@article{SchofferSchueleinArandetal.2016, author = {Schoffer, Olaf and Sch{\"u}lein, Stefanie and Arand, Gerlinde and Arnholdt, Hans and Baaske, Dieter and Bargou, Ralf C. and Becker, Nikolaus and Beckmann, Matthias W. and Bodack, Yves and B{\"o}hme, Beatrix and Bozkurt, Tayfun and Breitsprecher, Regine and Buchali, Andre and Burger, Elke and Burger, Ulrike and Dommisch, Klaus and Elsner, Gudrun and Fernschild, Karin and Flintzer, Ulrike and Funke, Uwe and Gerken, Michael and G{\"o}bel, Hubert and Grobe, Norbert and Gumpp, Vera and Heinzerling, Lucie and Kempfer, Lana Raffaela and Kiani, Alexander and Klinkhammer-Schalke, Monika and Kl{\"o}cking, Sabine and Kreibich, Ute and Knabner, Katrin and Kuhn, Peter and Lutze, Stine and M{\"a}der, Uwe and Maisel, Tanja and Maschke, Jan and Middeke, Martin and Neubauer, Andreas and Niedostatek, Antje and Opazo-Saez, Anabelle and Peters, Christoph and Schell, Beatrice and Schenkirsch, Gerhard and Schmalenberg, Harald and Schmidt, Peter and Schneider, Constanze and Schubotz, Birgit and Seide, Anika and Strecker, Paul and Taubenheim, Sabine and Wackes, Matthias and Weiß, Steffen and Welke, Claudia and Werner, Carmen and Wittekind, Christian and Wulff, J{\"o}rg and Zettl, Heike and Klug, Stefanie J.}, title = {Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011}, series = {BMC Cancer}, volume = {16}, journal = {BMC Cancer}, number = {936}, doi = {10.1186/s12885-016-2963-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164544}, year = {2016}, abstract = {Background Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. Methods Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. Results The number of annually documented cases increased by 53.2\% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95\% CI 0.97-0.97), sex (OR 1.18, 95\% CI 1.11-1.25), date of diagnosis (OR 1.05, 95\% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95\% CI 2.50-4.19) and place of residence (OR 1.23, 95\% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4\% (95\% CI 82.8-83.9\%). Conclusions No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008. "}, language = {en} } @article{SchwenderKoenigKlapperstuecketal.2014, author = {Schwender, Joerg and Koenig, Christina and Klapperstueck, Matthias and Heinzel, Nicolas and Munz, Eberhard and Hebbelmann, Inga and Hay, Jordan O. and Denolf, Peter and De Bodt, Stefanie and Redestig, Henning and Caestecker, Evelyne and Jakob, Peter M. and Borisjuk, Ljudmilla and Rolletschek, Hardy}, title = {Transcript abundance on its own cannot be used to infer fluxes in central metabolism}, series = {Frontiers in Plant Science}, volume = {5}, journal = {Frontiers in Plant Science}, issn = {1664-462X}, doi = {10.3389/fpls.2014.00668}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114586}, year = {2014}, abstract = {An attempt has been made to define the extent to which metabolic flux in central plant metabolism is reflected by changes in the transcriptome and metabolome, based on an analysis of in vitro cultured immature embryos of two oilseed rape (Brassica napus) accessions which contrast for seed lipid accumulation. Metabolic flux analysis (MFA) was used to constrain a flux balance metabolic model which included 671 biochemical and transport reactions within the central metabolism. This highly confident flux information was eventually used for comparative analysis of flux vs. transcript (metabolite). Metabolite profiling succeeded in identifying 79 intermediates within the central metabolism, some of which differed quantitatively between the two accessions and displayed a significant shift corresponding to flux. An RNA-Seq based transcriptome analysis revealed a large number of genes which were differentially transcribed in the two accessions, including some enzymes/proteins active in major metabolic pathways. With a few exceptions, differential activity in the major pathways (glycolysis, TCA cycle, amino acid, and fatty acid synthesis) was not reflected in contrasting abundances of the relevant transcripts. The conclusion was that transcript abundance on its own cannot be used to infer metabolic activity/fluxes in central plant metabolism. This limitation needs to be borne in mind in evaluating transcriptome data and designing metabolic engineering experiments.