Sialyl–Lewis X–modified glycoprotein E-selectin P-selectin Leukocyte Macrophage with microbes Cytokines (TNF, IL-1) Integrin (low-affinity state) Integrin (high-affinity state) Proteoglycan ROLLING INTEGRIN ACTIVATION BY CHEMOKINES MIGRATION THROUGH ENDOTHELIUM STABLE ADHESION Integrin ligand (ICAM-1) Chemokines Microbes Fibrin and fibronectin (extracellular matrix) PECAM-1 (CD31)
Fig. 3.4 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and move toward chemoattractants emanating from the source of injury. Different molecules play predominant roles at each step of this process: selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, Inter-cellular adhesion molecule-1; PECAM-1 (CD31), platelet endothelial cell adhesion molecule-1; TNF, tumor necrosis factor.
Table 3.4 Endothelial and Leukocyte Adhesion Molecules
Ig CD31 Endothelial cells, leukocytes CD31 (homotypic interaction)
CLA, Cutaneous lymphocyte antigen-1; GlyCAM-1, glycan-bearing cell adhesion molecule-1; HEV, high endothelial venule; ICAM, intercellular adhesion molecule; Ig, immunoglobulin; IL-1, interleukin-1; MAdCAM-1, mucosal adhesion cell adhesion molecule-1; PSGL-1, P-selectin glycoprotein ligand-1; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.
http://ebooksmedicine.net antigen (Mac-1) (CD11bCD18), and vascular cell adhesion molecule-1 (VCAM-1), which binds to the integrin very late antigen-4 (VLA-4) (
Table 3.4 ). The combination of cytokine-induced expression of integrin ligands on the endothelium and increased affinity of integrins on the leukocytes results in firm integrin-mediated binding of the leukocytes to the endothelium at the site of inflammation. The leukocytes stop rolling, and engagement of integrins by their ligands delivers signals leading to cytoskeletal changes that arrest the leukocytes and firmly attach them to the endothelium.
The most telling proof of the importance of leukocyte adhesion molecules is the existence of genetic deficiencies in these molecules that result in recurrent bacterial infections as a consequence of impaired leukocyte adhesion and defective inflammation. These leukocyte adhesion deficiencies are described in Chapter 5.