TY - JOUR A1 - Aguzzi, A. A1 - Both, K. A1 - Anhauser, I. A1 - Horak, I. A1 - Rethwilm, Axel A1 - Wagner, EF. T1 - Expression of human foamy virus is differentially regulated during development in transgenic mice N2 - Tbe human foamy virus (HFV) is a recently characterized member ofthe spumavirus family. Although no diseases have been unequivocally associated with HFV infection, expression of HFV regulatory genes in transgenie mice induces a characteristic aeute neuro degenerative disease and a myopathy. To better eharaeterize the sequenee of events leading to disease, and to gain a better understanding of the underlying pathogenetic meehanisms, we have analyzed in detail the transgene expression pattern during development. Transcription of a construet containing all regulatory elements and aneillary genes of mv was analyzed by in situ hybridization and was shown to occur in two distinct phases. At midgestation, low but widespread expression was first deteeted in eells of extraembryonie tissues. Later, various tissues originating from embryonie mesoderm, neuroeetoderm, and neural erest transeribed the transgene at moderate levels. However, expression deereased dramatically during late gestation and was suppressed shortly after birth. After a latency period of up to 5 weeks, transeription of the transgene resumed in single eelJs distributed irregularly in the central nervous system and in the skeletal museIe. By the age of 8 weeks, an increasing number of eells displayed much higher expression levels than in embryonie Iife and eventually underwent severe degenerative ehanges. These findings demonstrate that HFV transgene expression is differentially regulated in development and that HFV cytotoxicity may be dose-dependent. Such biphasic pattern of expression differs from that of murine retroviruses and may be explained by the specificity of HFV regulatory elements in combination with cellular faetors. Future studies of this model system should, therefore, provide novel insights in the mechanisms controlling retrovirallatency. KW - Virologie Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-55290 ER - TY - JOUR A1 - Aguzzi, A. A1 - Wagner, E. F. A1 - Netzer, K. O. A1 - Bothe, K. A1 - Anhauser, I. A1 - Rethwilm, Axel T1 - Human foamy virus proteins accumulate in neurons and induce multinucleated giant cells in the brain of transgenic mice N2 - Humanfoamy virus (HFV) is a retrovirus encoding structural genes and, like human immunodeficiency virus and human T ceU leukemia virus I, several anciUary reading frames collectively termed the belgenes. We have previously shown that HFV transgenic mice develop an encephalopathy with neuronal loss in hippocampus and cerebral cortex. We have now raised and characterized rabbit antisera to various recombinant portions of gag, pot, env, and bel-I, the viraltransactivator. Immunoreactivity for gag and bel-I was observed in nuclei and processes of hippocampal and cortical neurons before the onset of morphological lesions and correlated with the appearance of HFV mRNA. Astrocyte-derived multinucleated giant ceUs containing HFV proteins were present in the brain oftransgenic mice coexpressingfuU- length HFV genes but not in mice expressing truncated gag and env, suggesting that these genes contain afusogenic domain. Expression of fuU-length structural genes decreased the life expectancy oftransgenic mice, implying an a4Juvant rolefor these proteins in HFV-induced brain damage. (Am] Pathol 1993, 142:1061-1072) KW - Molekularpathologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47356 ER - TY - JOUR A1 - Archelos, J. J. A1 - Roggenbuck, K. A1 - Schneider-Schaulies, Jürgen A1 - Toyka, K. V. A1 - Hartung, H. P. T1 - Detection and quantification of antibodies to the extracellular domain of Po during experimental allergic neuritis N2 - Quantification of the peripheral nerve myelin glycoprotein PO and antibodies to PO is difficult due to insolubility of PO in physiological solutions. We have overcome this problern by using the water-soluble recombinant form of the extracellular domain of PO (PO-ED) and describe newly developed assays which allow detection and quantitation of PO and antibodies to PO, in serum and cerebraspinal fluid (CSF). These sensitive and specific assays based on the ELISA technique were used to study humoral immune responses to PO during experimental autoimmune ("allergic") neuritis (EAN). In order to establish these tests, monoclonal antiborlies to different epitopes of rodent and human PO-ED were produced. A two-antibody sandwich-ELISA allowing quantitation of PO Oower detection Iimit of 0.5 ngjml or 30 fmoljml) and an antibody-capture ELISA (lower detection Iimit 1 ng specific antibody jml) to detect antiborlies to PO in serum