Krejsgaard, Thorbjørn, Geisler, Carsten, Ralfkiaer, Elisabeth, Gniadecki, Robert, Andersen, Anders Woetmann, and Odum, Niels
- Abstract
Eosinophil granulocytes have been implicated in anticancer immunity but recent data indicate that eosinophils can also promote cancer. Herein, we studied eosinophils in skin lesions from 43 patients with mycosis fungoides (MF). The presence of eosinophils correlated with disease stage: 78% of patients with advanced disease displayed eosinophil infiltration, whereas this was only seen in 11% of patients with patches (p<0.01), and in 48% of those with plaque disease. Importantly, 72% of patients with positive staining for phospho-signal-transducer-and-activator-of-transcription (pY-STAT3) in malignant T-cells also stained positively for eosinophils, whereas this was only observed in 28% of pY-STAT3-negative patients (p<0.01). Notably, malignant T-cells expressed eosinophilic activation and trafficking factors: High-mobility group BOX-1 protein (HMGB1) and interleukin 5 (IL5). STAT3 siRNA profoundly inhibited IL5 but not HMGB1 expression. In conclusion, these data suggest that malignant T-cells orchestrate accumulation and activation of eosinophils supporting the notion of STAT3 being a putative target for therapy.
- Published
- 2014
214. Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent and interleukin-1-dependent pathway
- Author
-
Vennegaard, Marie T, Dyring-Andersen, Beatrice, Skov, Lone, Nielsen, Morten M, Schmidt, Jonas D, Bzorek, Michael, Poulsen, Steen S, Thomsen, Allan Randrup, Andersen, Anders Woetmann, Thyssen, Jacob P, Johansen, Jeanne D, Odum, Niels, Menné, Torkil, Geisler, Carsten, Bonefeld, Charlotte M, Vennegaard, Marie T, Dyring-Andersen, Beatrice, Skov, Lone, Nielsen, Morten M, Schmidt, Jonas D, Bzorek, Michael, Poulsen, Steen S, Thomsen, Allan Randrup, Andersen, Anders Woetmann, Thyssen, Jacob P, Johansen, Jeanne D, Odum, Niels, Menné, Torkil, Geisler, Carsten, and Bonefeld, Charlotte M
- Abstract
BACKGROUND: Several attempts to establish a model in mice that reflects nickel allergy in humans have been made. Most models use intradermal injection of nickel in combination with adjuvant to induce nickel allergy. However, such models poorly reflect induction of nickel allergy following long-lasting epicutaneous exposure to nickel.OBJECTIVE: To develop a mouse model reflecting nickel allergy in humans induced by epicutaneous exposure to nickel, and to investigate the mechanisms involved in such allergic responses.METHODS: Mice were exposed to NiCl2 on the dorsal side of the ears. Inflammation was evaluated by the swelling and cell infiltration of the ears. T cell responses were determined as numbers of CD4(+) and CD8(+) T cells in the draining lymph nodes. Localization of nickel was examined by dimethylglyoxime staining.RESULTS: Epicutaneous exposure to nickel results in prolonged localization of nickel in the epidermis, and induces nickel allergy in mice. The allergic response to nickel following epicutaneous exposure is MyD88-dependent and interleukin (IL)-1 receptor-dependent, but independent of toll-like receptor (TLR)-4.CONCLUSION: This new model for nickel allergy that reflects epicutaneous exposure to nickel in humans shows that nickel allergy is dependent on MyD88 and IL-1 receptor signalling, but independent of TLR4.
- Published
- 2014
215. Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells
- Author
-
Boding, Lasse, Hansen, Ann K, Meroni, Germana, Johansen, Bo B, Braunstein, Thomas H, Bonefeld, Charlotte M, Kongsbak, Martin, Jensen, Benjamin A H, Woetmann, Anders, Thomsen, Allan Randrup, Odum, Niels, von Essen, Marina R, Geisler, Carsten, Boding, Lasse, Hansen, Ann K, Meroni, Germana, Johansen, Bo B, Braunstein, Thomas H, Bonefeld, Charlotte M, Kongsbak, Martin, Jensen, Benjamin A H, Woetmann, Anders, Thomsen, Allan Randrup, Odum, Niels, von Essen, Marina R, and Geisler, Carsten
- Abstract
Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X-linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/-) CTLs completely rescued lytic granule exocytosis, and vice versa, knock-down of MID1 inhibited exocytosis of lytic granules in wild-type CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity. This article is protected by copyright. All rights reserved.
