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Sergij Goerdt

Publications and source records attributed to Sergij Goerdt.

At least 19 recordsLinked to original sources
PubMed2007

Multiple juvenile xanthogranulomas successfully treated with CO laser.

Juvenile xanthogranulomas are a rare disease entity within the spectrum of cutaneous non-Langerhans cell histiocytoses characterized by single or multiple cutaneous xanthogranulomas without further organ involvement. A 16-year-old girl developed multiple xanthogranulomas in various skin regions, especially the trunk and the flexural areas, over a period of 6 months. The clinical diagnosis was confirmed by H&E histology, showing a histiocytic infiltrate admixed with foam cells and Touton giant cells, and by immunohistochemistry using anti-bodies to stabilin-1 whose expression is highly specific for cutaneous non-Langerhans cell histiocytoses. No diabetes insipidus, pituitary hyperplasia or paraproteinemia were observed. Skin lesions were treated with a CO(2) laser and did not reappear during a 5 years follow-up period.

Adolescent↗
PubMed2006

The expression of metastasis suppressor MIM/MTSS1 is regulated by DNA methylation.

MIM/MTSS1 was initially described as a gene missing in invasive bladder cancer cell lines. Functional analysis revealed that MIM is an actin binding protein involved in the regulation of actin cytoskeleton dynamics. MIM was shown to be sonic hedgehog (Shh) signaling dependent and synergizes with the effects of Gli transcription factors. Overexpression of MIM in cell lines leads to the inhibition of cell proliferation. In this study, we showed that the inhibition of cell growth by MIM is anchorage independent. We identified and cloned the promoter region of MIM and located the main promoter activity to 276 bp of 5' flanking sequence sited within a CpG island. Analysis of DNA methylation using bisulphite sequencing revealed that MIM promoter is methylated in its 5' region in cells and tissue samples with reduced endogenous MIM expression. Using luciferase reporter assay, we demonstrated that nonmethylated MIM promoter has a similar activity in cell lines with different endogenous MIM expression. Inhibition of DNA methylation by 5-Aza-2'-deoxycytidine led to upregulation of MIM expression in a low expressing cell line. In conclusion, we clearly demonstrate here that the expression of metastasis suppressor MIM is regulated by DNA methylation of a CpG island within its promoter region.

Antimetabolites, Antineoplastic↗
PubMed2006

Identification of HLA class I dependent immunogenic peptides from clonotypic TCRbeta expressed in cutaneous T-cell lymphoma.

The clonotypic T-cell receptor (TCR) is a potential target antigen for specific immunotherapy of cutaneous T-cell lymphoma (CTCL). We identified T-cell epitopes from the rearranged TCR beta chain of the malignant T-cell population by the "reverse immunology" approach. Peptide-specific T-cell lines were generated against predicted epitopes and tested for the recognition of tumor cells and cells transfected with the full-length DNA coding for TCRV beta chain. Two peptides derived from the clonotypic TCRVbeta of a HLA-A2 positive patient could induce peptide-specific T cells from peripheral blood mononuclear cells of healthy donors and the patient as assessed by IFN-gamma ELISpot assay. Furthermore, the reactive CTLs efficiently recognized autologous Sézary tumor cells, as well as HLA-A2 positive 293 cells transfected with recombinant plasmid expressing the corresponding TCRVbeta29 protein. Similar results were obtained in a HLA-A3+ patient for TCRVbeta7-Jbeta2.7. In conclusion, our experiments show that the TCR beta chain harbors epitopes suitable as targets for specific vaccination which might be a promising approach for the specific immunotherapy of cutaneous T-cell lymphoma patients.

Epitopes↗
PubMed2006

Enhanced T-cell activation and T-cell-dependent IL-2 production by CD83+, CD25high, CD43high human monocyte-derived dendritic cells.

