Lysosomal Destabilization Contributes to Apoptosis of Germinal Center B-lymphocytes

Kirsten van Nierop ¹, Femke J.M. Muller ¹, Jan Stap ¹, Cornelis J.F. Van Noorden ^1*, Marco van Eijk ¹ and Cornelis de Groot ¹

¹ Departments of Cell Biology and Histology (KvN,FJMM,JS,CJFVN,CdG) and Medical Biochemistry (MvE), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

^* To whom correspondence should be addressed. E-mail: c.j.vannoorden{at}amc.uva.nl.

Submitted on March 10, 2006
Accepted on 5 August 2006

	Abstract

During germinal center (GC) reactions, B-lymphocytes with high affinity B-cell receptors are selected. Regulation of apoptosis is a key process to select such wanted B-cells and to eliminate 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, both in the absence and presence of MSDH. Our study demonstrates that lysosomal leakage induces apoptosis of GC B-cells in a caspase-3-independent manner and high-affinity binding to FDCs prevents lysosomal leakage and apoptosis in GC B-cells.

Key Words: human, B-cells, lysosome, apoptosis

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

Guidelines | Subscriptions | About | exPRESS - Current - Archive | Business Information | Contact

The Journal of Histochemistry & Cytochemistry is owned, published, and licensed by The Histochemical Society © 2006