@article{ThomasZengRiviereetal.2016,
  author    = {Thomas, Anna C. and Zeng, Zhiqiang and Rivi{\`e}re, Jean-Baptiste and O'Shaughnessy, Ryan and Al-Olabi, Lara and St.-Onge, Judith and Atherton, David J. and Aubert, H{\´e}l{\`e}ne and Bagazgoitia, Lorea and Barbarot, S{\´e}bastien and Bourrat, Emmanuelle and Chiaverini, Christine and Chong, W. Kling and Duffourd, Yannis and Glover, Mary and Groesser, Leopold and Hadj-Rabia, Smail and Hamm, Henning and Happle, Rudolf and Mushtaq, Imran and Lacour, Jean-Philippe and Waelchli, Regula and Wobser, Marion and Vabres, Pierre and Patton, E. Elizabeth and Kinsler, Veronica A.},
  title     = {Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis},
  series = {Journal of Investigative Dermatology},
  volume    = {136},
  journal   = {Journal of Investigative Dermatology},
  number    = {4},
  doi       = {10.1016/j.jid.2015.11.027},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189689},
  pages     = {770-778},
  year      = {2016},
  abstract  = {Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Ga subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11\(^R183C\) and GNA11\(^Q209L\) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11\(^R183C\) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.},
  language  = {en}
}
@article{AlmanzarKleinSchmalzingetal.2016,
  author    = {Almanzar, Giovanni and Klein, Matthias and Schmalzing, Marc and Hilligardt, Deborah and El Hajj, Nady and Kneitz, Hermann and Wild, Vanessa and Rosenwald, Andreas and Benoit, Sandrine and Hamm, Henning and Tony, Hans-Peter and Haaf, Thomas and Goebeler, Matthias and Prelog, Martina},
  title     = {Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis},
  series = {International Archives of Allergy and Immunology},
  volume    = {171},
  journal   = {International Archives of Allergy and Immunology},
  number    = {2},
  issn      = {1018-2438},
  doi       = {10.1159/000450949},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196577},
  pages     = {141-154},
  year      = {2016},
  abstract  = {Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.},
  language  = {en}
}