and CSF were developed. EAN was induced in rats by active immunization with bovine myelin or the neuritogenic protein P2 or by adoptive transfer using P2 specific CD4 positive T cells. Serum and CSF were assayed for the presence of PO-ED and antibodies to PO-ED or P2. Antibodies to PO-ED were detected during active myelin-induced EAN, but not during P2-induced or adaptive transfer EAN. The anti-PO-ED antibodies in the CSF showed a correJation with disease activity. In contrast, in the same model antibodies to P2 persisted long after the disease ceased. No soluble PO-Iike fragments could be found in serum or CSF during any of the three types of EAN. We conclude that PO may be a B-eeil epitope in EAN. These findings warrant a screen for antibodies to PO-ED in human immune neuropathies. KW - Immunologie KW - PO KW - Extracellular domain KW - Neuritis KW - GBS KW - Auto-antibodies Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-54896 ER - TY - JOUR A1 - Archelos, JJ A1 - Roggenbuck, K. A1 - Schneider-Schaulies, Jürgen A1 - Linington, C. A1 - Toyka, KV A1 - Hartung, H.-P. T1 - Production and characterization of monoclonal antibodies to the extracellular domain of PO N2 - Seven monoclonal antibodies were raised against the immunoglobulin-like extracellular domain of PO (POED), the major protein of peripheral nervous system myelin. Mice were immunized with purified recombinant rat PO-ED. After fusion, 7 clones (POI-P07) recognizing either recombinant, rat, mouse, or human PO-ED were selected by ELlS A and were characterized by Western blot, immunohistochemistry, and a competition assay. Antibodies belonged to the IgG or IgM class, and P04-P07, reacted with PO in fresh-frozen and paraffin-embedded sections of human or rat peripheral nerve, but not with myelin proteins of the central nervous system of either species. Epitope specificity of the antibodies was determined by a competition enzyme-linked immunosorbent assay (ELISA) and a direct ELlS A using short synthetic peptides spanning the entire extracellular domain of PO. These assays showed that POl and P02 exhibiting the same reaction pattern in Western blot and immunohistochemistry reacted with different distant epitopes of PO. Furthermore, the monoclonal antibodies P05 and P06 recognized 2 different epitopes in close proximity within the neuritogenic extracellular sequence of PO. This panel of monoclonal antibodies, each binding to a different epitope of the extracellular domain of PO, will be useful for in vitro and in vivo studies designed to explore the role of PO during myelination and in demyelinating diseases of the peripheral nervous system. KW - Immunologie KW - peripheral nervous system KW - myelin KW - epitope specificity KW - demyelination Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-54889 ER - TY - JOUR A1 - Armbruster, Nicole A1 - Krieg, Jennifer A1 - Weißenberger, Manuel A1 - Scheller, Carsten A1 - Steinert, Andre F. T1 - Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer JF - Frontiers in Pharmacology N2 - Background: Mesenchymal stem cells (MSCs) and their chondrogenic differentiation have been extensively investigated in vitro as MSCs provide an attractive source besides chondrocytes for cartilage repair therapies. Here we established prototype foamyviral vectors (FVV) that are derived from apathogenic parent viruses and are characterized by a broad host range and a favorable integration pattern into the cellular genome. As the inflammatory cytokine interleukin 1 beta (IL1β) is frequently present in diseased joints, the protective effects of FVV expressing the human interleukin 1 receptor antagonist protein (IL1RA) were studied in an established in vitro model (aggregate culture system) of chondrogenesis in the presence of IL1β. Materials and Methods: We generated different recombinant FVVs encoding enhanced green fluorescent protein (EGFP) or IL1RA and examined their transduction efficiencies and transgene expression profiles using different cell lines and human primary MSCs derived from bone marrow-aspirates. Transgene expression was evaluated by fluorescence microscopy (EGFP), flow cytometry (EGFP), and ELISA (IL1RA). For evaluation of the functionality of the IL1RA transgene to block the inhibitory effects of IL1β on chondrogenesis of primary MSCs and an immortalized MSC cell line (TERT4 cells), the cells were maintained following transduction as aggregate cultures in standard chondrogenic media in the presence or absence of IL1β. After 3 weeks of culture, pellets were harvested and analyzed by histology and immunohistochemistry for chondrogenic phenotypes. Results: The different FVV efficiently transduced cell lines as well as primary MSCs, thereby reaching high transgene expression levels in 