Although standardized protocols are widely used for the generation of monocyte-derived immunostimulatory dendritic cells (DC(ims)), the inducibility of Th1 cells by DC(ims) may considerably differ. As a measure for the quality of DC(ims) generated from an individual donor at a certain time point, CD83 is used in combination with HLA-DR and CD86 to assess DC maturation. When phenotypically analyzing DC(ims), we identified a subpopulation ( approximately 60%) of CD83+, CD86+, and HLA-DR+ DC(ims) that co-expressed CD25. DC within a given DC(ims) preparation identified by lower expression of CD83 and by selective expression of CD14, however, did not co-express CD25. In order to establish CD25 as an additional maturation marker of DC(ims), we studied the DC phenotype of these cells as well as the DC-dependent T-cell proliferation and T-cell cytokine production profile after co-incubation with sorted CD25(high) and CD25(low) subpopulations of CD83+, HLA-DR+, CD86+ DC(ims). CD25(high) DC(ims) showed significant up-regulation of the DC activation molecule CD43 and induced increased levels of IL-2 secretion in allogeneic T-cells (170.7+/-86.7pg/mL) as compared to T-cells coincubated with CD25(low) DC(ims) (86.6+/-37.6pg/mL) [p=0.0224]. This was reflected by a significantly lower T-cell stimulatory capacity of CD25(low) DC(ims) (84.0% of CD25(high) DC(ims), 1:10 ratio; p=0.014) whereas the T-cell stimulatory capacity of CD25(low) DC(ims) was much higher when compared to IL-10 induced regulatory DC (55.3% of CD25(high) DC(ims); 1:10 ratio). With regard to cancer vaccination protocols, we propose to use CD25 and CD43 as additional markers for DC quality control, assessment of maturational status, and positive selection.

Antigens, CD↗
PubMed2006

Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals.

Macrophages (Mphi) represent a dynamic cell population that develops and operates within a changing microenvironment. In parallel to Th1/Th2 cells, primary Mphi may undergo classical (Mphi1) or alternative (Mphi2) activation. Here, we investigated whether Mphi1/Mphi2 may be re-polarized by a secondary stimulation by Th1 or Th2 cytokines or by exogenous danger signals. We established that Mphi1IFNgamma respond to alternative activation by IL-4 and IL-10 by de novo secretion of Th2 cytokines AMAC-1 and IL-1ra, and by an increase in phagocytic capacity and a decrease in bactericidal activity. Vice versa, Mphi2 responded to classical activation by IFNgamma exhibiting reduced phagocytosis and significantly increased bacterial killing while being refractory regarding secretion of TNFalpha, IL-1beta and IL-12. In response to the bacterial danger signals LPS and MDP, both Mphi1 and Mphi2 produced IL-1beta and TNFalpha; in addition Mphi2 expressed the Th1-inducing cytokine IL-12. The ability of Mphi to be re-polarized and to react to exogenous danger signals is a precondition to down-regulate an outdated immune reaction and to retain the capacity to mount an adequate anti-bacterial response. Selective refractoriness of Mphi1 and Mphi2 to IFNgamma- and LPS-induced cytokine secretion may contribute to prevent autoimmunity.

Cells, Cultured↗
PubMed2006

Functional characterization of the epidermal cholinergic system in vitro.

The aim of this study was to analyze the influence of cholinergic and anticholinergic drugs on epidermal physiology using organotypic cocultures (OTCs). Blocking of all acetylcholine receptors (AChRs) by combined treatment with mecamylamine and atropine or treatment with strychnine (blocking alpha9nAChR) for 7-14 days resulted in a complete inhibition of epidermal differentiation and proliferation. Blockage of nicotinic (n)AChR with mecamylamine led to a less pronounced delay in epidermal differentiation and proliferation than blockage of muscarinic (m)AChR with atropine, evidenced by reduced epithelial thickness and expression of terminal differentiation markers like cytokeratin 2e or filaggrin. In OTCs treated with atropine, mecamylamine, or strychnine, we could demonstrate intracellular lipid accumulation in the lower epidermal layers, indicating a severely disturbed epidermal barrier. In addition, we observed prominent acantholysis in the basal and lower suprabasal layers in mecamylamine-, atropine-, and strychnine-treated cultures, accompanied by a decreased expression of cell adhesion proteins. This globally reduced cell adhesion led to cell death via intrinsic activation of apoptosis. In contrast, stimulation of nAChR and mAChR with cholinergic drugs resulted in a significantly thickened epithelium, accompanied by an improved epithelial maturation. In summary, we show that epidermal AChR are crucially involved in the regulation of epidermal homeostasis.

Acetylcholine↗
PubMed2006

Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC.

