Biomedical subjects

Kirsten van Nierop

Publications and source records attributed to Kirsten van Nierop.

3 recordsLinked to original sources

PubMed2006

Lysosomal destabilization contributes to apoptosis of germinal center B-lymphocytes.

During germinal center (GC) reactions, B-lymphocytes with high-affinity B-cell receptors are selected. Regulation of apoptosis is a key process in selecting such wanted B-cells and in eliminating B-cells with unwanted specificities. In this paper, we show that apoptosis in human GC B-cells involves lysosomal destabilization, which is strictly controlled by caspase-8 activity, but not by caspase-9 activity. Ligation of CD40 provides resistance to lysosomal destabilization. Experimental lysosomal rupture by the lysosomotropic drug O-methyl-l-serine dodecylamide hydrochloride (MSDH) induces apoptosis in GC B-cells, including phosphatidyl serine exposure, mitochondrial inactivation, and DNA fragmentation. These apoptotic features occur in the absence of caspase-3 activity. Follicular dendritic cells (FDCs) protect binding B-lymphocytes from lysosomal destabilization, in both the absence and the presence of MSDH. Our study demonstrates that lysosomal leakage induces apoptosis of GC B-cells in a caspase-3-independent manner and that high-affinity binding to FDCsprevents lysosomal leakage and apoptosis in GC B-cells.

Amides↗

PubMed2002

Human follicular dendritic cells: function, origin and development.

Follicular dendritic cells (FDCs) have important functions in the selection of memory B lymphocytes during germinal center reactions (GCR). They present native antigens to potential memory cells, of which only B cells with high affinity B cell receptors (BCR) can bind. These B lymphocytes survive, whereas nonbinding B cells undergo apoptotic cell death. FDCs are present in follicles of any secondary lymphoid organ and belong to the stromal cells of these organs. Ectopic FDC-formation can be found in a number of autoimmune diseases and/or chronic inflammatory situations. This indicates that the development of FDCs is not restricted to secondary lymphoid organs, but that it is rather a matter of local conditions that drives a precursor cell type into FDC-maturation. A precursor of FDCs has presently not been identified, but phenotypic marker studies, in vitro experiments with fibroblast-like cell lines, and recent data on mesenchymal precursor cells from the peripheral blood suggest a close relation to fibroblast-like cells.

Animals↗

PubMed2002

Ribosomal scanning on the highly structured insulin-like growth factor II-leader 1.

The complex architecture of human insulin-like growth factor (IGF) II-leader 1 of 592 nucleotides (nt), with one open reading frame (ORF), and the potential to fold into stable structures makes efficient linear ribosomal scanning difficult to comprehend. Indeed, leader 1-driven reporter expression is low in rabbit reticulocyte lysate. Contrarily, leader 1 is very efficient in cells. Therefore, we tested whether this 5'UTR uses an alternative mechanism for translation initiation in vivo, internal entry or ribosomal shunting. Internal initiation was tested by introducing leader 1 into the intercistronic region of a bicistronic vector. Second cistron expression, driven by leader 1, was lower than by the intercistronic beta-globin 5'UTR, indicating that leader 1 does not contain an internal ribosomal entry site (IRES). Shunting was tested by inserting hairpin (HP) structures, capable of blocking ribosomal scanning, at eight positions in leader 1. After transfection, these mutant 5'UTRs were incapable of directing reporter expression. Less stable HPs at the same positions increased the activity to 50% of wild-type activity, indicating that insertions at these positions are not disastrous for initiation. These data indicate that the translational machinery encounters major parts of leader 1. As scanning seems unlikely, and internal entry and shunting were shown not to occur, we discuss a modified scanning mechanism for architecturally complex 5'UTRs.

5' Untranslated Regions↗