IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 5. Cell Migration and Inflammation

■ Inflammation is the body's response that recruits leukocytes and soluble plasma components to sites of infection or tissue damage. Its key manifestations include increased capillary Blood flow and permeability to serum macromolecules, as well as enhanced leukocyte migration toward the inflammatory site through the endothelium of nearby vessels.

■ Leukocyte migration is a complex process governed by the Specific features of the migrating Cell population, their activation state, and The Nature of their interactions with the endothelium in different Regions of the vascular bed.

■ The migration pathway is partly determined by the level of cell activation: resting or naive (antigen-inexperienced) lymphocytes tend to migrate via high endothelial venules into lymphoid Tissues, whereas activated lymphocytes home in on sites of inflammation.

■ Adhesion molecules regulating leukocyte migration belong structurally to distinct yet related families, including the immunoglobulin superfamily (endothelial Cell adhesion molecules), the selectin family, and the integrin family. In endothelial Cells, the synthesis of adhesion molecules is induced by cytokines. The expression of leukocyte adhesion molecules depends on The Cell population and its stage of differentiation.

■ Chemotactic molecules determine the direction of leukocyte migration and also trigger this process upon contact between leukocytes and the endothelial surface.

■ Inflammatory mediators released by mast cells, platelets, and leukocytes during immunological reactions or tissue damage act in concert with the products of plasma enzyme systems to regulate vascular permeability and blood flow.

Normally, leukocytes circulating in the blood migrate throughout all body tissues, yet each population exhibits a distinct migration pattern. Furthermore, the migration pathway depends on the stage of differentiation and the level of cell activation:

✵ phagocytes, including neutrophils and monocytes, leave the Bone Marrow and migrate to peripheral tissues harboring sites of inflammation; for neutrophils, this is a one-way journey, whereas monocytes, upon differentiating into macrophages, can return to secondary lymphoid tissues and function there as antigen-presenting cells (APCs):

✵ naive (antigen-inexperienced) lymphocytes migrate from the Thymus and bone marrow into secondary lymphoid tissues; following antigen activation, T cells tend to infiltrate inflammatory sites (Fig. 5.1), whereas B cells and memory T cells take up residence in neighboring Lymphoid Organs and structures.

✵ dendritic cells, particularly cutaneous Langerhans cells, are descendants of bone marrow stem cells that have colonized secondary lymphoid tissues; upon capturing an antigen, they can migrate to regional Lymph Nodes to present it to CD4⁺ T cells.

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Fig. 5.1. Lymphocyte-endothelium interactions. 1. An antigen-activated T cell bound in vitro to retinal endothelium. Migrating along the endothelium, it adheres to the surface and then extends pseudopodia, probing for a suitable point of translocation. Scanning Electron Microscopy (micrograph kindly provided by Dr. J. Greenwood). 2. A lymphocyte adhered to cerebral vessel endothelium near an intercellular junction (experimental allergic encephalomyelitis). Adhesion is followed by transendothelial migration of the lymphocyte into the site of inflammation. Transmission electron microscopy (micrograph kindly provided by Dr. S. Hawkins).

Lymphocyte migration enables every "handful" of lymphocytes specific to a given individual antigen to encounter it precisely. Lymph drainage pathways and cell trafficking ensure that lymphocytes, APCs, and Antigens arriving from infected and inflamed tissues meet within the lymph nodes; antigens entering the bloodstream are trapped by the Spleen. Primary clonal expansion of antigen-specific lymphocytes takes place in secondary lymphoid tissues, after which they enter the Circulation via efferent Lymphatic vessels (Fig. 5.2). Their subsequent migration from the bloodstream depends on the expression of adhesion molecules on endothelial cells; for instance, when such molecules appear on the endothelium at an inflammatory site, they are recognized by receptors on activated lymphocytes or phagocytes, resulting in the accumulation of these cells at that Location. The entire complex of tissue reactions arising in response to injury or infection is termed inflammation. Inflammation is characterized by three main features:

✵ increased blood supply to the inflamed area, facilitating the delivery of leukocytes and soluble plasma components;

✵ increased capillary permeability leading to the exudation of Plasma Proteins (Antibodies, Complement, kininogens, etc.) required to contain the infection;

✵ enhanced leukocyte migration.

Fig. 5.2. Naive lymphocytes migrate from primary lymphoid tissues, such as the bone marrow, to secondary lymphoid tissues, such as the spleen and lymph nodes. Antigen-presenting cells (APCs), including dendritic cells and mononuclear phagocytes, also originate from bone marrow stem cells. APCs infiltrate various body tissues, capture antigens there, and deliver them to lymphoid tissues for presentation to T AND B cells. Subsequently, primed lymphocytes leave the lymphoid tissue and accumulate predominantly at sites of infection and inflammation.