The matricellular protein SPARC (secreted protein acidic and rich in cysteine) has been implicated in development, differentiation, response to injury, and tumor biology by virtue of its regulation of extracellular matrix production/assembly and its antiadhesive and antiproliferative effects on different cell types. Despite numerous biological activities described for SPARC, cell surface receptors for this protein have not been identified. By phage display and in vitro-binding assays, we now show that SPARC interacts with stabilin-1, a scavenger receptor expressed by tissue macrophages and sinusoidal endothelial cells. The interaction is mediated by the extracellular epidermal growth factor-like region of stabilin-1 containing the sequence FHGTAC. Using FACS analysis and confocal microscopy, we demonstrate that stabilin-1 internalizes and targets SPARC to an endosomal pathway in Chinese hamster ovary cells stably transfected with this receptor. In human macrophages, stabilin-1 expression is required for receptor-mediated endocytosis of SPARC. SPARC was efficiently endocytosed by alternatively activated macrophages stimulated by IL-4 and dexamethasone, but not solely by Th1 or Th2 cytokines. A time course of ligand exposure to alternatively activated macrophages revealed that stabilin-1-mediated endocytosis of SPARC was followed by its targeting for degradation, similar to the targeting of acetylated low density lipoprotein, another stabilin-1 ligand. We propose that alternatively activated macrophages coordinate extracellular matrix remodeling, angiogenesis, and tumor progression via stabilin-1-mediated endocytosis of SPARC and thereby regulate its extracellular concentration.

Animals↗
PubMed2006

Dynamics of the actin-binding protein drebrin in motile cells and definition of a juxtanuclear drebrin-enriched zone.

The actin-binding protein (ABP) drebrin, isoform E2, is involved in remodelling of the actin cytoskeleton and in formation of cell processes, but its role in cell migration has not yet been investigated. Therefore, we have studied the organization of drebrin in motile cultured cells such as murine B16F1 melanoma and human SV80 fibroblast cells, using live cell confocal microscopy. In cells overexpressing DNA constructs encoding drebrin linked to EGFP, numerous long, branched cell processes were formed which slowly retracted and extended, whereas forward movement was halted. In contrast, stably transfected B16F1 cells containing drebrin-EGFP at physiological levels displayed lamellipodia and were able to migrate on laminin. Surprisingly, in such cells, drebrin was absent from anterior lamellipodia but was enriched in a specific juxtanuclear zone, the "drebrin-enriched zone" (DZ), and in the tail. In leading edges of SV80 cells, characterized by pronounced actin microspikes, drebrin was specifically enriched along posterior portions of the microspikes, together with tropomyosin. Drebrin knock-down by small interfering RNAs did not impair movements of SV80 cells. Our results confirm the role of drebrin E2 in the formation of branching processes and further indicate that during cell migration, the protein contributes to retraction of the cell body and the tail but not to lamellipodia formation. In particular, the novel, sizable juxtanuclear DZ structure will have to be characterized in future experiments with respect to its molecular assembly and cell biological functions.

Actins↗
PubMed2006

Cutaneous leiomyosarcoma with myxoid alteration arising in a setting of multiple cutaneous smooth muscle neoplasms.

BACKGROUND: Cutaneous leiomyomas and leiomyosarcomas are rare tumors that originate from the arrector muscle of hair follicles or the smooth muscle of blood vessels. CASE REPORT: A 74-year-old male presented with a single, erythematous nodule on the left upper arm. This lesion developed within the excision scar of a piloleiomyoma that had been excised 3 years ago. Additionally, physical examination revealed a tender nodule on the right ear. RESULTS: Histological examination showed a cutaneous leiomyosarcoma with myxoid alteration on the upper arm and an angioleiomyoma on the right ear. CONCLUSION: Myxoid leiomyosarcomas have exclusively been reported in the uterus and gastrointestinal tract, but not in the skin. Here, we describe a case of cutaneous leiomyosarcoma with myxoid alteration that developed in the excision scar of a piloleiomyoma and was accompanied by a cutaneous angioleiomyoma in a different location.

Aged↗
PubMed2006

New insights into the molecular biology and targeted therapy of cutaneous T-cell lymphomas.

Cutaneous T-cell lymphoma is an extra-nodal non-Hodgkin lymphoma of mature T cells. These tumor cells home to and persist in the skin,producing a broad spectrum of clinical entities. Recent results of basic research on tumor biology and tumor immunology as well as molecular genetics of cutaneous T-cell lymphoma have fostered the development of new therapeutic approaches. Several clinical trials testing these targeted therapies have shown encouraging results. This article provides an overview of recent research developments and therapeutic strategies for cutaneous T-cell lymphoma.