- Published
- 2014
216. IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF)
- Author
-
Willerslev-Olsen, Andreas, Litvinov, Ivan V, Fredholm, Simon M, Petersen, David L, Sibbesen, Nina A, Gniadecki, Robert, Zhang, Qian, Bonefeld, Charlotte M, Wasik, Mariusz A, Geisler, Carsten, Zhou, Youwen, Woetmann, Anders, Sasseville, Denis, Krejsgaard, Thorbjørn, Ødum, Niels, Willerslev-Olsen, Andreas, Litvinov, Ivan V, Fredholm, Simon M, Petersen, David L, Sibbesen, Nina A, Gniadecki, Robert, Zhang, Qian, Bonefeld, Charlotte M, Wasik, Mariusz A, Geisler, Carsten, Zhou, Youwen, Woetmann, Anders, Sasseville, Denis, Krejsgaard, Thorbjørn, and Ødum, Niels
- Abstract
Skin lesions from mycosis fungoides (MF) patients display an increased expression of interleukin-15 (IL-15), IL-17F, and other cytokines implicated in inflammation and malignant cell proliferation in cutaneous T-cell lymphoma (CTCL). In the leukemic variant of CTCL, Sézary syndrome (SS), IL-2 and IL-15 trigger activation of the Jak-3/STAT3 pathway and transcription of IL17A gene, whereas it is unknown what causes IL-15 expression, Jak3/STAT3 activation, and production of IL-17F in MF. Here, we studied the expression and regulation of IL-15 and its relation to IL-17F in MF cell lines and skin lesions from 60 MF patients. We show that: (1) the spontaneous IL-15 mRNA expression is resistant to Jak3 and STAT3 inhibitors at concentrations that profoundly inhibit STAT3 activation and IL-17F mRNA expression; (2) anti-IL-15 antibody blocks STAT3 activation induced by exogenous IL-15 in non-malignant MF T cells, whereas the spontaneous STAT3 activation and IL-17F expression in malignant T cells is not inhibited; (3) patients display heterogeneous IL-15/IL-17F mRNA expression patterns in skin lesions; and (4) IL-15 expression (in contrast to IL-17F) is not associated with progressive disease. Taken together, these findings indicate that IL-15 and IL-17F are differentially regulated and expressed in MF. We propose that IL-15 and IL-17F are markers for different inflammatory environments and play distinct roles in the development and progression of MF.
- Published
- 2014
217. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation
- Author
-
Krejsgaard, Thorbjørn Frej, Willerslev-Olsen, Andreas, Lindahl, Lise Maria, Bonefeld, Charlotte Menne, Koralov, Sergei B., Geisler, Carsten, Wasik, Mariusz A., Gniadecki, Robert, Kilian, Mogens, Iversen, Lars, Andersen, Anders Woetmann, Ødum, Niels, Krejsgaard, Thorbjørn Frej, Willerslev-Olsen, Andreas, Lindahl, Lise Maria, Bonefeld, Charlotte Menne, Koralov, Sergei B., Geisler, Carsten, Wasik, Mariusz A., Gniadecki, Robert, Kilian, Mogens, Iversen, Lars, Andersen, Anders Woetmann, and Ødum, Niels
- Abstract
Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with significant clinical improvement suggesting that SA promotes the disease activity but the underlying mechanisms remain poorly characterized. Here we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) which induce cross-talk between malignant and benign T cells leading to Stat3-mediated IL-10 production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease.
- Published
- 2014
218. Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells
- Author
-
Kongsbak, Martin, von Essen, Marina R, Boding, Lasse, Levring, Trine B, Schjerling, Peter, Lauritsen, Jens P H, Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte M, Geisler, Carsten, Kongsbak, Martin, von Essen, Marina R, Boding, Lasse, Levring, Trine B, Schjerling, Peter, Lauritsen, Jens P H, Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte M, and Geisler, Carsten
- Abstract
The active form of vitamin D3, 1,25(OH)2D3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH)2D3 by itself regulates VDR expression in human CD4+ T cells. We found that activated CD4+ T cells have the capacity to convert the inactive 25(OH)D3 to the active 1,25(OH)2D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2D3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH)2D3-induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2D3, and that 1,25(OH)2D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation.
- Published
- 2014
219. Validation of a diagnostic miRNA classifier in cutaneous T-cell lymphomas
- Author
-
Marstrand, Troels, Ahler, Charlotte B, Ralfkiaer, Ulrik, Clemmensen, Anders, Kopp, Katharina L, Sibbesen, Nina A, Krejsgaard, Thorbjørn, Litman, Thomas, Wasik, Mariusz A, Bonefeld, Charlotte M, Grønbæk, Kirsten, Gjerdum, Lise Mette Rahbek, Gniadecki, Robert, Ralfkiaer, Elisabeth, Geisler, Carsten, Woetmann, Anders, Røpke, Mads A, Glue, Christian, Skov, Lone, Odum, Niels, Marstrand, Troels, Ahler, Charlotte B, Ralfkiaer, Ulrik, Clemmensen, Anders, Kopp, Katharina L, Sibbesen, Nina A, Krejsgaard, Thorbjørn, Litman, Thomas, Wasik, Mariusz A, Bonefeld, Charlotte M, Grønbæk, Kirsten, Gjerdum, Lise Mette Rahbek, Gniadecki, Robert, Ralfkiaer, Elisabeth, Geisler, Carsten, Woetmann, Anders, Røpke, Mads A, Glue, Christian, Skov, Lone, and Odum, Niels
- Published
- 2014
220. Midline 1 controls polarization and migration of murine cytotoxic T cells
- Author
-
Boding, Lasse, primary, Hansen, Ann K., additional, Nielsen, Morten M., additional, Meroni, Germana, additional, Braunstein, Thomas H., additional, Woetmann, Anders, additional, Ødum, Niels, additional, Bonefeld, Charlotte M., additional, and Geisler, Carsten, additional
- Published
- 2014
- Full Text
- View/download PDF
221. Enzyme Immunoassay for the Detection of Autoantibodies Against the Nuclear Protein Scl-7O
- Author
-
GEISLER, CARSTEN, primary and HØIER-MADSEN, MIMI, additional
- Published
- 1985
- Full Text
- View/download PDF
222. Immunological, chemical and clinical aspects of exposure to mixtures of contact allergens.
- Author
-
Bonefeld, Charlotte M., Geisler, Carsten, Gimenéz‐Arnau, Elena, Lepoittevin, Jean‐Pierre, Uter, Wolfgang, and Johansen, Jeanne D.
