TY  - JOUR
A1  - Bousquet, J.
A1  - Anto, J. M.
A1  - Akdis, M.
A1  - Auffray, C.
A1  - Keil, T.
A1  - Momas, I.
A1  - Postma, D. S.
A1  - Valenta, R.
A1  - Wickman, M.
A1  - Cambon-Thomsen, A.
A1  - Haahtela, T.
A1  - Lambrecht, B. N.
A1  - Lodrup Carlsen, K. C.
A1  - Koppelman, G. H.
A1  - Sunyer, J.
A1  - Zuberbier, T.
A1  - Annesi-Maesano, I.
A1  - Arno, A.
A1  - Bindslev-Jensen, C.
A1  - De Carlo, G.
A1  - Forastiere, F.
A1  - Heinrich, J.
A1  - Kowalski, M. L.
A1  - Maier, D.
A1  - Melen, E.
A1  - Palkonen, S.
A1  - Smit, H. A.
A1  - Standl, M.
A1  - Wright, J.
A1  - Asarnoj, A.
A1  - Benet, M.
A1  - Ballardini, N.
A1  - Garcia-Aymerich, J.
A1  - Gehring, U.
A1  - Guerra, S.
A1  - Hohman, C.
A1  - Kull, I.
A1  - Lupinek, C.
A1  - Pinart, M.
A1  - Skrindo, I.
A1  - Westman, M.
A1  - Smagghe, D.
A1  - Akdis, C.
A1  - Albang, R.
A1  - Anastasova, V.
A1  - Anderson, N.
A1  - Bachert, C.
A1  - Ballereau, S.
A1  - Ballester, F.
A1  - Basagana, X.
A1  - Bedbrook, A.
A1  - Bergstrom, A.
A1  - von Berg, A.
A1  - Brunekreef, B.
A1  - Burte, E.
A1  - Carlsen, K.H.
A1  - Chatzi, L.
A1  - Coquet, J.M.
A1  - Curin, M.
A1  - Demoly, P.
A1  - Eller, E.
A1  - Fantini, M.P.
A1  - Gerhard, B.
A1  - Hammad, H.
A1  - von Hertzen, L.
A1  - Hovland, V.
A1  - Jacquemin, B.
A1  - Just, J.
A1  - Keller, T.
A1  - Kerkhof, M.
A1  - Kiss, R.
A1  - Kogevinas, M.
A1  - Koletzko, S.
A1  - Lau, S.
A1  - Lehmann, I.
A1  - Lemonnier, N.
A1  - McEachan, R.
A1  - Makela, M.
A1  - Mestres, J.
A1  - Minina, E.
A1  - Mowinckel, P.
A1  - Nadif, R.
A1  - Nawijn, M.
A1  - Oddie, S.
A1  - Pellet, J.
A1  - Pin, I.
A1  - Porta, D.
A1  - Rancière, F.
A1  - Rial-Sebbag, A.
A1  - Schuijs, M.J.
A1  - Siroux, V.
A1  - Tischer, C.G.
A1  - Torrent, M.
A1  - Varraso, R.
A1  - De Vocht, J.
A1  - Wenger, K.
A1  - Wieser, S.
A1  - Xu, C.
T1  - 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
JF  - Allergy
N2  - 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.
KW  - asthma
KW  - birth cohort
KW  - atopic-dermatitis
KW  - immune-responses
KW  - IgE
KW  - multimorbidity
KW  - polysensitization
KW  - rhinitis
KW  - chronic respiratory-diseases
KW  - childhood asthma
KW  - immunological reactivity
KW  - IgE sensitazion
KW  - immunoglobulin-e
KW  - integraed care
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186858
VL  - 71
IS  - 11
ER  - 
TY  - JOUR
A1  - Dumont, Martine
A1  - Weber-Lassalle, Nana
A1  - Joly-Beauparlant, Charles
A1  - Ernst, Corinna
A1  - Droit, Arnaud
A1  - Feng, Bing-Jian
A1  - Dubois, Stéphane
A1  - Collin-Deschesnes, Annie-Claude
A1  - Soucy, Penny
A1  - Vallée, Maxime
A1  - Fournier, Frédéric
A1  - Lemaçon, Audrey
A1  - Adank, Muriel A.
A1  - Allen, Jamie
A1  - Altmüller, Janine
A1  - Arnold, Norbert
A1  - Ausems, Margreet G. E. M.