Animals↗
PubMed2006

[Angioma serpiginosum following the lines of Blaschko--an effective treatment with the IPL technology].

Angioma serpiginosum, first described by Hutchinson in 1889, is a rare benign vascular nevus with dilatation and proliferation of the capillaries in the upper dermis. A 15-year-old boy presented with an angioma serpiginosum on the right side of the body following the lines of Blaschko. Both the clinical pattern and the appearance in a male are unusual. Treatment with IPL technology (intense pulsed light), which emits polychromatic light from a high-intensity flashlamp, proved to be an effective approach.

Adolescent↗
PubMed2005

Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway.

Mammalian Glyco_18-domain-containing proteins include catalytically active chitinases and chitinase-like proteins with cytokine activity involved in host defense and Th2-type inflammatory reactions. Here, we describe a novel human Glyco_18-domain-containing protein, SI-CLP, as an interacting partner of the endocytic/sorting receptor stabilin-1. Similarly to the chitinase-like cytokines YKL-39, YKL-40, and YM1/2, SI-CLP lacks a chitin-binding domain and catalytic amino acids. Using a novel mAb 1C11, we demonstrated that SI-CLP is sorted into late endosomes and secretory lysosomes in human alternatively activated macrophages. The direct interaction of SI-CLP with stabilin-1, their colocalization in the trans-Golgi network, and the reduced sorting of SI-CLP into lysosomes in macrophages treated with stabilin-1 siRNA suggest that stabilin-1 is involved in intracellular sorting of SI-CLP. Expression of SI-CLP in macrophages was strongly up-regulated by the Th2 cytokine IL-4 and by dexamethasone. This effect was suppressed by IFNgamma but not affected by IL-10. In contrast, expression of YKL-40 was induced by IFNgamma and suppressed by dexamethasone. Macrophages treated with IL-4 secreted SI-CLP, while costimulation with dexamethasone blocked secretion and resulted in intracellular accumulation of SI-CLP. The 1C11 mAb detected SI-CLP in human bronchoalveolar lavage and peripheral-blood leukocytes (PBLs), and can be used to analyze the role of SI-CLP in human disorders.

Anti-Inflammatory Agents↗
PubMed2005

Additional Her 2/neu gene copies in patients with Sézary syndrome.

BACKGROUND: Her 2/neu gene amplification has been reported in several types of cancer. Monoclonal antibodies against the Her 2/neu receptor are used as a treatment in e.g. metastatic breast cancer. AIM: The aim of this study was to determine the frequency of additional Her 2/neu gene copies in relations to the number of chromosome 17 centromeres of patients with Sézary syndrome. METHODS: Fluorescence in situ hybridization (FISH) with probes specific for the Her 2/neu gene locus and the centromere of chromosome 17 was performed on nuclei from peripheral blood cells of 9 patients with Sézary syndrome. For analysis of Her 2/neu protein expression immunostaining was performed. In addition, FISH was used to analyze distribution of typical lymphocytes on cryo-cut sections of affected skin of two patients. RESULTS: 7/9 cases showed additional Her 2/neu gene copies in relation to the number of chromosome 17 centromeres. 4/5 cases with additional Her 2/neu gene copies in which immunostaining was performed expressed Her 2/neu protein. On cryo-cut sections atypical lymphocytes with additional Her 2/neu gene copies were detected in the dermis as well as in the epidermis of affected skin. DISCUSSION: These data suggest that Her 2/neu might be involved in the pathogenesis of Sézary syndrome and that Her 2/neu might be a promising target for antitumor therapy in a subgroup of patients.

Aged↗
PubMed2005

Immunosuppressive agents mediate reduced allostimulatory properties of myeloid-derived dendritic cells despite induction of divergent molecular phenotypes.