}, language = {en} } @article{DasariShopovaStroeetal.2018, author = {Dasari, Prasad and Shopova, Iordana A. and Stroe, Maria and Wartenberg, Dirk and Martin-Dahse, Hans and Beyersdorf, Niklas and Hortschansky, Peter and Dietrich, Stefanie and Cseresny{\´e}s, Zolt{\´a}n and Figge, Marc Thilo and Westermann, Martin and Skerka, Christine and Brakhage, Axel A. and Zipfel, Peter F.}, title = {Aspf2 From Aspergillus fumigatus Recruits Human Immune Regulators for Immune Evasion and Cell Damage}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, number = {1635}, issn = {1664-3224}, doi = {10.3389/fimmu.2018.01635}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197013}, year = {2018}, abstract = {The opportunistic fungal pathogen Aspergillus fumigatus can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first A. fumigatus Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 via two regions located in SCRs6-7 and SCR20. FHL-1 binds via SCRs6-7, and FHR1 via SCRs3-5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δaspf2 knockout strain was generated which bound Factor H with 28\% and FHL-1 with 42\% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δaspf2 conidia had substantially more C3b (>57\%) deposited on their surface. Consequently, Δaspf2 conidia were more efficiently phagocytosed (>20\%) and killed (44\%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of A. fumigatus. By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration.}, language = {en} } @article{ArltBiehlTayloretal.2011, author = {Arlt, Wiebke and Biehl, Michael and Taylor, Angela E. and Hahner, Stefanie and Lib{\´e}, Rossella and Hughes, Beverly A. and Schneider, Petra and Smith, David J. and Stiekema, Han and Krone, Nils and Porfiri, Emilio and Opocher, Giuseppe and Bertherat, Jer{\^o}me and Mantero, Franco and Allolio, Bruno and Terzolo, Massimo and Nightingale, Peter and Shackleton, Cedric H. L. and Bertagna, Xavier and Fassnacht, Martin and Stewart, Paul M.}, title = {Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors}, series = {The Journal of Clinical Endocrinology \& Metabolism}, volume = {96}, journal = {The Journal of Clinical Endocrinology \& Metabolism}, number = {12}, doi = {10.1210/jc.2011-1565}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154682}, pages = {3775 -- 3784}, year = {2011}, abstract = {Context: Adrenal tumors have a prevalence of around 2\% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2-11\% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values. Objective: Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy. Design: Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19-84 yr) and 45 ACC patients (20-80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26-201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids. Results: Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90\% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88\% (area under the curve = 0.96) when using only the nine most differentiating markers. Conclusions: Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas.}, language = {en} } @article{MambrettiKistnerMayeretal.2016, author = {Mambretti, Egle M. and Kistner, Katrin and Mayer, Stefanie and Massotte, Dominique and Kieffer, Brigitte L. and Hoffmann, Carsten and Reeh, Peter W. and Brack, Alexander and Asan, Esther and Rittner, Heike L.}, title = {Functional and structural characterization of axonal opioid receptors as targets for analgesia}, series = {Molecular Pain}, journal = {Molecular Pain}, number = {12}, doi = {10.1177/1744806916628734}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145917}, pages = {1-17}, year = {2016}, abstract = {Background Opioids are the gold standard for the treatment of acute pain despite serious side effects in the central and enteric nervous system. µ-opioid receptors (MOPs) are expressed and functional at the terminals of sensory axons, when activated by exogenous or endogenous ligands. However, the presence and function of MOP along nociceptive axons remains controversial particularly in na{\"i}ve animals. Here, we characterized axonal MOPs by immunofluorescence, ultrastructural, and functional analyses. Furthermore, we evaluated hypertonic saline as a possible enhancer of opioid receptor function. Results Comparative immunolabeling showed that, among several tested antibodies, which all provided specific MOP detection in the rat central nervous system (CNS), only one monoclonal