Gby chemokines adhesionendothelium

FIGURE 3-3 Multistep leukocyte-endothelial interactions mediating leukocyte recruitment into tissues. At sites of infection, macrophages that have encountered microbes produce cytokines (such as TNF and IL-1) that activate the endothelial cells of nearby venules to produce selectins, ligands for integrins, and chemokines. Selectins mediate weak tethering and rolling of blood leukocytes on the endothelium, and the shear force of blood flow causes the leukocytes to roll along the endothelial surface. Chemokines produced in the surrounding infected tissues or by the endothelial cells are displayed on the endothelial surface and bind to receptors on the rolling leukocytes, which results in activation of the leukocyte integrins to a high-affinity binding state. The activated integrins bind to their Ig superfamily ligands on the endothelial cells, and this mediates firm adhesion of leukocytes. The leukocytes then crawl to junctions between endothelial cells and migrate through the venular wall. Neutrophils, monocytes, and T lymphocytes use essentially the same mechanisms to migrate out of the blood.

FIGURE 3-3 Multistep leukocyte-endothelial interactions mediating leukocyte recruitment into tissues. At sites of infection, macrophages that have encountered microbes produce cytokines (such as TNF and IL-1) that activate the endothelial cells of nearby venules to produce selectins, ligands for integrins, and chemokines. Selectins mediate weak tethering and rolling of blood leukocytes on the endothelium, and the shear force of blood flow causes the leukocytes to roll along the endothelial surface. Chemokines produced in the surrounding infected tissues or by the endothelial cells are displayed on the endothelial surface and bind to receptors on the rolling leukocytes, which results in activation of the leukocyte integrins to a high-affinity binding state. The activated integrins bind to their Ig superfamily ligands on the endothelial cells, and this mediates firm adhesion of leukocytes. The leukocytes then crawl to junctions between endothelial cells and migrate through the venular wall. Neutrophils, monocytes, and T lymphocytes use essentially the same mechanisms to migrate out of the blood.

for their ligands and membrane clustering of the integrins, resulting in increased avidity of binding of leukocyte integrins to their ligands on the endothelial surface.

• Stable integrin-mediated adhesion of leukocytes to endothelium. In parallel with the activation of integrins and their conversion to the high-affinity state, cytokines (TNF and IL-1) also enhance endothelial expression of integrin ligands, mainly VCAM-1, the ligand for the VLA-4 integrin, and ICAM-1, the ligand for the LFA-1 and Mac-1 integrins. The net result of these changes is that the leukocytes attach firmly to the endothelium, their cytoskeleton is reorganized, and they spread out on the endothelial surface.

• Transmigration of leukocytes through the endothelium. Most often, leukocytes transmigrate between the borders of endothelial cells, a process called paracel-lular transmigration, to reach extravascular tissues. Paracellular transmigration depends on leukocyte integrins and their ligands on the endothelial cells as well as other proteins, notably CD31, which is expressed on the leukocytes and endothelial cells. This process requires a transient and reversible disruption of adherens junction proteins that hold postcapillary endothelial cells together, primarily the VE-cadherin complex. The mechanism responsible for disruption of the VE-cadherin complex is thought to involve activation of kinases when leukocyte integrins bind ICAM-1 or VCAM-1. The kinases phosphorylate the cytoplasmic tail of VE-cadherin and lead to reversible disruption of the adherens complex. Less often, leukocytes have been observed to move through endothelial cells rather then between them, by a less well understood process called transcellular migration.

There is specificity in this process of leukocyte migration based on the expression of distinct combinations of adhesion molecule and chemokine receptors on neutro-phils, monocytes, and different subsets of lymphocytes, as we will discuss in more detail later.

Evidence for the essential role of selectins, integrins, and chemokines in leukocyte migration has come from gene knockout mice and rare human diseases caused by gene mutations. For example, mice lacking fucosyltrans-ferases, which are enzymes required to synthesize the carbohydrate ligands that bind to selectins, have marked defects in leukocyte migration and immune responses. Humans who lack one of the enzymes needed to express the carbohydrate ligands for E-selectin and P-selectin on neutrophils have similar problems, resulting in a syndrome called type 2 leukocyte adhesion deficiency (LAD-2) (see Chapter 20). Similarly, an autosomal recessive inherited deficiency in the CD18 gene, which encodes the P subunit of LFA-1 and Mac-1, is the cause of an immune deficiency disease called type 1 leukocyte adhesion deficiency (LAD-1). These disorders are characterized by recurrent bacterial and fungal infections, lack of neutrophil accumulation at sites of infection, and defects in adherence-dependent lymphocyte functions. Rare human mutations in the signaling pathways linking che-mokine receptors to integrin activation also result in impaired leukocyte adhesion and recruitment into tissues and therefore ineffective leukocyte defense against infections.

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