title: Lysosomal destabilization contributes to apoptosis of germinal center B-lymphocytes.
abstract: 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.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: van Nierop
authors.forename: Femke J M
authors.initials: FJ
authors.lastname: Muller
authors.forename: Jan
authors.initials: J
authors.lastname: Stap
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: Van Noorden
authors.forename: Marco
authors.initials: M
authors.lastname: van Eijk
authors.forename: Cornelis
authors.initials: C
authors.lastname: de Groot
mesh_terms: D000577:Amides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D020566:Dendritic Cells, Follicular / Q000378:metabolism; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000577:Amides; D019013:CD40 Antigens; C407126:O-methyl-serine dodecylamide hydrochloride; D010718:Phosphatidylserines; D012694:Serine; D053148:Caspase 3; D053181:Caspase 8