MOP-antibody yielded specificity and reproducibility for MOP detection in the rat peripheral nervous system including the sciatic nerve. Double immunolabeling documented that MOP immunoreactivity was confined to calcitonin gene-related peptide (CGRP) positive fibers and fiber bundles. Almost identical labeling and double labeling patterns were found using mcherry-immunolabeling on sciatic nerves of mice producing a MOP-mcherry fusion protein (MOP-mcherry knock-in mice). Preembedding immunogold electron microscopy on MOP-mcherry knock-in sciatic nerves indicated presence of MOP in cytoplasm and at membranes of unmyelinated axons. Application of [D-Ala\(^2\), N-MePhe\(^4\), Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve axons ex vivo, which was blocked by naloxone. When the lipophilic opioid fentanyl was applied perisciatically in na{\"i}ve Wistar rats, mechanical nociceptive thresholds increased. Subthreshold doses of fentanyl or the hydrophilic opioid DAMGO were only effective if injected together with hypertonic saline. In vitro, using β-arrestin-2/MOP double-transfected human embryonic kidney cells, DAMGO as well as fentanyl lead to a recruitment of β-arrestin-2 to the membrane followed by a β-arrestin-2 reappearance in the cytosol and MOP internalization. Pretreatment with hypertonic saline prevented MOP internalization. Conclusion MOPs are present and functional in the axonal membrane from na{\"i}ve animals. Hypertonic saline acutely decreases ligand-induced internalization of MOP and thereby might improve MOP function. Further studies should explore potential clinical applications of opioids together with enhancers for regional analgesia.}, language = {en} } @article{CouchWangMcGuffogetal.2013, author = {Couch, Fergus J. and Wang, Xianshu and McGuffog, Lesley and Lee, Andrew and Olswold, Curtis and Kuchenbaecker, Karoline B. and Soucy, Penny and Fredericksen, Zachary and Barrowdale, Daniel and Dennis, Joe and Gaudet, Mia M. and Dicks, Ed and Kosel, Matthew and Healey, Sue and Sinilnikova, Olga M. and Lee, Adam and Bacot, Fran{\c{c}}ios and Vincent, Daniel and Hogervorst, Frans B. L. and Peock, Susan and Stoppa-Lyonnet, Dominique and Jakubowska, Anna and Radice, Paolo and Schmutzler, Rita Katharina and Domchek, Susan M. and Piedmonte, Marion and Singer, Christian F. and Friedman, Eitan and Thomassen, Mads and Hansen, Thomas V. O. and Neuhausen, Susan L. and Szabo, Csilla I. and Blanco, Ingnacio and Greene, Mark H. and Karlan, Beth Y. and Garber, Judy and Phelan, Catherine M. and Weitzel, Jeffrey N. and Montagna, Marco and Olah, Edith and Andrulis, Irene L. and Godwin, Andrew K. and Yannoukakos, Drakoulis and Goldgar, David E. and Caldes, Trinidad and Nevanlinna, Heli and Osorio, Ana and Terry, Mary Beth and Daly, Mary B. and van Rensburg, Elisabeth J. and Hamann, Ute and Ramus, Susan J. and Toland, Amanda Ewart and Caligo, Maria A. and Olopade, Olufunmilayo I. and Tung, Nadine and Claes, Kathleen and Beattie, Mary S. and Southey, Melissa C. and Imyanitov, Evgeny N. and Tischkowitz, Marc and Janavicius, Ramunas and John, Esther M. and Kwong, Ava and Diez, Orland and Kwong, Ava and Balma{\~n}a, Judith and Barkardottir, Rosa B. and Arun, Banu K. and Rennert, Gad and Teo, Soo-Hwang and Ganz, Patricia A. and Campbell, Ian and van der Hout, Annemarie H. and van Deurzen, Carolien H. M. and Seynaeve, Caroline and Garcia, Encarna B. G{\´o}mez and van Leeuwen, Flora E. and Meijers-Heijboer, Hanne E. J. and Gille, Johannes J. P. and Ausems, Magreet G. E. M. and Blok, Marinus J. and Ligtenberg, Marjolinjin J. L. and Rookus, Matti A. and Devilee, Peter and Verhoef, Senno and van Os, Theo A. M. and Wijnen, Juul T. and Frost, Debra and Ellis, Steve and Fineberg, Elena and Platte, Radke and Evans, D. Gareth and Izatt, Luise and Eeles, Rosalind A. and Adlard, Julian and Eccles, Diana M. and Cook, Jackie and Brewer, Carole and Douglas, Fiona and Hodgson, Shirley and Morrison, Patrick J. and Side, Lucy E. and Donaldson, Alan and Houghton, Catherine and Rogers, Mark T. and Dorkins, Huw and Eason, Jacqueline and Gregory, Helen and McCann, Emma and Murray, Alex and Calender, Alain and Hardouin, Agn{\`e}s and Berthet, Pascaline and Delnatte, Capucine and Nogues, Catherine and Lasset, Christine and Houdayer, Claude and Leroux,, Dominique and Rouleau, Etienne and Prieur, Fabienne and Damiola, Francesca and