6-well plates with levels of around 100 ng/ml IL1RA. MSC aggregate cultures which were maintained in chondrogenic media without IL1β supplementation revealed a chondrogenic phenotype by means of strong positive staining for collagen type II and matrix proteoglycan (Alcian blue). Addition of IL1β was inhibitory to chondrogenesis in untreated control pellets. In contrast, foamyviral mediated IL1RA expression rescued the chondrogenesis in pellets cultured in the presence of IL1β. Transduced MSC pellets reached thereby very high IL1RA transgene expression levels with a peak of 1087 ng/ml after day 7, followed by a decrease to 194 ng/ml after day 21, while IL1RA concentrations of controls were permanently below 200 pg/ml. Conclusion: Our results indicate that FVV are capable of efficient gene transfer to MSCs, while reaching IL1RA transgene expression levels, that were able to efficiently block the impacts of IL1β in vitro. FVV merit further investigation as a means to study the potential as a gene transfer tool for MSC based therapies for cartilage repair. KW - mesenchymal stem cell KW - chondrogenesis KW - pellet culture KW - foamy virus KW - virus vectors KW - IL1RA KW - interleukin 1 receptor antagonist KW - arthritis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170919 VL - 8 IS - 255 ER - TY - JOUR A1 - Avota, Elita A1 - Bodem, Jochen A1 - Chithelen, Janice A1 - Mandasari, Putri A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - The Manifold Roles of Sphingolipids in Viral Infections JF - Frontiers in Physiology N2 - Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach. KW - sphingolipid KW - ceramide KW - sphingosine-1-phosphate KW - plasma membrane KW - virus entry KW - virus replication KW - virus budding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246975 SN - 1664-042X VL - 12 ER - TY - JOUR A1 - Avota, Elita A1 - de Lira, Maria Nathalia A1 - Schneider-Schaulies, Sibylle T1 - Sphingomyelin breakdown in T cells: role of membrane compartmentalization in T cell signaling and interference by a pathogen JF - Frontiers in Cell and Developmental Biology N2 - Sphingolipids are major components of cellular membranes, and at steady-state level, their metabolic fluxes are tightly controlled. On challenge by external signals, they undergo rapid turnover, which substantially affects the biophysical properties of membrane lipid and protein compartments and, consequently, signaling and morphodynamics. In T cells, external cues translate into formation of membrane microdomains where proximal signaling platforms essential for metabolic reprograming and cytoskeletal reorganization are organized. This review will focus on sphingomyelinases, which mediate sphingomyelin breakdown and ensuing ceramide release that have been implicated in T-cell viability and function. Acting at the sphingomyelin pool at the extrafacial or cytosolic leaflet of cellular membranes, acid and neutral sphingomyelinases organize ceramide-enriched membrane microdomains that regulate T-cell homeostatic activity and, upon stimulation, compartmentalize receptors, membrane proximal signaling complexes, and cytoskeletal dynamics as essential for initiating T-cell motility and interaction with endothelia and antigen-presenting cells. Prominent examples to be discussed in this review include death receptor family members, integrins, CD3, and CD28 and their associated signalosomes. Progress made with regard to experimental tools has greatly aided our understanding of the role of bioactive sphingolipids in T-cell biology at a molecular level and of targets explored by a model pathogen (measles virus) to specifically interfere with their physiological activity. KW - T cell KW - sphingomyelinase KW - activation KW - motility KW - measles virus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199168 SN - 2296-634X VL - 7 IS - 152 ER - TY - JOUR A1 - Avota, Elita A1 - Gassert, Evelyn A1 - Schneider-Schaulies, Sibylle T1 - Cytoskeletal Dynamics: Concepts in Measles Virus Replication and Immunomodulation N2 - In common with most viruses, measles virus (MV) relies on the integrity of the cytoskeleton of its host cells both with regard to efficient replication in these cells, but also retention of their motility which favors viral dissemination. It is, however, the surface interaction of the viral glycoprotein (gp) complex with receptors present on lymphocytes and dendritic cells (DCs), that signals effective initiation of host cell cytoskeletal dynamics. For DCs, these may act to regulate processes as diverse as viral uptake and sorting, but also the ability of these cells to successfully establish and maintain functional immune synapses (IS) with T cells. In T cells, MV signaling causes actin cytoskeletal paralysis