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Lysosomal Destabilization Contributes to Apoptosis of Germinal Center B-lymphocytes

Kirsten van Nierop, Femke J.M. Muller, Jan Stap, Cornelis J.F. Van Noorden¹, Marco van Eijk¹ and Cornelis de Groot¹

Departments of Cell Biology and Histology (KVN,FJMM,JS,CJFVN,CDG) and Medical Biochemistry (MVE), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Correspondence to: C.J.F. Van Noorden, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail: c.j.vannoorden{at}amc.uva.nl

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. (J Histochem Cytochem 54:1425–1435, 2006)

Key Words: human B-cells • lysosome • apoptosis

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