@article{BousquetAntoAkdisetal.2016, author = {Bousquet, J. and Anto, J. M. and Akdis, M. and Auffray, C. and Keil, T. and Momas, I. and Postma, D. S. and Valenta, R. and Wickman, M. and Cambon-Thomsen, A. and Haahtela, T. and Lambrecht, B. N. and Lodrup Carlsen, K. C. and Koppelman, G. H. and Sunyer, J. and Zuberbier, T. and Annesi-Maesano, I. and Arno, A. and Bindslev-Jensen, C. and De Carlo, G. and Forastiere, F. and Heinrich, J. and Kowalski, M. L. and Maier, D. and Melen, E. and Palkonen, S. and Smit, H. A. and Standl, M. and Wright, J. and Asarnoj, A. and Benet, M. and Ballardini, N. and Garcia-Aymerich, J. and Gehring, U. and Guerra, S. and Hohman, C. and Kull, I. and Lupinek, C. and Pinart, M. and Skrindo, I. and Westman, M. and Smagghe, D. and Akdis, C. and Albang, R. and Anastasova, V. and Anderson, N. and Bachert, C. and Ballereau, S. and Ballester, F. and Basagana, X. and Bedbrook, A. and Bergstrom, A. and von Berg, A. and Brunekreef, B. and Burte, E. and Carlsen, K.H. and Chatzi, L. and Coquet, J.M. and Curin, M. and Demoly, P. and Eller, E. and Fantini, M.P. and Gerhard, B. and Hammad, H. and von Hertzen, L. and Hovland, V. and Jacquemin, B. and Just, J. and Keller, T. and Kerkhof, M. and Kiss, R. and Kogevinas, M. and Koletzko, S. and Lau, S. and Lehmann, I. and Lemonnier, N. and McEachan, R. and Makela, M. and Mestres, J. and Minina, E. and Mowinckel, P. and Nadif, R. and Nawijn, M. and Oddie, S. and Pellet, J. and Pin, I. and Porta, D. and Ranci{\`e}re, F. and Rial-Sebbag, A. and Schuijs, M.J. and Siroux, V. and Tischer, C.G. and Torrent, M. and Varraso, R. and De Vocht, J. and Wenger, K. and Wieser, S. and Xu, C.}, title = {Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story Mechanisms of the Development of ALLergy; EUFP7-CP-IP; Project No: 261357; 2010-2015}, series = {Allergy}, volume = {71}, journal = {Allergy}, number = {11}, doi = {10.1111/all.12880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186858}, pages = {1513-1525}, year = {2016}, abstract = {MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.}, language = {en} } @article{DumontWeberLassalleJolyBeauparlantetal.2022, author = {Dumont, Martine and Weber-Lassalle, Nana and Joly-Beauparlant, Charles and Ernst, Corinna and Droit, Arnaud and Feng, Bing-Jian and Dubois, St{\´e}phane and Collin-Deschesnes, Annie-Claude and Soucy, Penny and Vall{\´e}e, Maxime and Fournier, Fr{\´e}d{\´e}ric and Lema{\c{c}}on, Audrey and Adank, Muriel A. and Allen, Jamie and Altm{\"u}ller, Janine and Arnold, Norbert and Ausems, Margreet G. E. M. and Berutti, Riccardo and Bolla, Manjeet K. and Bull, Shelley and Carvalho, Sara and Cornelissen, Sten and Dufault, Michael R. and Dunning, Alison M. and Engel, Christoph and Gehrig, Andrea and Geurts-Giele, Willemina R. R. and Gieger, Christian and Green, Jessica and Hackmann, Karl and Helmy, Mohamed and Hentschel, Julia and Hogervorst, Frans B. L. and Hollestelle, Antoinette and Hooning, Maartje J. and Horv{\´a}th, Judit and Ikram, M. Arfan and Kaulfuß, Silke and Keeman, Renske and Kuang, Da and Luccarini, Craig and Maier, Wolfgang and Martens, John W. M. and Niederacher, Dieter and N{\"u}rnberg, Peter and Ott, Claus-Eric and Peters, Annette and Pharoah, Paul D. P. and Ramirez, Alfredo and Ramser, Juliane and Riedel-Heller, Steffi and Schmidt, Gunnar and Shah, Mitul and Scherer, Martin and St{\"a}bler, Antje and Strom, Tim M. and Sutter, Christian and Thiele, Holger and van Asperen, Christi J. and van der Kolk, Lizet and van der Luijt, Rob B. and Volk, Alexander E. and Wagner, Michael and Waisfisz, Quinten and Wang, Qin and Wang-Gohrke, Shan and Weber, Bernhard H. F. and Devilee, Peter and Tavtigian, Sean and Bader, Gary D. and Meindl, Alfons and Goldgar, David E. and Andrulis, Irene L. and Schmutzler, Rita K. and Easton, Douglas F. and Schmidt, Marjanka K. and Hahnen, Eric and Simard, Jacques}, title = {Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {14}, issn = {2072-6694}, doi = {10.3390/cancers14143363}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281768}, year = {2022}, abstract = {Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.