TY  - JOUR
A1  - Almanzar, Giovanni
A1  - Klein, Matthias
A1  - Schmalzing, Marc
A1  - Hilligardt, Deborah
A1  - El Hajj, Nady
A1  - Kneitz, Hermann
A1  - Wild, Vanessa
A1  - Rosenwald, Andreas
A1  - Benoit, Sandrine
A1  - Hamm, Henning
A1  - Tony, Hans-Peter
A1  - Haaf, Thomas
A1  - Goebeler, Matthias
A1  - Prelog, Martina
T1  - Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis
JF  - International Archives of Allergy and Immunology
N2  - 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.
KW  - methylation
KW  - systemic sclerosis
KW  - suppression
KW  - Tregs
KW  - Th17
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196577
SN  - 1018-2438
SN  - 1423-0097
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  - 171
IS  - 2
ER  - 
TY  - JOUR
A1  - Alrefai, Hani
A1  - Muhammad, Khalid
A1  - Rudolf, Ronald
A1  - Pham, Duong Anh Thuy
A1  - Klein-Hessling, Stefan
A1  - Patra, Amiya K.
A1  - Avots, Andris
A1  - Bukur, Valesca
A1  - Sahin,, Ugur
A1  - Tenzer, Stefan
A1  - Goebeler, Matthias
A1  - Kerstan, Andreas
A1  - Serfling, Edgar
T1  - NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells
JF  - Nature Communications
N2  - Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.
KW  - B cells
KW  - psoriasis
KW  - interleukins
KW  - inflammation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173053
VL  - 7
ER  -