- Subjects
- *
CONTACT dermatitis , *ALLERGIES , *ALLERGENS , *IMMUNE response , *ODORS - Abstract
Allergic contact dermatitis is one of the most frequent forms of skin inflammation. Very often, we are exposed to mixtures of allergens with varying potencies, doses/areas, and exposure times. Therefore, improved knowledge about immune responses to combinations of contact allergens is highly relevant. In this article, we provide a general introduction to immune responses to contact allergens, and discuss the literature concerning immune responses to mixtures of allergens. According to the existing evidence, increased responses are induced following sensitization with combinations of allergens as compared with single allergens. The response to a mixture of allergens can be both additive and synergistic, depending on the dose and combination of allergens. Importantly, sensitization with combinations of either fragrance allergens or metal salts can result in increased challenge responses to specific allergens within the mixture. Taken together, the immune responses to mixtures of allergens are complex, and further studies are required to obtain the necessary knowledge to improve consumer safety. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
223. Detection of local inflammation induced by repeated exposure to contact allergens by use of IVIS Spectrum CT analyses.
- Author
-
Nielsen, Morten M., Schmidt, Jonas D., Christensen, Jan P., Geisler, Carsten, Johansen, Jeanne D., and Bonefeld, Charlotte M.
- Subjects
SKIN inflammation diagnosis ,SKIN disease diagnosis ,ALLERGENS ,IMMUNOREGULATION ,PHENOTYPES ,THERAPEUTICS - Abstract
Background Contact allergy is characterized by local skin inflammation that, in some cases, can result in systemic immune activation. Objectives To investigate whether IVIS SpectrumCT analyses can be used to detect the immune response induced by contact allergens. Methods Mice were repeatedly exposed to vehicle or allergens on the ears. The local and systemic responses were analysed at different times with the ProSense 750 FAST probe in IVIS SpectrumCT measurements. In addition, changes in ear thickness, cytokine profile in the skin and immunological phenotype in the draining lymph nodes and spleen were determined. Results Local inflammation was detected by ProSense 750 FAST and correlated with changes in ear thickness, cytokine profile and immunological phenotype following exposure to the strong contact allergen 2,4-dinitrofluorobenzene. Analysis of the systemic response with ProSense 750 FAST did not show any difference between allergen-exposed and control mice, although fluorescence-activated cell sorting analysis of the spleen showed increased numbers of γδ T cells and CD11b
+ CD11c+ MHCII+ cells in allergen-treated mice. Conclusions IVIS SpectrumCT analyses with ProSense 750 FAST as the probe can be used to detect local immune responses induced by contact allergens. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
224. Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8+ T cells.
- Author
-
Schmidt, Jonas D., Ahlström, Malin G., Johansen, Jeanne D., Dyring ‐ Andersen, Beatrice, Agerbeck, Christina, Nielsen, Morten M., Poulsen, Steen S., Woetmann, Anders, Ødum, Niels, Thomsen, Allan R., Geisler, Carsten, and Bonefeld, Charlotte M.
- Subjects
INTERLEUKIN-17 ,INTERFERONS ,REGULATION of secretion ,SECRETION ,CD8 antigen ,PHYSIOLOGY - Abstract
Background Skin-resident memory T (T
RM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby TRM cells induce rapid recall responses need further investigation. Objectives To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin. Methods To address these questions, we analysed responses to contact allergens in mice and humans sensitized to 2,4-dinitrofluorobenzene and nickel, respectively. Results Challenge responses in both mice and humans were dramatically increased at sites previously exposed to allergens as compared with previously unexposed sites. Importantly, the magnitude of the challenge response correlated with the epidermal accumulation of interleukin (IL)-17A-producing and interferon (IFN)-γ-producing TRM cells. Moreover, IL-17A and IFN-γ enhanced allergen-induced IL-1β production in keratinocytes. Conclusions We show that sensitization with contact allergens induces a strong, long-lasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN-γ-producing CD8+ TRM cells. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
225. Increased prevalence of LTi cells in CSF of patients with early MS
- Author
-
Degn, Matilda, primary, Modvig, Signe, additional, Andersen, Beatrice D., additional, Bonefeld, Charlotte M., additional, Frederiksen, Jette L., additional, Geisler, Carsten, additional, and Von Essen, Marina Rode, additional
- Published
- 2014
- Full Text
- View/download PDF
226. Vitamin D-binding protein controls T cell responses to vitamin D
- Author
-
Kongsbak, Martin, primary, von Essen, Marina Rode, additional, Levring, Trine Bøegh, additional, Schjerling, Peter, additional, Woetmann, Anders, additional, Ødum, Niels, additional, Bonefeld, Charlotte Menné, additional, and Geisler, Carsten, additional
- Published
- 2014
- Full Text
- View/download PDF
227. Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells
- Author
-
Boding, Lasse, primary, Hansen, Ann K., additional, Meroni, Germana, additional, Johansen, Bo B., additional, Braunstein, Thomas H., additional, Bonefeld, Charlotte M., additional, Kongsbak, Martin, additional, Jensen, Benjamin A. H., additional, Woetmann, Anders, additional, Thomsen, Allan R., additional, Ødum, Niels, additional, von Essen, Marina R., additional, and Geisler, Carsten, additional
- Published
- 2014
- Full Text
- View/download PDF
228. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation
- Author
-
Krejsgaard, Thorbjørn, primary, Willerslev-Olsen, Andreas, additional, Lindahl, Lise M., additional, Bonefeld, Charlotte M., additional, Koralov, Sergei B., additional, Geisler, Carsten, additional, Wasik, Mariusz A., additional, Gniadecki, Robert, additional, Kilian, Mogens, additional, Iversen, Lars, additional, Woetmann, Anders, additional, and Odum, Niels, additional
- Published
- 2014
- Full Text
- View/download PDF
229. Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88‐dependent and interleukin‐1‐dependent pathway
- Author
-
Vennegaard, Marie T., primary, Dyring‐Andersen, Beatrice, additional, Skov, Lone, additional, Nielsen, Morten M., additional, Schmidt, Jonas D., additional, Bzorek, Michael, additional, Poulsen, Steen S., additional, Thomsen, Allan R., additional, Woetmann, Anders, additional, Thyssen, Jacob P., additional, Johansen, Jeanne D., additional, Ødum, Niels, additional, Menné, Torkil, additional, Geisler, Carsten, additional, and Bonefeld, Charlotte M., additional
- Published
- 2014
- Full Text
- View/download PDF
230. Vitamin D Up-Regulates the Vitamin D Receptor by Protecting It from Proteasomal Degradation in Human CD4+ T Cells
- Author
-
Kongsbak, Martin, primary, von Essen, Marina R., additional, Boding, Lasse, additional, Levring, Trine B., additional, Schjerling, Peter, additional, Lauritsen, Jens P. H., additional, Woetmann, Anders, additional, Ødum, Niels, additional, Bonefeld, Charlotte M., additional, and Geisler, Carsten, additional
- Published
- 2014
- Full Text
- View/download PDF
231. IL-1β–Dependent Activation of Dendritic Epidermal T Cells in Contact Hypersensitivity
- Author
-
Nielsen, Morten M., primary, Lovato, Paola, additional, MacLeod, Amanda S., additional, Witherden, Deborah A., additional, Skov, Lone, additional, Dyring-Andersen, Beatrice, additional, Dabelsteen, Sally, additional, Woetmann, Anders, additional, Ødum, Niels, additional, Havran, Wendy L., additional, Geisler, Carsten, additional, and Bonefeld, Charlotte M., additional
- Published
- 2014
- Full Text
- View/download PDF
232. IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF)
- Author
-
Willerslev-Olsen, Andreas, primary, Litvinov, Ivan V, additional, Fredholm, Simon M, additional, Petersen, David L, additional, Sibbesen, Nina A, additional, Gniadecki, Robert, additional, Zhang, Qian, additional, Bonefeld, Charlotte M, additional, Wasik, Mariusz A, additional, Geisler, Carsten, additional, Zhou, Youwen, additional, Woetmann, Anders, additional, Sasseville, Denis, additional, Krejsgaard, Thorbjørn, additional, and Ødum, Niels, additional
- Published
- 2014
- Full Text
- View/download PDF
233. An immune response study of oakmoss absolute and its constituents atranol and chloroatranol
- Author
-
Menné Bonefeld, Charlotte, primary, Nielsen, Morten Milek, additional, Gimenéz‐Arnau, Elena, additional, Lang, Matthieu, additional, Vennegaard, Marie Torp, additional, Geisler, Carsten, additional, Johansen, Jeanne Duus, additional, and Lepoittevin, Jean‐Pierre, additional
- Published
- 2014
- Full Text
- View/download PDF
234. PKC-θ exists in an oxidized inactive form in naive human T cells
- Author
-
von Essen, Marina Rode, Kongsbak, Martin, Levring, Trine Bøegh, Hansen, Ann Kathrine, Boding, Lasse, Lauritsen, Jens Peter Holst, Woetmann, Anders, Baier, Gottfried, Odum, Niels, Bonefeld, Charlotte Menné, Geisler, Carsten, von Essen, Marina Rode, Kongsbak, Martin, Levring, Trine Bøegh, Hansen, Ann Kathrine, Boding, Lasse, Lauritsen, Jens Peter Holst, Woetmann, Anders, Baier, Gottfried, Odum, Niels, Bonefeld, Charlotte Menné, and Geisler, Carsten
- Abstract
PKC-θ plays a central role in TCR-induced IL-2 production and T-cell proliferation. The aim of the present study was to analyse how PKC-θ is regulated in human T cells during T-cell activation and differentiation. We show that PKC-θ is found in a high-molecular disulfide-linked complex in naïve T cells, and that PKC-θ most likely is inactive in this form. In parallel with the accumulation of the major redox regulators, glutathione and thioredoxin, PKC-θ is gradually reduced to the 82 kDa active form during T-cell activation. We demonstrate that PKC-θ is recruited to the plasma membrane in the disulfide-linked form in naïve T cells, and that activation of PKC-θ is redox dependent and requires de novo synthesis of glutathione. This is the first study that shows that the activity of PKC-θ is regulated by the intracellular redox state, and that PKC-θ is recruited to the plasma membrane in an inactive form in naïve T cells. Our observations underscore the existence of major differences in TCR signaling in naïve versus primed T cells.
