Leukocyte Migration and Inflammation CHAPTER 15 339 Efferent lymph A number of endothelial and leukocyte CAMs have (52%) loned 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 fam ily, the integrin family, and the immunoglobulin(lg)super- family( Figure 15-2 (45%)(42% SELECTINs The selectin family of membrane glycoproteins has a distal lectin -ike domain that enables these molecules Blood to bind to specific carbohydrate groups. Selectins interact lymphocyte pool lymph (10%) primarily with sialylated carbohydrate moieties, which are (30 min) often linked to mucin-like molecules. The selectin family includes three molecules, designated L, E, and P. Most cir- culating leukocytes express L-selectin, whereas E-selecti (10%)\ lymphocytes and P-selectin are expressed on vascular endothelial cells. Selectin molecules are responsible for the initial stickiness of leukocytes to vascular endothelium Tertiary extralymphoid Bone marrow Epithelial surface Mucosal epithelia in gut MUCINS The mucins are a group of serine- and threonine- lungs, and genitourinary tracts rich proteins that are heavily glycosylated. Their extended structure allows them to present sialylated carbohydrate recognizes sialylated carbohydrates on two mucin-like mole cules(CD34 and glyCAM-1)expressed on certain endothelial cells of lymph nodes. Another mucin-like molecule(PSGL-1) FIGURE15-1 Lymphocyte recirculation routes. The percentage of found on neutrophils interacts with E- and P-selectin ex- the lymphocyte pool that circulates to various sites and the average pressed on inflamed endothelium transit times in the major sites are indicated. Lymphocytes migrate from the blood into lymph nodes through specialized areas in post- INTEGRINS The integrins are heterodimeric proteins(consist- capillary venules called high-endothelial venules(HEVs). Although ing of an a and a B chain)that are expressed by leukocytes most lymphocytes circulate, some sites appear to contain lympho- and facilitate both adherence to the vascular endothelium and that do not. /Adapted from A. Ager, 1994, Trends Cell Biol. 4: 326] other cell-to-cell interactions. The integrins are grouped into categories according to which p subunit they contain. Differ at integrins are expressed by different populations of leuko- cytes, allowing these cells to bind to different CAMs that belong to the immunoglobulin superfamily expressed along the vascular endothelium. As described later, some integrins and leukocytes into the tissues. In order for circulating leuko- must be activated before they can bind with high affinity to cytes to enter inflamed tissue or peripheral lymphoid organs, their ligands. The importance of integrin molecules in leuko- the cells must adhere to and pass between the endothelial cyte extravasation is demonstrated by leukocyte-adhesion de- cells lining the walls of blood vessels, a process called extra- ficiency(LAD), an autosomal recessive disease described later vasation. Endothelial cells express leukocyte-specific cell- in this chapter(see the Clinical Focus). It is characterized by adhesion molecules(CAMs). Some of these membrane pro- recurrent bacterial infections and impaired healing of wounds. teins are expressed constitutively; others are expressed only in response to local concentrations of cytokines produced ICAMS Several adhesion molecules contain a variable num during an inflammatory response. Recirculating lympho- ber of immunoglobulin-like domains and thus are classified cytes, monocytes, and granulocytes bear receptors that bind in the immunoglobulin superfamily. Included in this group to CAMs on the vascular endothelium, enabling these cells to are ICAM-1, ICAM-2, ICAM-3, and VCAM, which are ex- extravasate into the tissues pressed on vascular endothelial cells and bind to various In addition to their role in leukocyte adhesion to vascular integrin molecules. An important cell-adhesion molecule endothelial cells, CAMs on leukocytes also serve to increase called MAdCAM-1 has both Ig-like domains and mucin-like the strength of the functional interactions between cells of domains. This molecule is expressed on mucosal endothe- the immune system. Various adhesion molecules have been lium and directs lymphocyte entry into mucosa. It binds to shown to contribute to the interactions between TH cells and integrins by its immunoglobulin-like domain and to selectins APCs, TH and b cells, and Ctls and target cells by its mucin-like domain.and leukocytes into the tissues. In order for circulating leuko￾cytes 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 extra￾vasation. Endothelial cells express leukocyte-specific cell￾adhesion molecules (CAMs). Some of these membrane pro￾teins are expressed constitutively; others are expressed only in response to local concentrations of cytokines produced during an inflammatory response. Recirculating lympho￾cytes, 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 fam￾ily, 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 cir￾culating 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 mole￾cules (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 ex￾pressed on inflamed endothelium. INTEGRINS The integrins are heterodimeric proteins (consist￾ing of an and a 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 subunit they contain. Differ￾ent integrins are expressed by different populations of leuko￾cytes, 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 leuko￾cyte extravasation is demonstrated by leukocyte-adhesion de￾ficiency (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 num￾ber 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 ex￾pressed 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. Leukocyte Migration and Inflammation CHAPTER 15 339 Spleen (5 h) Bone marrow Epithelial surface Peritoneum Activated lymphocytes Nonrecirculating cells Afferent lymph Naive lymphocytes (45%) (42%) Efferent lymph (52%) Blood lymphocyte pool (30 min) Lymph nodes (12 h) (?) (10%) (10%) Tertiary extralymphoid tissue: Mucosal epithelia in gut, lungs, and genitourinary tracts Liver Brain Skin 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 post￾capillary venules called high-endothelial venules (HEVs). Although most lymphocytes circulate, some sites appear to contain lympho￾cytes that do not. [Adapted from A. Ager, 1994, Trends Cell Biol. 4:326.]