Cell Adhesion Molecules

The vascular endothelium serves as an important "gatekeeper," regulating the movement of blood-borne molecules

Efferent lymph (52%)

Efferent lymph (52%)

Lymphocyte Recirculation Diagram

FIGURE 15-1

Lymphocyte recirculation routes. The percentage of the lymphocyte pool that circulates to various sites and the average transit times in the major sites are indicated. Lymphocytes migrate from the blood into lymph nodes through specialized areas in postcapillary venules called high-endothelial venules (HEVs). Although most lymphocytes circulate, some sites appear to contain lymphocytes that do not. ¡Adapted from A. Ager, 1994, Trends Cell Biol. 4:326]

FIGURE 15-1

Lymphocyte recirculation routes. The percentage of the lymphocyte pool that circulates to various sites and the average transit times in the major sites are indicated. Lymphocytes migrate from the blood into lymph nodes through specialized areas in postcapillary venules called high-endothelial venules (HEVs). Although most lymphocytes circulate, some sites appear to contain lymphocytes that do not. ¡Adapted from A. Ager, 1994, Trends Cell Biol. 4:326]

and leukocytes into the tissues. In order for circulating leukocytes to enter inflamed tissue or peripheral lymphoid organs, the cells must adhere to and pass between the endothelial cells lining the walls of blood vessels, a process called extravasation. Endothelial cells express leukocyte-specific cell-adhesion molecules (CAMs). Some of these membrane proteins are expressed constitutively; others are expressed only in response to local concentrations of cytokines produced during an inflammatory response. Recirculating lymphocytes, monocytes, and granulocytes bear receptors that bind to CAMs on the vascular endothelium, enabling these cells to extravasate into the tissues.

In addition to their role in leukocyte adhesion to vascular endothelial cells, CAMs on leukocytes also serve to increase the strength of the functional interactions between cells of the immune system. Various adhesion molecules have been shown to contribute to the interactions between TH cells and APCs, TH and B cells, and CTLs and target cells.

A number of endothelial and leukocyte CAMs have been cloned and characterized, providing new details about the extravasation process. Most of these CAMs belong to four families of proteins: the selectin family, the mucin-like family, the integrin family, and the immunoglobulin (Ig) super-family (Figure 15-2).

SELECTINS The selectin family of membrane glycoproteins has a distal lectin-like domain that enables these molecules to bind to specific carbohydrate groups. Selectins interact primarily with sialylated carbohydrate moieties, which are often linked to mucin-like molecules. The selectin family includes three molecules, designated L, E, and P. Most circulating leukocytes express L-selectin, whereas E-selectin and P-selectin are expressed on vascular endothelial cells. Selectin molecules are responsible for the initial stickiness of leukocytes to vascular endothelium.

MUCINS The mucins are a group of serine- and threonine-rich proteins that are heavily glycosylated. Their extended structure allows them to present sialylated carbohydrate ligands to selectins. For example, L-selectin on leukocytes recognizes sialylated carbohydrates on two mucin-like molecules (CD34 and GlyCAM-1) expressed on certain endothelial cells of lymph nodes. Another mucin-like molecule (PSGL-1) found on neutrophils interacts with E- and P-selectin expressed on inflamed endothelium.

INTEGRINS The integrins are heterodimeric proteins (consisting of an a and a p chain) that are expressed by leukocytes and facilitate both adherence to the vascular endothelium and other cell-to-cell interactions. The integrins are grouped into categories according to which p subunit they contain. Different integrins are expressed by different populations of leukocytes, allowing these cells to bind to different CAMs that belong to the immunoglobulin superfamily expressed along the vascular endothelium. As described later, some integrins must be activated before they can bind with high affinity to their ligands. The importance of integrin molecules in leukocyte extravasation is demonstrated by leukocyte-adhesion deficiency (LAD), an autosomal recessive disease described later in this chapter (see the Clinical Focus). It is characterized by recurrent bacterial infections and impaired healing of wounds.

ICAMS Several adhesion molecules contain a variable number of immunoglobulin-like domains and thus are classified in the immunoglobulin superfamily. Included in this group are ICAM-1, ICAM-2, ICAM-3, and VCAM, which are expressed on vascular endothelial cells and bind to various integrin molecules. An important cell-adhesion molecule called MAdCAM-1 has both Ig-like domains and mucin-like domains. This molecule is expressed on mucosal endothe-lium and directs lymphocyte entry into mucosa. It binds to integrins by its immunoglobulin-like domain and to selectins by its mucin-like domain.

(a) General structure of CAM families Mucin-like CAMs

(b) Selected CAMs belonging to each family

(a) General structure of CAM families Mucin-like CAMs

1

CHO side chains

- Lectin domain

Ig domains

Integrins r\

Fibrinonectin-type domains

- Lectin domain

Ig domains

Selectin Selectin

FIGURE 15-2

Ig-superfamily CAMs

Mucin-like CAMs: GlyCAM-1 CD34 PSGL-1 MAdCAM-1

Ig-superfamily CAMs: ICAM-1, -2, -3 VCAM-1 LFA-2 (CD2) LFA-3 (CD58) MAdCAM-1

Selectins: L-selectin P-selectin E-selectin

Integrins:

a4ß1 (VLA-4, LPAM-2) a4ß7 (LPAM-1) a6ß1 (VLA-6) aLß2 (LFA-1) aMß2 (Mac-1) aXß2 (CR4, p150/95)

Selectins

Ig-superfamily CAMs

FIGURE 15-2

Schematic diagrams depicting the general structures of the four families of cell-adhesion molecules (a) and a list of representative molecules in each family (b). The lectin domain in selectins interacts primarily with carbohydrate (CHO) moieties on mucin-like molecules. Both component chains in integrin molecules contribute to the binding site, which interacts with an Ig domain in CAMs belonging to the Ig superfamily. MAdCAM-1 contains both mucin-like and Ig-like domains and can bind to both selectins and integrins.

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