- Published
- 2013
235. CD4(+) T cells producing interleukin (IL)-17, IL-22 and interferon-? are major effector T cells in nickel allergy
- Author
-
Dyring Andersen, Beatrice, Skov, Lone, Løvendorf, Marianne B, Bzorek, Michael, Søndergaard, Knud, Lauritsen, Jens-Peter H, Dabelsteen, Sally Anne Malene, Geisler, Carsten, Bonefeld, Charlotte Menné, Dyring Andersen, Beatrice, Skov, Lone, Løvendorf, Marianne B, Bzorek, Michael, Søndergaard, Knud, Lauritsen, Jens-Peter H, Dabelsteen, Sally Anne Malene, Geisler, Carsten, and Bonefeld, Charlotte Menné
- Published
- 2013
236. Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma
- Author
-
Willerslev-Olsen, Andreas, Krejsgaard, Thorbjørn, Lindahl, Lise Maria, Bonefeld, Charlotte Menne, Wasik, Mariusz A, Koralov, Sergei B, Geisler, Carsten, Kilian, Mogens, Iversen, Lars, Woetmann, Anders, Odum, Niels, Willerslev-Olsen, Andreas, Krejsgaard, Thorbjørn, Lindahl, Lise Maria, Bonefeld, Charlotte Menne, Wasik, Mariusz A, Koralov, Sergei B, Geisler, Carsten, Kilian, Mogens, Iversen, Lars, Woetmann, Anders, and Odum, Niels
- Abstract
In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL. Here, we review links between bacterial infections and CTCL with focus on earlier studies addressing a direct role of SE on malignant T cells and recent data indicating novel indirect mechanisms involving SE- and cytokine-driven cross-talk between malignant- and non-malignant T cells.
- Published
- 2013
237. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma
- Author
-
Kopp, Katharina L, Ralfkiaer, Ulrik, Gjerdrum, Lise Mette R, Helvad, Rikke, Pedersen, Ida H, Litman, Thomas, Jønson, Lars, Hagedorn, Peter H, Krejsgaard, Thorbjørn, Gniadecki, Robert, Bonefeld, Charlotte M, Skov, Lone, Geisler, Carsten, Wasik, Mariusz A, Ralfkiaer, Elisabeth, Ødum, Niels, Woetmann, Anders, Kopp, Katharina L, Ralfkiaer, Ulrik, Gjerdrum, Lise Mette R, Helvad, Rikke, Pedersen, Ida H, Litman, Thomas, Jønson, Lars, Hagedorn, Peter H, Krejsgaard, Thorbjørn, Gniadecki, Robert, Bonefeld, Charlotte M, Skov, Lone, Geisler, Carsten, Wasik, Mariusz A, Ralfkiaer, Elisabeth, Ødum, Niels, and Woetmann, Anders
- Abstract
The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC. In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.
- Published
- 2013
238. The vitamin d receptor and T cell function
- Author
-
Kongsbak, Martin, Levring, Trine B, Geisler, Carsten, von Essen, Marina Rode, Kongsbak, Martin, Levring, Trine B, Geisler, Carsten, and von Essen, Marina Rode
- Abstract
The vitamin D receptor (VDR) is a nuclear, ligand-dependent transcription factor that in complex with hormonally active vitamin D, 1,25(OH)2D3, regulates the expression of more than 900 genes involved in a wide array of physiological functions. The impact of 1,25(OH)2D3-VDR signaling on immune function has been the focus of many recent studies as a link between 1,25(OH)2D3 and susceptibility to various infections and to development of a variety of inflammatory diseases has been suggested. It is also becoming increasingly clear that microbes slow down immune reactivity by dysregulating the VDR ultimately to increase their chance of survival. Immune modulatory therapies that enhance VDR expression and activity are therefore considered in the clinic today to a greater extent. As T cells are of great importance for both protective immunity and development of inflammatory diseases a variety of studies have been engaged investigating the impact of VDR expression in T cells and found that VDR expression and activity plays an important role in both T cell development, differentiation and effector function. In this review we will analyze current knowledge of VDR regulation and function in T cells and discuss its importance for immune activity.
- Published
- 2013
239. Elucidating the role of interleukin-17F in cutaneous T-cell lymphoma
- Author
-
Krejsgaard, Thorbjørn, Litvinov, Ivan V, Wang, Yang, Xia, Lixin, Willerslev-Olsen, Andreas, Koralov, Sergei B, Kopp, Katharina L, Bonefeld, Charlotte M, Wasik, Mariusz A, Geisler, Carsten, Woetmann, Anders, Zhou, Youwen, Sasseville, Denis, Odum, Niels, Krejsgaard, Thorbjørn, Litvinov, Ivan V, Wang, Yang, Xia, Lixin, Willerslev-Olsen, Andreas, Koralov, Sergei B, Kopp, Katharina L, Bonefeld, Charlotte M, Wasik, Mariusz A, Geisler, Carsten, Woetmann, Anders, Zhou, Youwen, Sasseville, Denis, and Odum, Niels
- Abstract
Inappropriately regulated expression of IL-17A is associated with the development of inflammatory diseases and cancer. However, little is known about the role of other IL-17 family members in carcinogenesis. Here, we show that a set of malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL) spontaneously secrete IL-17F and that inhibitors of Jak and Stat3 are able to block that secretion. Other malignant T-cell lines produce IL-17A but not IL-17F. Upon activation, however, some of the malignant T-cell lines are able to co-express IL-17A and IL-17F leading to formation of IL-17A/F heterodimers. Clinically, we demonstrate that IL-17F mRNA expression is significantly increased in CTCL skin lesions when compared to healthy donors and patients with chronic dermatitis. IL-17A expression is also increased and a significant number of patients express high levels of both IL-17A and IL-17F. Concomitantly, we observe that the expression of the IL-17 receptor is significantly increased in CTCL skin lesions when compared to control subjects. Importantly, analysis of a historic cohort of 60 CTCL patients indicates that IL-17F expression is associated with progressive disease. These findings implicate IL-17F in the pathogenesis of CTCL and suggest that IL-17 cytokines and their receptors may serve as therapeutic targets.