A1  - Berutti, Riccardo
A1  - Bolla, Manjeet K.
A1  - Bull, Shelley
A1  - Carvalho, Sara
A1  - Cornelissen, Sten
A1  - Dufault, Michael R.
A1  - Dunning, Alison M.
A1  - Engel, Christoph
A1  - Gehrig, Andrea
A1  - Geurts-Giele, Willemina R. R.
A1  - Gieger, Christian
A1  - Green, Jessica
A1  - Hackmann, Karl
A1  - Helmy, Mohamed
A1  - Hentschel, Julia
A1  - Hogervorst, Frans B. L.
A1  - Hollestelle, Antoinette
A1  - Hooning, Maartje J.
A1  - Horváth, Judit
A1  - Ikram, M. Arfan
A1  - Kaulfuß, Silke
A1  - Keeman, Renske
A1  - Kuang, Da
A1  - Luccarini, Craig
A1  - Maier, Wolfgang
A1  - Martens, John W. M.
A1  - Niederacher, Dieter
A1  - Nürnberg, Peter
A1  - Ott, Claus-Eric
A1  - Peters, Annette
A1  - Pharoah, Paul D. P.
A1  - Ramirez, Alfredo
A1  - Ramser, Juliane
A1  - Riedel-Heller, Steffi
A1  - Schmidt, Gunnar
A1  - Shah, Mitul
A1  - Scherer, Martin
A1  - Stäbler, Antje
A1  - Strom, Tim M.
A1  - Sutter, Christian
A1  - Thiele, Holger
A1  - van Asperen, Christi J.
A1  - van der Kolk, Lizet
A1  - van der Luijt, Rob B.
A1  - Volk, Alexander E.
A1  - Wagner, Michael
A1  - Waisfisz, Quinten
A1  - Wang, Qin
A1  - Wang-Gohrke, Shan
A1  - Weber, Bernhard H. F.
A1  - Devilee, Peter
A1  - Tavtigian, Sean
A1  - Bader, Gary D.
A1  - Meindl, Alfons
A1  - Goldgar, David E.
A1  - Andrulis, Irene L.
A1  - Schmutzler, Rita K.
A1  - Easton, Douglas F.
A1  - Schmidt, Marjanka K.
A1  - Hahnen, Eric
A1  - Simard, Jacques
T1  - 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
JF  - Cancers
N2  - 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.
KW  - breast cancer
KW  - genetic susceptibility
KW  - whole-exome sequencing
KW  - moderate-penetrance genes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281768
SN  - 2072-6694
VL  - 14
IS  - 14
ER  - 
TY  - JOUR
A1  - Benz, Roland
A1  - Jones, Michael D.
A1  - Younas, Farhan
A1  - Maier, Elke
A1  - Modi, Niraj
A1  - Mentele, Reinhard
A1  - Lottspeich, Friedrich
A1  - Kleinekathöfer, Ulrich
A1  - Smit, John
T1  - OmpW of Caulobacter crescentus functions as an outer membrane channel for cations
JF  - PLoS ONE
N2  - 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.
KW  - matrix protein porin
KW  - amino acid sequence
KW  - escherichia coli
KW  - selective channel
KW  - molecular basis
KW  - lipid bilayer membranes
KW  - S-layer protein
KW  - pseudomonas aeruginosa
KW  - ionic selectivity
KW  - cell wall
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145114
VL  - 10
IS  - 11
ER  - 
TY  - JOUR
A1  - Noster, Rebecca
A1  - de Koning, Heleen D.
A1  - Maier, Elisabeth
A1  - Prelog, Martina
A1  - Lainka, Elke
A1  - Zielinski, Christina E.
T1  - Dysregulation of proinflammatory versus anti-inflammatory human T\(_H\)17 cell functionalities in the autoinflammatory Schnitzler syndrome
JF  - Journal of Allergy and Clinical Immunology
N2  - 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.
KW  - Regulatory T-cells
KW  - IL-1 blockade
KW  - Big picture
KW  - Cytokine GM-CSF
KW  - Mechanisms
KW  - IL-1 beta
KW  - Diseases
KW  - Gamma
KW  - Autoinflammation
KW  - Schnitzler syndrome
KW  - T\(_H\)17 cells
KW  - IL-10
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187205
VL  - 138
IS  - 4
ER  -