Immunosuppressive drugs such as glucocorticoids (dexamethasone (Dexa)), cyclosporin A (CsA) and tacrolimus (Tacro) have been shown to impair differentiation and/or function of immunostimulatory dendritic cells (DC(ims)). Phenotypes and functions of the resultant myeloid dendritic cells, however, have not yet been thoroughly elucidated. We show here that all DC subsets generated by treatment with immunosuppressive agents exhibited considerably reduced allostimulatory properties as measured in the primary mixed lymphocyte reaction (tacrolimus>cyclosporin A>dexamethasone, used at equimolar concentrations). In the MLR, all these DC subsets furthermore inhibited secretion of the T-helper type 1 cytokine IFN-gamma; in addition, DC-Tacro and, less so, DC-CsA induced the T-helper type 2 cytokine IL-4. Upon FACS analysis, DC-Tacro and DC-CsA exhibited phenotypic features similar to DC(ims). In addition, DC-CsA and, to a smaller extent, DC-Tacro were characterized by increased mRNA expression of the novel costimulatory molecule B7-H2 (ICOS-ligand). In contrast, dexamethasone induced the generation of DC characterized by decreased expression of CD83 and CD86, by de novo expression of plasmacytoid and myeloid cell markers CD123 and CD14, respectively, and by sustained expression of Toll-like receptor 2. Interestingly, activation of DC-Dexa with a specific TLR2 ligand induced a strong up-regulation of IL-10 along with TNF-alpha and IL-6, a combination of cytokines that allow amplification of regulatory DC populations. In conclusion, myeloid DC induced by dexamethasone as well as by CsA or tacrolimus show reduced allostimulatory properties; however, they are equipped with different molecular repertoires to exert these functions.

CD4-Positive T-Lymphocytes↗
PubMed2005

Stabilin-1 and stabilin-2 are both directed into the early endocytic pathway in hepatic sinusoidal endothelium via interactions with clathrin/AP-2, independent of ligand binding.

Liver sinusoidal endothelial cells (LSECs) mediate clearance of hyaluronan (HA) and scavenger receptor ligands, for example, advanced glycation end product (AGE)-modified proteins and oxidized lipids from the circulation. We recently cloned stabilin-1 and -2, two members of a novel family of transmembrane proteins expressed in LSECs. By using primary LSECs and HEK293 cells separately expressing either stabilin, we have investigated their roles in the early events of endocytosis with respect to localization, ligand-binding properties, and associations with clathrin and adaptor protein (AP)-2. Both stabilins were present at the cell surface, although surface levels of stabilin-1 were limited. In addition, stabilins were present in early endosomal antigen (EEA)-1+ organelles colocalizing with endocytosed AGE-modified bovine serum albumin (BSA). Treating cells with monensin further pronounced this distribution. Recombinant stabilin-2, but not recombinant stabilin-1, bound HA and the scavenger receptor ligands AGE-modified BSA, formaldehyde-treated BSA, and collagen N-terminal propeptides. In LSECs, both stabilins were associated with clathrin and AP-2, but not with each other. These interactions did not change upon addition of exogenous HA, suggesting that stabilins are constitutively internalized. In conclusion, hepatic stabilins are both present in the early endocytic pathway, associating with clathrin/AP-2, but whereas stabilin-2 has a clear scavenging profile, stabilin-1 does not recognize these ligands.

Amino Acid Sequence↗
PubMed2005

Phosphatidylinositide 3-kinase activity is required for stabilin-1-mediated endosomal transport of acLDL.

Stabilin-1 is a type 1 transmembrane receptor specifically expressed by tissue macrophages and sinusoidal endothelial cells. We recently demonstrated that stabilin-1 is involved in the endocytic/recycling pathway and shuttles between the endosomal system and the trans-Golgi network (TGN) in human macrophages. In the present study, we designed a model cell system to study the mechanisms of stabilin-1-mediated endocytosis. Using CHO-K1 cells stably transfected with stabilin-1, we demonstrated that acetylated low-density lipoprotein (acLDL) induces recruitment of stabilin-1 into the endocytic pathway. Stabilin-1 mediates internalisation of acLDL and its delivery to early endosomes, and it is translocated together with its ligand to the late endosomal compartment. Treatment with wortmannin, a specific inhibitor of phosphatidylinositide 3-kinase (PI3K), did not block stabilin-1 mediated internalisation of acLDL as well as its trafficking to early endosomes, whereas it induced enlargement of stabilin-1/acLDL positive endosomes as well as partial dissociation of EEA1 from these structures. The major effect of wortmannin was the abrogation of stabilin-1/acLDL trafficking into the late endocytic pathway. In stabilin-1 positive human type 2 macrophages, wortmannin treatment resulted in formation of both enlarged and small stabilin-1 positive endosomes. This effect, however, was significantly weaker in macrophages as compared to CHO-stabilin-1 cells. Our data indicate that PI3K activity is required for the transfer of stabilin-1 and its ligand acLDL from early to late endosomal compartments.

Androstadienes↗