Sobol, Hagay and Coupier, Isabelle and Venat-Bouvet, Laurence and Castera, Laurent and Gauthier-Villars, Marion and L{\´e}on{\´e}, M{\´e}lanie and Pujol, Pascal and Mazoyer, Sylvie and Bignon, Yves-Jean and Zlowocka-Perlowska, Elzbieta and Gronwald, Jacek and Lubinski,, Jan and Durda, Katarzyna and Jaworska, Katarzyna and Huzarski, Tomasz and Spurdle, Amanda B. and Viel, Alessandra and Peissel, Bernhard and Bonanni, Bernardo and Melloni, Guilia and Ottini, Laura and Papi, Laura and Varesco, Liliana and Tibiletti, Maria Grazia and Peterlongo, Paolo and Volorio, Sara and Manoukian, Siranoush and Pensotti, Valeria and Arnold, Norbert and Engel, Christoph and Deissler, Helmut and Gadzicki, Dorothea and Gehrig, Andrea and Kast, Karin and Rhiem, Kerstin and Meindl, Alfons and Niederacher, Dieter and Ditsch, Nina and Plendl, Hansjoerg and Preisler-Adams, Sabine and Engert, Stefanie and Sutter, Christian and Varon-Mateeva, Raymenda and Wappenschmidt, Barbara and Weber, Bernhard H. F. and Arver, Brita and Stenmark-Askmalm, Marie and Loman, Niklas and Rosenquist, Richard and Einbeigi, Zakaria and Nathanson, Katherine L. and Rebbeck, Timothy R. and Blank, Stephanie V. and Cohn, David E. and Rodriguez, Gustavo C. and Small, Laurie and Friedlander, Michael and Bae-Jump, Victoria L. and Fink-Retter, Anneliese and Rappaport, Christine and Gschwantler-Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Lindor, Noralane M. and Kaufman, Bella and Paluch, Shani Shimon and Laitman, Yael and Skytte, Anne-Bine and Gerdes, Anne-Marie and Pedersen, Inge Sokilde and Moeller, Sanne Traasdahl and Kruse, Torben A. and Jensen, Uffe Birk and Vijai, Joseph and Sarrel, Kara and Robson, Mark and Kauff, Noah and Mulligan, Anna Marie and Glendon, Gord and Ozcelik, Hilmi and Ejlertsen, Bent and Nielsen, Finn C. and J{\o}nson, Lars and Andersen, Mette K. and Ding, Yuan Chun and Steele, Linda and Foretova, Lenka and Teul{\´e}, Alex and Lazaro, Conxi and Brunet, Joan and Pujana, Miquel Angel and Mai, Phuong L. and Loud, Jennifer T. and Walsh, Christine and Lester, Jenny and Orsulic, Sandra and Narod, Steven A. and Herzog, Josef and Sand, Sharon R. and Tognazzo, Silvia and Agata, Simona and Vaszko, Tibor and Weaver, Joellen and Stravropoulou, Alexandra V. and Buys, Saundra S. and Romero, Atocha and de la Hoya, Miguel and Aittom{\"a}ki, Kristiina and Muranen, Taru A. and Duran, Mercedes and Chung, Wendy K. and Lasa, Adriana and Dorfling, Cecilia M. and Miron, Alexander and Benitez, Javier and Senter, Leigha and Huo, Dezheng and Chan, Salina B. and Sokolenko, Anna P. and Chiquette, Jocelyne and Tihomirova, Laima and Friebel, Tara M. and Agnarsson, Bjarne A. and Lu, Karen H. and Lejbkowicz, Flavio and James, Paul A. and Hall, Per and Dunning, Alison M. and Tessier, Daniel and Cunningham, Julie and Slager, Susan L. and Chen, Wang and Hart, Steven and Stevens, Kristen and Simard, Jacques and Pastinen, Tomi and Pankratz, Vernon S. and Offit, Kenneth and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk}, series = {PLOS Genetics}, volume = {9}, journal = {PLOS Genetics}, number = {3}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127947}, pages = {e1003212}, year = {2013}, abstract = {BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95\% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95\% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95\% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5\% of BRCA1 carriers at lowest risk are 28\%-50\% compared to 81\%-100\% for the 5\% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5\% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28\% or lower, whereas the 5\% at highest risk will have a risk of 63\% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.}, language = {en} } @article{HohnmannMillesSchinkeetal.2014, author = {Hohnmann, Christopher and Milles, Bianca and Schinke, Michael and Schroeter, Michael and Ulzheimer, Jochen and Kraft, Peter and Kleinschnitz, Christoph and Lehmann, Paul V. and Kuerten, Stefanie}, title = {Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood}, series = {Acta Neuropathologica Communications}, volume = {2}, journal = {Acta Neuropathologica Communications}, number = {138}, doi = {10.1186/s40478-014-0138-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126124}, year = {2014}, abstract = {Introduction B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Results Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5\%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40\%) with a pattern II and three of 14 patients (21.4\%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95\% confidence interval 1.87-19.77). Conclusions Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.