Fig. 2.

Schematic diagram illustrating factors involved in lymphocyte migration into, retention within, and egress from lymph nodes. Migration into, within, and through lymphoid tissues is a complex multistep process. The major steps are illustrated here, along with the pathways/proteins that are altered in UM-CLL versus M-CLL. On initial contact with the endothelium, the lymphocytes become loosely tethered (A). If the cell encounters chemokine presented on the endothelial cell surface, it then becomes firmly adherent in a process involving integrin activation and chemokine signaling (B). The cell then crawls along the endothelium until it reaches an intercellular junction, where it undergoes diapedesis in response to chemokine (C); this process also requires integrin activation. Once within the lymphoid tissue (D), two different mechanisms mediate the adherence of CLL cells within the tissues; these involve α4β1 and CD44 binding to their respective ligands, fibronectin and hyaluronan. Adhesion mediated by both substrata is influenced by chemokine signaling. The final step of transit though the lymph node is egress (E), a process that is entirely dependent on S1PR1 and is independent of integrins.