- Published
- 2013
240. SATB1 in Malignant T Cells
- Author
-
Fredholm, Simon, Willerslev-Olsen, Andreas, Met, Özcan, Kubat, Linda, Gluud, Maria, Mathiasen, Sarah L., Friese, Christina, Blümel, Edda, Petersen, David L., Hu, Tengpeng, Nastasi, Claudia, Lindahl, Lise M., Buus, Terkild B., Krejsgaard, Thorbjørn, Wasik, Mariusz A., Kopp, Katharina L., Koralov, Sergei B., Persson, Jenny L., Bonefeld, Charlotte M., Geisler, Carsten, Woetmann, Anders, Iversen, Lars, Becker, Jürgen C., and Ødum, Niels
- Abstract
Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.
- Published
- 2018
- Full Text
- View/download PDF
241. Allergic contact dermatitis induces upregulation of identical microRNAs in humans and mice
- Author
-
Vennegaard, Marie T, Bonefeld, Charlotte M, Hagedorn, Peter, Bangsgaard, Nannie, Løvendorf, Marianne B, Odum, Niels, Woetmann, Anders, Geisler, Carsten, Skov, Lone, Vennegaard, Marie T, Bonefeld, Charlotte M, Hagedorn, Peter, Bangsgaard, Nannie, Løvendorf, Marianne B, Odum, Niels, Woetmann, Anders, Geisler, Carsten, and Skov, Lone
- Abstract
MicroRNAs are short, endogenous RNA molecules that can bind to parts of target mRNAs, thus inhibiting their translation and causing accelerated turnover or degradation of transcripts, thereby regulating gene expression. Several microRNAs have been found to be upregulated in atopic dermatitis and psoriasis, indicating a role in inflammatory skin diseases. However, there have been no studies on the expression of microRNAs in allergic contact dermatitis.
- Published
- 2012
242. Vascular endothelial growth factor receptor-3 expression in mycosis fungoides
- Author
-
Pedersen, Ida Holst, Willerslev-Olsen, Andreas, Vetter-Kauczok, Claudia, Krejsgaard, Thorbjørn, Lauenborg, Britt, Kopp, Katharina Luise, Geisler, Carsten, Bonefeld, Charlotte M, Zhang, Qian, Wasik, Mariusz A, Dabelsteen, Sally, Andersen, Anders Woetmann, Becker, Jurgen C, Odum, Niels, Pedersen, Ida Holst, Willerslev-Olsen, Andreas, Vetter-Kauczok, Claudia, Krejsgaard, Thorbjørn, Lauenborg, Britt, Kopp, Katharina Luise, Geisler, Carsten, Bonefeld, Charlotte M, Zhang, Qian, Wasik, Mariusz A, Dabelsteen, Sally, Andersen, Anders Woetmann, Becker, Jurgen C, and Odum, Niels
- Abstract
Here, we have studied vascular endothelial growth factor receptor-3 (VEGFR-3) expression in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). Immunohistochemistry revealed that in two-thirds of 34 patients, VEGFR-3 was expressed in situ by both tumor and stromal cells irrespective of the disease stage. The natural VEGFR-3 ligand, VEGF-C, partially protected malignant T-cell lines from growth inhibition by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA). Whereas the malignant T cells did not produce VEGF-C in vitro, its expression was induced during tumor formation in vivo in a xenograft mouse model of MF. In conclusion, malignant and stromal cells express high levels of VEGFR-3 in all stages of MF. Moreover, malignant T cells trigger enhanced VEGF-C expression in fibroblasts, suggesting that cross-talk between tumor and stromal cells plays a role in lymphangiogenesis and possibly disease progression.
- Published
- 2012
243. Activated human CD4 T cells express transporters for both cysteine and cystine
- Author
-
Levring, Trine Bøegh, Hansen, Ann Kathrine, Nielsen, Bodil Lisbeth, Kongsbak, Martin, von Essen, Marina Rode, Woetmann, Anders, Odum, Niels, Bonefeld, Charlotte Menné, Geisler, Carsten, Levring, Trine Bøegh, Hansen, Ann Kathrine, Nielsen, Bodil Lisbeth, Kongsbak, Martin, von Essen, Marina Rode, Woetmann, Anders, Odum, Niels, Bonefeld, Charlotte Menné, and Geisler, Carsten
- Abstract
Because naïve T cells are unable to import cystine due to the absence of cystine transporters, it has been suggested that T cell activation is dependent on cysteine generated by antigen presenting cells. The aim of this study was to determine at which phases during T cell activation exogenous cystine/cysteine is required and how T cells meet this requirement. We found that early activation of T cells is independent of exogenous cystine/cysteine, whereas T cell proliferation is strictly dependent of uptake of exogenous cystine/cysteine. Naïve T cells express no or very low levels of both cystine and cysteine transporters. However, we found that these transporters become strongly up-regulated during T cell activation and provide activated T cells with the required amount of cystine/cysteine needed for T cell proliferation. Thus, T cells are equipped with mechanisms that allow T cell activation and proliferation independently of cysteine generated by antigen presenting cells.
