Robert M. J. Keehnen

Cross-talk Between CD44 and c-Met in B cells

Activation of naive B cells in the T cell areas of the secondary lymphoid tissues initiates T cell dependent humoral immune responses. As a consequence of this primary B cell activation, germinal center (GC) cell precursors migrate into B cell follicles where they engage T cells and follicular dendritic cells (FDC), and differentiate into plasma cells or memory B cells. Both the homing of B cells to the GC and their interaction with FDC critically depend on integrin-mediated adhesion. We have recently identified the growth and motility factor, hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the c-met-encoded receptor tyrosine kinase, as a novel paracrine signaling pathway regulating B cell adhesion within the GC microenvironment [22]. The c-Met protein is expressed on B cells localized in the dark zone of the GC (centroblasts) and is induced by combined CD40 and B-cell receptor ligation. Stimulation of c-Met with HGF/SF, which is produced at high levels by tonsillar stromal cells and FDC, leads to enhanced integrin-mediated adhesion of B cells to fibronectin and VCAM-1 [22].

Interaction Through the Lfa-1/Icam-1 Pathway Prevents Programmed Cell Death of Germinal Center B Cells

Germinal centers play a key role in the maturation of the B cell immune response. Although the initial B cell triggering after interaction of the immunoglobulin receptor molecule with the antigen is thought to take place in the paracortical areas of lymph node and MALT, the isotype switch, affinity maturation and differentiation of B cells into memory cells all take place in the germinal center1-3. B cells that enter the germinal center divide rapidly. Through the process of somatic hypermutation a great heterogeneity in antigen binding specificity in the proliferating B cell population is generated4. However only cells with Ig receptors with high affinity for the antigen are selected for further maturation into memory cells, while the non selected cells die through a process of programmed cell death (PCD)5,6. PCD, also called apoptosis constitutes a cell elimination program, that involves generation of DNA strand breaks, chromatin condensation and cell fragmentation.

Paracrine regulation of germinal center B cell adhesion through the c-Met-hepatocyte growth factor/scatter factor pathway

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