CD20‐mediated apoptosis: signalling through lipid rafts

Abstract

SUMMARYCD20 is an effective target for therapeutic B-cell depletion with monoclonal antibodies. One proposed mechanism of action is direct cytotoxicity mediated via tyrosine kinase-dependent signalling pathways activated upon CD20 cross-linking. The association of CD20 with membrane microdomains known as lipid rafts, enriched in src-family tyrosine kinases and other signalling effectors, suggests an indirect mechanism of anti-CD20-induced apoptosis in which activation of src-family kinases occurs as a consequence of lipid raft clustering.

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

“…There is controversy concerning the possible mechanisms of anti-CD20-induced cell death. Although some reports indicated that cell death induced by CD20 crosslinking has features of classical apoptosis, 17,[45][46][47] others were unable to confirm these findings. 17,27,48,49 A number of findings in our study strongly suggest that rituximab-induced cell death is a form of nonclassical apoptosis.…”

Imaging and measuring the rituximab-induced changes of mechanical properties in B-lymphoma cells using atomic force microscopy

“…Flieger et al [32] have shown that rituximab alone induced apoptosis in Raji lymphoma cell lines at a concentration above 100 ng/ml. There is general agreement that hyper-cross-linking enhances the apoptotic effects of CD20 mAbs [33]. Shan et al [34] have shown that the anti-CD20 mAb could induce the apoptosis in Ramos lymphoma cell lines in the presence of GAM cross-linker.…”

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

“…Anti-CD20 monoclonal antibodies are a class of drugs recognizing a 35-kD integral protein (CD20) expressed on the surface of B lymphocytes at various stages of differentiation, starting from pre-B cells to the mature lineage, at which phase it reaches the highest concentration (9). Rituximab was the first chimeric molecule developed to treat B cell nonHodgkin lymphomas (10).…”

“…Its use was then extended to autoimmune anemia, rheumatic diseases (11,12) and, more recently, antibody-mediated conditions affecting the kidney, including ANCA-associated vasculitis (13) and membranous GN (14). Upon binding, the complex rituximab-CD20 is translocated into the lipid raft of the cell membrane, where it crossreacts with sphigomyelin phosphodieterase acid-like 3b protein (SMPDL-3b) (9). At this stage, B cells undergo a process that ends with their disappearance and that is postulated to be based on three different pathways: one is apoptosis, and the other two involve external mechanisms based on antibody-and complement-dependent cell-mediated cytotoxicity.…”