associated with a loss of polarization, adhesion and motility, which has been linked to activation of sphingomyelinases and subsequent accumulation of membrane ceramides. MV modulation of both DC and T cell cytoskeletal dynamics may be important for the understanding of MV immunosuppression at the cellular level. KW - Virologie KW - measles virus KW - cytoskeleton KW - sphingomyelinase Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69092 ER - TY - JOUR A1 - Avota, Elita A1 - Gulbins, Erich A1 - Schneider-Schaulies, Sibylle T1 - DC-SIGN Mediated Sphingomyelinase-Activation and Ceramide Generation Is Essential for Enhancement of Viral Uptake in Dendritic Cells N2 - As pattern recognition receptor on dendritic cells (DCs), DC-SIGN binds carbohydrate structures on its pathogen ligands and essentially determines host pathogen interactions because it both skews T cell responses and enhances pathogen uptake for cis infection and/or T cell trans-infection. How these processes are initiated at the plasma membrane level is poorly understood. We now show that DC-SIGN ligation on DCs by antibodies, mannan or measles virus (MV) causes rapid activation of neutral and acid sphingomyelinases followed by accumulation of ceramides in the outer membrane leaflet. SMase activation is important in promoting DC-SIGN signaling, but also for enhancement of MV uptake into DCs. DCSIGN-dependent SMase activation induces efficient, transient recruitment of CD150, which functions both as MV uptake receptor and microbial sensor, from an intracellular Lamp-1+ storage compartment shared with acid sphingomyelinase (ASM) within a few minutes. Subsequently, CD150 is displayed at the cell surface and co-clusters with DC-SIGN. Thus, DCSIGN ligation initiates SMase-dependent formation of ceramide-enriched membrane microdomains which promote vertical segregation of CD150 from intracellular storage compartments along with ASM. Given the ability to promote receptor and signalosome co-segration into (or exclusion from) ceramide enriched microdomains which provide a favorable environment for membrane fusion, DC-SIGN-dependent SMase activation may be of general importance for modes and efficiency of pathogen uptake into DCs, and their routing to specific compartments, but also for modulating T cell responses. KW - Dendritische Zelle Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69056 ER - TY - JOUR A1 - Avota, Elita A1 - Schneider-Schaulies, Sibylle T1 - The Role of Sphingomyelin Breakdown in Measles Virus Immunmodulation JF - Cellular Physiology and Biochemistry N2 - Measles virus (MV) efficiently causes generalized immunosuppression which accounts to a major extent for cases of measles-asscociated severe morbidity and mortality. MV infections alter many functions of antigen presenting cells (APC) (dendritic cells (DCs)) and lymphocytes, yet many molecular targets of the virus remain poorly defined. Cellular interactions and effector functions of DCs and lymphocytes are regulated by surface receptors. Associating with other proteins involved in cell signaling, receptors form part of receptosomes that respond to and transmit external signals through dynamic interctions with the cytoskeleton. Alterations in the composition and metabolism of membrane sphingolipids have a substantial impact on both processes. In this review we focus on the regulation of sphingomyelinase activity and ceramide release in cells exposed to MV and discuss the immunosuppressive role of sphingomyelin breakdown induced by MV. KW - sphingomyelinase KW - measles virus KW - immunosuppression KW - T cell silencing KW - dendritic cell Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120004 SN - 1015-8987 VL - 34 IS - 1 ER - TY - JOUR A1 - Badr, Mohammad A1 - McFleder, Rhonda L. A1 - Wu, Jingjing A1 - Knorr, Susanne A1 - Koprich, James B. A1 - Hünig, Thomas A1 - Brotchie, Jonathan M. A1 - Volkmann, Jens A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson’s disease mice JF - Journal of Neuroinflammation N2 - Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson’s disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson’s disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson’s disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson’s disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson’s disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson’s disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson’s disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson’s disease patients. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - regulatory T cells KW - neuroprotection Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300580 VL - 19 ER - TY - JOUR A1 - Baptista, Marisa A.P. A1 - Keszei, Marton A1 - Oliveira, Mariana A1 - Sunahara, Karen K.S. A1 - Andersson, John A1 - Dahlberg, Carin I.M. A1 - Worth, Austen J. A1 - Liedén, Agne A1 - Kuo, I-Chun A1 - Wallin, Robert P.A. A1 - Snapper, Scott B. A1 - Eidsmo, Liv A1 - Scheynius, Annika A1 - Karlsson, Mikael C.I. A1 - Bouma, Gerben A1 - Burns, Siobhan O. A1 - Forsell, Mattias N.E. A1 - Thrasher, Adrian J. A1 - Nylén, Susanne A1 - Westerberg, Lisa S. T1 - Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells JF - Nature Communications N2 - Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in theWASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8þ T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNg-producing CD8þ T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8þ T cells at the expense of CD4þ T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8þ T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells. KW - Cell signalling KW - Dendritic cells KW - Disease genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165966 VL - 7 ER - TY - JOUR A1 - Batool, Farwa A1 - Saeed, Muhammad A1 - Saleem, Hafiza Nosheen A1 - Kirschner, Luisa A1 - Bodem, Jochen T1 - Facile synthesis and in vitro activity of N-substituted 1,2-benzisothiazol-3(2H)-ones against dengue virus NS2BNS3 protease JF - Pathogens N2 - Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition. Contrary to the conventional multistep synthesis, we achieved structurally diverse BITs with excellent yields using a two-step, one-pot reaction strategy. All the synthesised compounds were prescreened for drug-like properties using the online Swiss Absorption, Distribution, Metabolism and Elimination (SwissADME) model, indicating their favourable pharmaceutical properties. Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease. Dose–response experiments and computational docking analyses revealed that several BITs bind to the protease in the vicinity of the catalytic triad with IC\(_{50}\) values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2H)-one and 2-(2,6-dichlorophenyl)benzo[d]isothiazol-3(2H)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics. KW - dengue virus KW - direct-acting antivirals KW - 1,2-benzisothiazolinone KW - drug discovery KW - infectivity assays Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236605 SN - 2076-0817 VL - 10 IS - 4 ER - TY - JOUR A1 - Bauer, Boris A1 - Goebeler, Matthias A1 - Weissbrich, Benedikt A1 - Kerstan, Andreas T1 - Kerinokeratosis papulosa of childhood JF - Dermatology N2 - Background: Kerinokeratosis papulosa (KP) is considered an extremely rare genodermatosis presenting usually as waxy papules on the trunk in childhood. Objective: To describe and analyze the clinical, histological and potential etiopathological aspects of KP. Methods: The dermatoscopic features of a new case of KP of childhood are investigated. The presence of human papillomavirus (HPV) DNA in lesional skin was studied by polymerase chain reaction. Furthermore, all cases of KP of childhood reported so far were reviewed. Results: As a diagnostic tool, we describe for the first time a dermatoscopic feature, namely a cribriform pattern of KP, in an 11-year-old boy. In addition, we detected HPV (type 57) in his KP lesions. Conclusions: Dermatoscopic examination might be a useful tool to distinguish KP from other skin lesions, e.g. common warts. The detection of HPV type 57 might hint to an etiological role of HPV for KP. KW - Waxy papulosis of childhood KW - Human papillomavirus KW - EVER1 KW - EVER2 KW - Kerinokeratosis papulosa Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198997 SN - 1018-8665 SN - 1421-9832 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 231 IS - 1 SP - 1 EP - 4 ER - TY - JOUR A1 - Baunach, Gerald A1 - Maurer, Bernd A1 - Hahn, Heidi A1 - Kranz, Manuela A1 - Rethwilm, Axel T1 - Functional analysis of human foamy virus accessory reading frames N2 - No abstract available KW - Virologie Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61398 ER - TY - JOUR A1 - Berges, Carsten A1 - Kerkau, Thomas A1 - Werner, Sandra A1 - Wolf, Nelli A1 - Winter, Nadine A1 - Hünig, Thomas A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Beyersdorf, Niklas T1 - Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice JF - Immunity, Inflammation and Disease N2 - Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication. Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition. Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. KW - Hsp90 KW - leukemia KW - acute Graft versus Host Disease KW - Graft versus Tumor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168318 VL - 4 IS - 4 ER - TY - JOUR A1 - Bergfeld, Arne A1 - Dasari, Prasad A1 - Werner, Sandra A1 - Hughes, Timothy R. A1 - Song, Wen-Chao A1 - Hortschansky, Peter A1 - Brakhage, Axel A. A1 - Hünig, Thomas A1 - Zipfel, Peter F. A1 - Beyersdorf, Niklas T1 - Direct binding of the pH-regulated Protein 1 (Pra1) from Candida albicans inhibits cytokine secretion by mouse CD4\(^{+}\) T cells JF - Frontiers in Microbiology N2 - Opportunistic infections with the saprophytic yeast Candida albicans are a major cause of morbidity in immunocompromised patients. While the interaction of cells and molecules of innate immunity with C. albicans has been studied to great depth, comparatively little is known about the modulation of adaptive immunity by C. albicans. In particular, direct interaction of proteins secreted by C. albicans with CD4\(^{+}\) T cells has not been studied in detail. In a first screening approach, we identified the pH-regulated antigen 1 (Pra1) as a molecule capable of directly binding to mouse CD4\(^{+}\) T cells in vitro. Binding of Pra1 to the T cell surface was enhanced by extracellular Zn\(^{2+}\) ions which Pra1 is known to scavenge from the host in order to supply the fungus with Zn\(^{2+}\). In vitro stimulation assays using highly purified mouse CD4\(^{+}\) T cells showed that Pra1 increased proliferation of CD4\(^{+}\) T cells in the presence of plate-bound anti-CD3 monoclonal antibody. In contrast, secretion of effector cytokines such as IFNγ and TNF by CD4\(^{+}\) T cells upon anti-CD3/ anti-CD28 mAb as well as cognate antigen stimulation was reduced in the presence of Pra1. By secreting Pra1 C. albicans, thus, directly modulates and partially controls CD4\(^{+}\) T cell responses as shown in our in vitro assays. KW - Candida albicans KW - pH-regulated antigen 1 (Pra1) KW - CD4\(^{+}\) T cells KW - immune evasion KW - cytokine secretion Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158274 VL - 8 IS - 844 ER - TY - JOUR A1 - Berkhout, Ben A1 - Bodem, Jochen A1 - Erlwein, Otto A1 - Herchenröder, Ottmar A1 - Khan, Arifa S. A1 - Lever, Andrew M. L. A1 - Lindemann, Dirk A1 - Linial, Maxine L. A1 - Löchelt, Martin A1 - McClure, Myra O. A1 - Scheller, Carsten A1 - Weiss, Robin A. T1 - Obituary: Axel Rethwilm (1959–2014) JF - Retrovirology N2 - No abstract available Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120781 VL - 11 IS - 85 ER - TY - JOUR A1 - Beyersdorf, Niklas A1 - Werner, Sandra A1 - Wolf, Nelli A1 - Herrmann, Thomas A1 - Kerkau, Thomas T1 - Characterization of a New Mouse Model for Peripheral T Cell Lymphoma in Humans JF - PLoS One N2 - Peripheral T cell lymphomas (PTCLs) are associated with a poor prognosis due to often advanced disease at the time of diagnosis and due to a lack of efficient therapeutic options. Therefore, appropriate animal models of PTCL are vital to improve clinical management of this disease. Here, we describe a monoclonal CD8\(^+\) CD4\(^−\) αβ T cell receptor Vβ2\(^+\) CD28\(^+\) T cell lymphoma line, termed T8-28. T8-28 cells were isolated from an un-manipulated adult BALB/c mouse housed under standard pathogen-free conditions. T8-28 cells induced terminal malignancy upon adoptive transfer into syngeneic BALB/c mice. Despite intracellular expression of the cytotoxic T cell differentiation marker granzyme B, T8-28 cells appeared to be defective with respect to cytotoxic activity as read-out in vitro. Among the protocols tested, only addition of interleukin 2 in vitro could partially compensate for the in vivo micro-milieu in promoting growth of the T8-28 lymphoma cells. KW - T cells KW - cytotoxic T cells KW - mouse models KW - interleukins KW - cell staining KW - lymphomas KW - fluorescence-activated cell sorting KW - lymph nodes Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137946 VL - 6 IS - 12 ER - TY - JOUR A1 - Bodem, Jochen A1 - Rethwilm, Axel T1 - Evolution of Foamy Viruses: The Most Ancient of All Retroviruses JF - Viruses N2 - Recent evidence indicates that foamy viruses (FVs) are the oldest retroviruses (RVs) that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy viral vectors in gene therapy. However, various questions on the molecular evolution of FVs remain still unanswered. The analysis of the spectrum of animal species infected by exogenous FVs or harboring endogenous FV elements in their genome is pivotal. Furthermore, animal studies might reveal important issues, such as the identification of the FV in vivo target cells, which than require a detailed characterization, to resolve the molecular basis of the accuracy with which FVs copy their genome. The issues of the extent of FV viremia and of the nature of the virion genome (RNA vs. DNA) also need to be experimentally addressed. KW - foamy viruses KW - retroviruses KW - hepadnaviruses KW - evolution KW - genetic conservation KW - recombination Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97312 ER -