}, language = {en} } @article{HohmannMillesSchinkeetal.2014, author = {Hohmann, Christopher and Milles, Bianca and Schinke, Michael and Schroeter, Michael and Ulzheimer, Jochen and Kraft, Peter and Kleinschnitz, Christoph and Lehmann, Paul V. and Kuerten, Stefanie}, title = {Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood}, series = {Acta Neuropathologica Communications}, volume = {2}, journal = {Acta Neuropathologica Communications}, number = {138}, issn = {2051-5960}, doi = {10.1186/s40478-014-0138-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120580}, year = {2014}, abstract = {INTRODUCTION: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). RESULTS: Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5\%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40\%) with a pattern II and three of 14 patients (21.4\%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95\% confidence interval 1.87-19.77). CONCLUSIONS: Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.}, language = {en} } @article{ArndtHoffackerZellmeretal.2014, author = {Arndt, Andreas and Hoffacker, Peter and Zellmer, Konstantin and Goecer, Oktay and Recks, Mascha S. and Kuerten, Stefanie}, title = {Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0099794}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119603}, pages = {e99794}, year = {2014}, abstract = {BACKGROUND: The etiology of multiple sclerosis (MS) has remained unclear, but a causative contribution of factors outside the central nervous system (CNS) is conceivable. It was recently suggested that gut bacteria trigger the activation of CNS-reactive T cells and the development of demyelinative disease. METHODS: C57BL/6 (B6) mice were kept either under specific pathogen free or conventional housing conditions, immunized with the myelin basic protein (MBP)-proteolipid protein (PLP) fusion protein MP4 and the development of EAE was clinically monitored. The germinal center size of the Peyer's patches was determined by immunohistochemistry in addition to the level of total IgG secretion which was assessed by ELISPOT. ELISPOT assays were also used to measure MP4-specific T cell and B cell responses in the Peyer's patches and the spleen. Ear swelling assays were performed to determine the extent of delayed-type hypersensitivity reactions in specific pathogen free and conventionally housed mice. RESULTS: In B6 mice that were actively immunized with MP4 and kept under conventional housing conditions clinical disease was significantly attenuated compared to specific pathogen free mice. Conventionally housed mice displayed increased levels of IgG secretion in the Peyer's patches, while the germinal center formation in the gut and the MP4-specific TH17 response in the spleen were diminished after immunization. Accordingly, these mice displayed an attenuated delayed type hypersensitivity (DTH) reaction in ear swelling assays. CONCLUSIONS: The data corroborate the notion that housing conditions play a substantial role in the induction of murine EAE and suggest that the presence of gut bacteria might be associated with a decreased immune response to antigens of lower affinity. This concept could be of importance for MS and calls for caution when considering the therapeutic approach to treat patients with antibiotics."}, language = {en} } @article{BiehlDreslerReifetal.2011, author = {Biehl, Stefanie C. and Dresler, Thomas and Reif, Andreas and Scheuerpflug, Peter and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Dopamine Transporter (DAT1) and Dopamine Receptor D4 (DRD4) Genotypes Differentially Impact on Electrophysiological Correlates of Error Processing}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0028396}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137930}, pages = {e28396}, year = {2011}, abstract = {Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing—the error-related negativity (ERN) and the error positivity (Pe)—are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes.}, language = {en} }