Arrest

The overall goal of inflammation is leukocyte infiltration—that is, getting the immune cells to enter the tissue at the region of insult. In order to do this, the leukocytes must adhere firmly to the endothelium, resisting the forces of the flowing blood. Firm adhesion is mediated by another set of adhesion molecules, known as integrins, with properties distinct from those of selectins (Table I). Arrest of the cell on the endothelial surface occurs through integrin binding, usually after selectin-mediated rolling.

Integrins are less nimble than selectins (they have more difficulty engaging their counter-receptors because of their relative bulk, slow diffusion, and inflexibility), but once engaged, the bond is much stronger. Integrins are classified into several subfamilies according to their common b sub-units; these b subunits form heterodimers with various a subunits.

Several members of the integrin family participate in leukocyte adhesion to endothelium: VLA-4, LFA-1, Mac-1, and p150,95. LFA-1, Mac-1, and p150,95 share the b2 subunit (and are thus called b2 integrins). The b2 subunit is a very important component of the leukocyte adhesion mechanism—patients who have a mutation in this molecule have a disorder known as leukocyte adhesion deficiency (LAD), which results in recurrent bacterial infections due to the inability to effectively recruit leukocytes in response to infections.

The parallel-plate flow chamber has also contributed to our current understanding of integrins and their binding properties. By studying adhesion after genetic manipulation of adhesion molecules or blocking them with antibodies, their contributions and binding kinetics could be determined. In addition, much has been learned about endothelial adhesion molecules and their regulation using this device.

Recently, it has been shown that integrin molecules can increase their affinity in response to certain stimuli. Remarkably, this can be triggered by leukocyte binding to endothelial cells, and it can produce extremely rapid changes in receptor configuration, bringing the leukocyte to an abrupt halt. Although still not well characterized, the mechanism might involve selectin or integrin signaling. Intriguingly, binding of immobilized chemokines on the endothelium to their receptors on the leukocyte can also achieve this response. It remains to be seen what role this plays in leukocyte trafficking and inflammation.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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