}, language = {en} } @article{BenzJonesYounasetal.2015, author = {Benz, Roland and Jones, Michael D. and Younas, Farhan and Maier, Elke and Modi, Niraj and Mentele, Reinhard and Lottspeich, Friedrich and Kleinekath{\"o}fer, Ulrich and Smit, John}, title = {OmpW of Caulobacter crescentus functions as an outer membrane channel for cations}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0143557}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145114}, pages = {e0143557}, year = {2015}, abstract = {Caulobacter crescentus is an oligotrophic bacterium that lives in dilute organic environments such as soil and freshwater. This bacterium represents an interesting model for cellular differentiation and regulation because daughter cells after division have different forms: one is motile while the other is non-motile and can adhere to surfaces. Interestingly, the known genome of C. crescentus does not contain genes predicted to code for outer membrane porins of the OmpF/C general diffusion type present in enteric bacteria or those coding for specific porins selective for classes of substrates. Instead, genes coding for 67 TonB-dependent outer membrane receptors have been identified, suggesting that active transport of specific nutrients may be the norm. Here, we report that high channel-forming activity was observed with crude outer membrane extracts of C. crescentus in lipid bilayer experiments, indicating that the outer membrane of C. crescentus contained an ion-permeable channel with a single-channel conductance of about 120 pS in 1M KCl. The channel-forming protein with an apparent molecular mass of about 20 kDa was purified to homogeneity. Partial protein sequencing of the protein indicated it was a member of the OmpW family of outer membrane proteins from Gram-negative bacteria. This channel was not observed in reconstitution experiments with crude outer membrane extracts of an OmpW deficient C. crescentus mutant. Biophysical analysis of the C. crescentus OmpW suggested that it has features that are special for general diffusion porins of Gram-negative outer membranes because it was not a wide aqueous channel. Furthermore, OmpW of C. crescentus seems to be different to known OmpW porins and has a preference for ions, in particular cations. A putative model for OmpW of C. crescentus was built on the basis of the known 3D-structures of OmpW of Escherichia coli and OprG of Pseudomonas aeruginosa using homology modeling. A comparison of the two known structures with the model of OmpW of C. crescentus suggested that it has a more hydrophilic interior and possibly a larger diameter.}, language = {en} } @article{NosterdeKoningMaieretal.2016, author = {Noster, Rebecca and de Koning, Heleen D. and Maier, Elisabeth and Prelog, Martina and Lainka, Elke and Zielinski, Christina E.}, title = {Dysregulation of proinflammatory versus anti-inflammatory human T\(_H\)17 cell functionalities in the autoinflammatory Schnitzler syndrome}, series = {Journal of Allergy and Clinical Immunology}, volume = {138}, journal = {Journal of Allergy and Clinical Immunology}, number = {4}, doi = {10.1016/j.jaci.2015.12.1338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187205}, pages = {1161-1169.e6}, year = {2016}, abstract = {Background: T\(_H\)17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of T\(_H\)17 cells have been described recently, which differed in their polarization requirement for IL-1b and in their cytokine repertoire. Whether these distinct T\(_H\)17 phenotypes translate into distinct T\(_H\)17 cell functions with implications for human health or disease has not been addressed yet. Objective: We hypothesized the existence of proinflammatory and anti-inflammatory human T\(_H\)17 cell functions based on the differential expression of IL-10, which is regulated by IL-1 beta. Considering the crucial role of IL-1 beta in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1 beta mediates the loss of anti-inflammatory T\(_H\)17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. Methods: To assess proinflammatory versus anti-inflammatory T\(_H\)17 cell functions, we performed suppression assays and tested the effects of IL-1 beta dependent and independent T\(_H\)17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in T\(_H\)17 cell functions before and during therapy with IL-1 beta-blocking drugs. Results: Both T\(_H\)17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1 beta translates into a profound loss of anti-inflammatory T\(_H\)17 cell functionalities, which can be reversed by anti-IL-1b treatment. Conclusion: IL-1 beta signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory T\(_H\)17 cell functions. Our data introduce T\(_H\)17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1 beta mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes.}, language = {en} }