Selected articles, January 2014
New Insights into the Development and Maturation of Monocyte-derived dendritic cells.
Activation of peroxisome Proliferator-Activated Receptor Gamma Leads to Upregulation of ESE-3 Expression in Human Monocyte-derived Dendritic Cells
F. Sprater, W. Azeem and S. Appel
In this paper, the group of Silke Appel for the first time describes that the expression of the transcription factor ESE-3 is regulated by the proliferator-activated receptor gamma (PPAR-γ) pathway. The group has previously shown that high ESE-3 expression correlates with the immunogenic functions of dendritic cells, and that tolerogenic dendritic cells have low ESE-3 expression. Dendritic cells have an outstanding ability to modulate immune responses and are therefore an interesting target for use in immunotherapy towards cancer and autoimmune diseases. Vaccines based on dendritic cells have shown promising results in mouse models. Monocyte-derived dendritic cells (moDCs) can be generated in vitro from peripheral blood mononuclear cells. A better understanding of the molecular mechanisms involved in moDC development and maturation is important to fully exploit the therapeutic potential of moDCs.
Florian Sprater was a PhD student in Silke Appel´s research group and this paper is included in his thesis. He was the one who performed all the pilot experiments and also carried out a lot of the final experiments.
– For me, the most fun with this project was the work in the lab, Florian says.
Florian Sprater and co-workers found two putative binding sites for PPAR-γ upstream of the ESE-3 gene. Therefore the effect of PPAR-gamma activation of ESE-3 expression in moDCs was investigated. They were able to show that ESE-3 expression is upregulated in moDCs, despite the tolerogenic phenotype of these cells. This could be due to the choice of method to generate the cells, indicating the importance of careful investigation of the phenotype and function of in vitro-derived cells before they are used clinically.
CD40L, an interesting target in autoimmune disease?
Upregulation of Membrane-Bound CD40L on CD4+ T cells in Women with Primary Sjögren´s Syndrome
R. Belkhir, N. Gestermann, M. Koutero, R. Seror, J. Tost, X. Mariette and C. Miceli-Richard
This study shows that membrane-bound CD40L is overexpressed in ex vivo activated CD4+ T cells from females with the autoimmune disease primary Sjögren´s Syndrome (pSS). However, this overexpression did not involve epigenetic changes in key regulatory regions. This is in contrast to what has been reported previously for another autoimmune disease, systemic lupus erythematosus (SLE).
There is a female predominance of autoimmune diseases, which could be explained by epigenetic deregulation of genes encoded on the X chromosome. CD40L is one of the genes involved in adaptive and/or innate immunity that is located on the X chromosome.
X-inactivation and escape
X-inactivation is a process by which one of the two copies of the X chromosomes present in female mammals is inactivated. The inactive X chromosome is silenced by its being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin. As female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males. However, some genes escape this inactivation, and many studies have shown that epigenetics plays a crucial role. It has also been shown that women with autoimmune diseases have more frequent X-inactivation escape than women without the diseases. CD40L is located on the long arm of the X chromosome and is a good candidate to asses this hypothesis.
No epigenetic changes found in pSS patients
However, despite the fact that epigenetic changes such as hypomethylation of regulatory regions of CD40L was found both in patients with SLE and systematic sclerosis, this was not found in this study. Still, the overexpression found here, and in other studies, suggests that CD40L could be an interesting target in autoimmune disease.