IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 5. Cell Migration and Inflammation

CELL ADHESION MOLECULES

Cell Adhesion molecules are Plasma Membrane-associated Proteins that mediate mechanical interactions between Cells. Frequently, these are transmembrane molecules anchored to the Cytoskeleton, allowing cells to pull themselves along other cells or migrate through the Extracellular matrix during movement. In many cases, a single cell adhesion molecule can interact with multiple ligands via distinct binding sites. Although the binding of individual adhesion molecules to their ligands typically exhibits low affinity, the avidity of the interaction can be quite high due to adhesion molecules being arranged in compact patches, or clusters, on The Cell surface to form multipoint binding sites.

Adhesion between different cell types can be modulated by an increase in the number of adhesion molecules on the cell surface or by alterations in their affinity and/or avidity (Fig. 5.5). Two mechanisms increase the number of adhesion molecules on the cell surface: many cells store large reserves of these molecules in intracellular vesicles, which can be rapidly translocated to The Plasma Membrane within minutes of activation; another mechanism involves the de novo synthesis of such molecules and their subsequent transport to the surface (processes that typically take several hours).

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Fig. 5.5. Four mechanisms for enhancing leukocyte binding to the endothelium. 1. Many leukocytes possess internal stores of adhesion molecules that can be rapidly mobilized to the surface. 2. Endothelial cells at sites of inflammation can synthesize cell adhesion molecules de novo. 3. Cell activation can lead to an increase in binding affinity, as seen with LFA-1. 4. Redistribution of adhesion molecules on the cell surface results in The formation of high-avidity binding sites. Under physiological conditions, cells utilize multiple mechanisms simultaneously, and the binding affinity of adhesion molecules can change significantly following initial cell-cell contact.

The number of known cell adhesion molecules relevant to leukocyte migration is staggeringly large. Nevertheless, they can all be classified into four families of structurally related molecules. Cell migration is a complex process in which several sets of adhesion molecules are involved at different stages.

Some endothelial adhesion molecules belong to the immunoglobulin superfamily

A number of endothelial cell adhesion molecules belong to the immunoglobulin superfamily, including intercellular adhesion molecule-1 (ICAM-1) and intercellular adhesion molecule-2 (ICAM-2), vascular cell adhesion molecule-1 (VCAM-1), and the mucosal addressin cell adhesion molecule of mucosal lymphoid Tissues, previously designated as mucosal addressin-1 or MAdCAM-1. The expression of these molecules on the vascular endothelium can be constitutive or inducible. ICAM-1 features five extracellular domains, of which the two N-terminal domains are structurally homologous to the two extracellular domains of ICAM-2. VCAM-1 contains six extracellular domains, and similar features are present in The Structure of MAdCAM-1 (Fig. 5.6).

Fig. 5.6. Schematic representation of the endothelial cell adhesion molecules ICAM-1, ICAM-2, VCAM-1, and MAdCAM-1 with their Ig-like domains. Their ligands, belonging to the integrin family, are shown at the top of the figure. The structure of MAdCAM-1 also contains a heavily glycosylated mucin-like domain that binds L-selectin.

Leukocyte adhesion to the endothelium and extracellular matrix is mediated by Integrins

Integrins are a large family of cell adhesion molecules found On the surface of various cells, including leukocytes. All proteins within this major family consist of two non-covalently linked polypeptide chains (α and β), both of which span The cell membrane. The integrin family is divided into three main subfamilies based on the type of β-chain (β₁, β₂, or β₃). The specific type of α-chain paired with the β-chain proved less critical for functional activity than initially assumed. Broadly speaking, β₁ integrins are involved in binding cells to extracellular matrix structures, β₂ integrins mediate leukocyte adhesion to the endothelium or other immune cells, and β₃ integrins (cytoadhesins) participate in platelet-neutrophil aggregation at sites of inflammation or vascular injury. However, there are a few exceptions to this simple scheme, and additional β-chains (such as β₇) have also been described. Each β-chain can associate with a variety of α-chains, resulting in a diverse array of adhesion molecules. The ability of integrins to bind their ligands is divalent cation-dependent. For example, LFA-1 (an α_Lβ₂ integrin) is normally expressed on leukocytes in a low-affinity state, but transitions to a high-affinity state upon an increase in Mg²⁺ concentration. Elevated Ca²⁺ concentrations induce the redistribution of surface integrins into high-avidity clusters. Several integrins important for migration are shown in Fig. 5.7.

Fig. 5.7. Top: schematic diagram of an integrin molecule composed of two non-covalently linked polypeptide chains. The table summarizes The properties of selected integrins that mediate leukocyte binding (adhesion) to the vascular endothelium or extracellular matrix.

Selectins are a group of leukocyte and endothelial cell adhesion molecules that bind CARBOHYDRATES

The selectin family includes E-selectin, P-selectin, and L-selectin, expressed on the endothelium, platelets, and certain leukocyte subsets, respectively (Fig. 5.8). Selectin molecules span the Cell Membrane and contain a series of extracellular domains homologous to those of Complement regulatory proteins, such as factor H. Their extracellular region also features a domain structurally related to the epidermal growth factor (EGF) receptor and an N-terminal lectin-like domain capable of binding carbohydrate moieties (hence the name "selectins"). Consequently, the ligands recognized by selectins contain carbohydrates.

Fig. 5.8. STRUCTURE OF THE three selectins. The terminal lectin domain of each binds to the carbohydrate ligands of the cells listed at the top. Selectins also share other common structural features.

Selectin ligands are carbohydrate components of various Glycoproteins on the lymphocyte and endothelial surface.

Carbohydrate ligands for selectins are found in the structure of diverse proteins. For instance, the Sgp-200 glycoprotein, expressed on HEV endothelium, contains numerous O-linked carbohydrate residues that serve as ligands for lymphocyte L-selectin. (By binding L-selectin to these carbohydrate residues, lymphocytes are directed from the bloodstream into peripheral Lymph Nodes.) L-selectins can also bind to carbohydrates within MAdCAM-1, which is expressed on the endothelium of HEVs in mucosal lymphoid structures. These glycoproteins, named vascular addressins in accordance with their function, are primarily present on HEV cells in lymphoid tissues, but can also be induced during chronic inflammation in other PARTS OF THE body (Fig. 5.9).

Fig. 5.9. Mucosal addressins on the endothelial surface. Electron micrograph of a Brain section from Biozzi AB/H mice with chronic experimental relapsing-remitting allergic encephalomyelitis induced by immunization with myelin basic protein. The section is stained to reveal MAdCAM-1 (dark border indicated by the arrow) expressed on the luminal surface of a brain Blood vessel endothelium. (Micrograph kindly provided by Dr. J.K. O'Neill and Dr. C. Butter with permission from the publisher; Immunology, 1991; 72: 520-525.)

E- and P-selectins, expressed on activated endothelial cells, bind to the sialylated form of the carbohydrate determinant Le^x (Lewis-X blood group antigen) associated with the CD15 protein, which is present on many leukocyte subpopulations. This binding halts the movement of leukocytes with the blood flow and initiates The first phase of migration (Fig. 5.10).