- Published
- 2012
244. Regulatory T cells and immunodeficiency in mycosis fungoides and Sézary syndrome
- Author
-
Krejsgaard, Thorbjørn Frej, Ødum, Niels, Geisler, Carsten, Wasik, M.A., Woetmann, Anders, Krejsgaard, Thorbjørn Frej, Ødum, Niels, Geisler, Carsten, Wasik, M.A., and Woetmann, Anders
- Abstract
Cutaneous T-cell lymphoma (CTCL) is the term for diseases characterized by primary accumulation of malignant T cells in the skin. Patients with the two predominant clinical forms of CTCL called mycosis fungoides (MF) and Sézary syndrome (SS) characteristically develop severe immunodeficiency during disease progression and consequently patients with advanced disease frequently die of infections and not from the tumor burden. For decades, it has been suspected that the malignant T cells actively drive the evolving immunodeficiency to avoid antitumor immunity, yet, the underlying mechanisms remain unclear. The identification of a subset of highly immunosuppressive regulatory T cells (Tregs) triggered a variety of studies investigating if MF and SS are malignant proliferations of Tregs but seemingly discordant findings have been reported. Here, we review the literature to clarify the role of Tregs in MF and SS and discuss the potential mechanisms driving the immunodeficiency.Leukemia advance online publication, 9 September 2011; doi:10.1038/leu.2011.237.
- Published
- 2012
245. IFN-α primes T- and NK-cells for IL-15-mediated signaling and cytotoxicity
- Author
-
Hansen, Mikkel L, Woetmann, Anders, Krejsgaard, Thorbjørn, Kopp, Katharina L M, Søkilde, Rolf, Litman, Thomas, Straten, Per T, Geisler, Carsten, Wasik, Mariusz A, Ødum, Niels, Eriksen, Karsten W, Hansen, Mikkel L, Woetmann, Anders, Krejsgaard, Thorbjørn, Kopp, Katharina L M, Søkilde, Rolf, Litman, Thomas, Straten, Per T, Geisler, Carsten, Wasik, Mariusz A, Ødum, Niels, and Eriksen, Karsten W
- Abstract
Recently it has become clear that interferon (IFN)-α, a type I interferon produced rapidly in response to infection, not only plays a key role in innate immunity, but also promotes adaptive immune responses by influencing the production or function of other cytokines. During infections IFN-α fosters the production of IL-15, which plays a pivotal role in the development, survival and function of NK cells and recruitment and activation of T cells. Since these two cytokines exert overlapping functions during infections, this investigation was undertaken to study the priming effect of IFN-α on the effect of IL-15 on human T and NK cells. We show that IFN-α induces an increased expression of IL-15Rα in human activated peripheral T cells, and in CD8(+) and CD4(+) T-cell lines. Functionally, the IFN-α-enhanced IL-15Rα expression resulted in an enhanced IL-15-mediated phosphorylation of STAT5 and STAT3 followed by a further increase in IL-15Rα expression. Moreover, IFN-α significantly increased the IL-15-induced cytotoxic activity of freshly isolated T and NK cells. Taken together, our data show that IFN-α boosts signaling and functional effects of IL-15, at least in part by fostering the increased IL-15R expression, thus add new facet to the emerging role of IFN-α as an important primer of adaptive immune responses.
- Published
- 2011
246. Reply to control of T cell activation by vitamin
- Author
-
Geisler, Carsten and Geisler, Carsten
- Published
- 2011
247. Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL)
- Author
-
Ralfkiaer, Ulrik, Hagedorn, Peter, Bangsgaard, Nannie, Løvendorf, Marianne B, Ahler, Charlotte B, Svensson, Lars, Kopp, Katharina L, Vennegaard, Marie T, Lauenborg, Britt, Zibert, John R, Krejsgaard, Thorbjørn, Bonefeld, Charlotte M, Søkilde, Rolf, Gjerdrum, Lise M, Labuda, Tord, Mathiesen, Anne-Merete, Grønbaek, Kirsten, Wasik, Mariusz A, Sokolowska-Wojdylo, Malgorzata, Queille-Roussel, Catherine, Gniadecki, Robert, Ralfkiaer, Elisabeth, Geisler, Carsten, Litman, Thomas, Andersen, Anders Woetmann, Glue, Christian, Røpke, Mads A, Skov, Lone, Ødum, Niels, Ralfkiaer, Ulrik, Hagedorn, Peter, Bangsgaard, Nannie, Løvendorf, Marianne B, Ahler, Charlotte B, Svensson, Lars, Kopp, Katharina L, Vennegaard, Marie T, Lauenborg, Britt, Zibert, John R, Krejsgaard, Thorbjørn, Bonefeld, Charlotte M, Søkilde, Rolf, Gjerdrum, Lise M, Labuda, Tord, Mathiesen, Anne-Merete, Grønbaek, Kirsten, Wasik, Mariusz A, Sokolowska-Wojdylo, Malgorzata, Queille-Roussel, Catherine, Gniadecki, Robert, Ralfkiaer, Elisabeth, Geisler, Carsten, Litman, Thomas, Andersen, Anders Woetmann, Glue, Christian, Røpke, Mads A, Skov, Lone, and Ødum, Niels
- Abstract
Cutaneous T-cell lymphomas (CTCLs) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult because of a clinical and histologic resemblance to benign inflammatory skin diseases. To address whether microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we studied miRNA expression levels in 198 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays, we show that the most induced (miR-326, miR-663b, and miR-711) and repressed (miR-203 and miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Quantitative (q)RT-PCR analysis of 103 patients with CTCL and benign skin disorders validates differential expression of 4 of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A qRT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity and sensitivity, and with a classification accuracy of 95%, indicating that miRNAs have a high diagnostic potential in CTCL.
- Published
- 2011
248. Malignant cutaneous T-cell lymphoma cells express IL-17 utilizing the Jak3/Stat3 signaling pathway
- Author
-
Krejsgaard, Thorbjørn Frej, Ralfkiær, Ulrik, Clasen-Linde, Erik, Eriksen, Karsten Wessel Kam, Kopp, Katharina Luise Maria, Bonefeld, Charlotte Menne, Geisler, Carsten, Dabelsteen, Sally, Wasik, Mariusz A., Ralfkiaer, Elisabeth Methner, Andersen, Anders Woetmann, Ødum, Niels, Krejsgaard, Thorbjørn Frej, Ralfkiær, Ulrik, Clasen-Linde, Erik, Eriksen, Karsten Wessel Kam, Kopp, Katharina Luise Maria, Bonefeld, Charlotte Menne, Geisler, Carsten, Dabelsteen, Sally, Wasik, Mariusz A., Ralfkiaer, Elisabeth Methner, Andersen, Anders Woetmann, and Ødum, Niels
- Abstract
IL-17 is a proinflammatory cytokine that is crucial for the host's protection against a range of extracellular pathogens. However, inappropriately regulated expression of IL-17 is associated with the development of inflammatory diseases and cancer. In cutaneous T-cell lymphoma (CTCL), malignant T cells gradually accumulate in skin lesions characterized by massive chronic inflammation, suggesting that IL-17 could be involved in the pathogenesis. In this study we show that IL-17 protein is present in 10 of 13 examined skin lesions but not in sera from 28 CTCL patients. Importantly, IL-17 expression is primarily observed in atypical lymphocytes with characteristic neoplastic cell morphology. In accordance, malignant T-cell lines from CTCL patients produce IL-17 and the synthesis is selectively increased by IL-2 receptor ß chain cytokines. Small-molecule inhibitors or small interfering RNA against Jak3 and signal transducer and activator of transcription 3 (Stat3) reduce the production of IL-17, showing that the Jak3/Stat3 pathway promotes the expression of the cytokine. In summary, our findings indicate that the malignant T cells in CTCL lesions express IL-17 and that this expression is promoted by the Jak3/Stat3 pathway.
- Published
- 2011
249. TCR down-regulation boosts T-cell-mediated cytotoxicity and protection against poxvirus infections
- Author
-
Hansen, Ann Kathrine, Regner, Matthias, Bonefeld, Charlotte Menne, Boding, Lasse, Kongsbak-Wismann, Martin, Ødum, Niels, Müllbacher, Arno, Geisler, Carsten, von Essen, Marina Rode, Hansen, Ann Kathrine, Regner, Matthias, Bonefeld, Charlotte Menne, Boding, Lasse, Kongsbak-Wismann, Martin, Ødum, Niels, Müllbacher, Arno, Geisler, Carsten, and von Essen, Marina Rode
- Abstract
Cytotoxic T (Tc) cells play a key role in the defense against virus infections. Tc cells recognize infected cells via the T-cell receptor (TCR) and subsequently kill the target cells by one or more cytotoxic mechanisms. Induction of the cytotoxic mechanisms is finely tuned by the activation signals from the TCR. To determine whether TCR down-regulation affects the cytotoxicity of Tc cells, we studied TCR down-regulation-deficient CD3¿LLAA mice. We found that Tc cells from CD3¿LLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether this defect was reflected in an increased susceptibility to virus infections, we studied the course of ectromelia virus (ECTV) infection. We found that the susceptibility to ECTV infection was significantly increased in CD3¿LLAA mice with a mortality rate almost as high as in granzyme B knock-out mice. Finally, we found that TCR signaling in CD3¿LLAA Tc cells caused highly increased tyrosine phosphorylation and activation of the c-Cbl ubiquitin ligase, and that the impaired exocytosis of lytic granules could be rescued by the knockdown of c-Cbl. Thus, our work demonstrates that TCR down-regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection.
- Published
- 2011
250. Consumer available permanent hair dye products cause major allergic immune activation in an animal model
- Author
-
Bonefeld, Charlotte Menne, Larsen, Jeppe Madura, Dabelsteen, Sally, Geisler, Carsten, White, I. R., Menne, Torkil, Johansen, Jeanne Duus, Bonefeld, Charlotte Menne, Larsen, Jeppe Madura, Dabelsteen, Sally, Geisler, Carsten, White, I. R., Menne, Torkil, and Johansen, Jeanne Duus
- Abstract
Udgivelsesdato: 2009-Jul-20, Summary Background p-Phenylenediamine (PPD) and related substances are ingredients of more than two-thirds of oxidative (permanent) hair dyes currently used. Although PPD is a potent skin sensitizer in predictive assays, the extent to which permanent hair dyes sensitize humans has been questioned due to the in-use conditions, e.g. the presence of couplers in the hair dye gel and rapid oxidation using a developer. Objectives To study the skin sensitizing potential of permanent hair dyes in mice. Methods Two different permanent hair dye products containing PPD were studied in CBA mice using a modified version of the local lymph node assay. The colour gel and developer (oxidant) were tested separately and in combination. Response was measured by ear swelling and cytokine production in ear tissue and serum by enzyme-linked immunosorbent assay. The immune cellular response in the draining lymph nodes was analysed by flow cytometry. Results Application of the colour gel both alone and mixed with the developer induced skin production of interleukin (IL)-1beta, tumour necrosis factor-alpha and IL-6 as well as systemic IL-6 release. Both treatments induced B- and T-cell infiltration as well as T-cell proliferation within the draining lymph nodes. Treatment with the mixture induced at least 20% more skin inflammation, cytokine production and CD4+ T-cell activation compared with the colour gel alone. Conclusions Consumer available PPD-containing permanent hair dyes can be potent and rapid immune activators. Mixing the colour gel and developer (oxidant) increased the induction of skin inflammation compared with application of the colour gel alone.
- Published
- 2010
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.