During an immunological reaction to an antigen, different populations of migrating cells typically appear in the tissue sequentially (phase shift). The type of cells present at any given moment, the predominance of specific populations, and the timing of their appearance all depend on the Nature of the antigen and the anatomical site where the Immune Response unfolds. Typically, neutrophils are the first to arrive at acute inflammatory sites caused by infection, remaining the predominant cell type for several days. By the second day, mononuclear phagocytes and lymphocytes begin to enter the lesion. Later arrivals usually include CD8⁺ T cells and a small number of B cells. The resolution of an acute response depends on whether the body successfully eliminates the antigen or infection. If not, the acute inflammatory response transitions into chronic inflammation, characterized by few neutrophils and a substantial accumulation of CD4⁺ T cells and mononuclear phagocytes. Responses to parasitic infections (such as Schistosomiasis) are frequently accompanied by eosinophil infiltration. Eosinophils, along with basophils and macrophages, also predominate in tissue infiltrates of the bronchial wall following asthma attacks.

CELL MIGRATION

Leukocyte migration comprises two major stages. The first is the adhesion of circulating cells to the vascular endothelium, followed by penetration between or through endothelial cells (Fig. 5.3). In the second stage, leukocytes that have crossed the endothelium migrate toward the site of infection or inflammation, guided by chemotactic cues. These processes are regulated by surface proteins on the migrating cells (which interact with the endothelium, tissue cells, or the Extracellular matrix), as well as by soluble signaling molecules such as chemokines and other chemoattractants.

Fig. 5.3. Three stages of neutrophil migration. 1. A polymorphonuclear leukocyte adheres to the capillary endothelium. 2. The leukocyte squeezes between endothelial cells. 3. A neutrophil passing through an endothelial cell. This overall process is sometimes referred to as "diapedesis." ×4,000. (Micrographs kindly provided by Dr. I. Jovis.)

Pathways of cellular migration are diverse and depend not only on the cell type, but also on its stage of differentiation or level of activation. Beyond these factors, there are CHARACTERISTICS OF THE vascular endothelium in different regions of the body that influence migration. For instance, high endothelial venules (HEVs), which are characteristic of secondary lymphoid tissue, differ completely in Structure from the venules of non-lymphoid tissues (see Ch. 3). The endothelium of small vessels in various non-lymphoid tissues is morphologically extremely diverse, and furthermore, any local inflammatory response leads to Changes in the expression of A number of its surface molecules. All of these factors determine which cell types will be able to penetrate the endothelial lining. As a rule, leukocyte migration across the endothelium is influenced by: 1) the magnitude of the surface charge of the interacting cells, 2) the force of hemodynamic shear in the vascular bed, and 3) the expression of a complementary set of adhesion molecules On the surface of both leukocytes and endothelial cells. Therefore, leukocytes migrate from the bloodstream through the walls of venules specifically, where the surface charge of endothelial cells is lowest, hemodynamic shear is negligible, and cell adhesion molecules are selectively expressed (Fig. 5.4).

Fig. 5.4. Leukocytes circulating in the vascular bed are capable of interacting with the venular endothelium through a variety of surface cell adhesion molecules. In venules, the force of hemodynamic shear is negligible, the endothelial surface charge is low, and the expression of adhesion molecules occurs selectively. Upon appropriate leukocyte stimulation, adhesion is followed by migration.

Lymphocyte migration into lymphoid tissue differs from migration into sites of inflammation

Different Stages of the lymphocyte life cycle are characterized by distinct migration pathways. For example, naive T cells tend to enter secondary lymphoid tissues via HEVs, whereas activated T cells migrate to sites of inflammation. In addition, selective migration to specific areas of the body is observed: lymphocytes isolated from Peyer's patches, when injected into the blood, home back to the intestine, while spleen lymphocytes return to the spleen.

The migration of lymphocytes from the bloodstream into lymph nodes, Peyer's patches, and mucosal lymphoid tissue occurs via HEVs (see Ch. 3). It is through the walls of these venules that up to 25% of the lymphocytes entering a lymph node via Blood Vessels exit the circulation. In contrast, only a negligible fraction of circulating lymphocytes penetrates the conventional endothelium of venules (in other tissues) during each cycle. Nevertheless, this low-level migration is critical as it allows lymphocytes to perform "surveillance" over all Tissues of the body; during The Development of inflammation, it increases manifold.

High endothelial venules thus play a crucial role in lymphocyte recirculation. Under normal conditions, HEVs are present only in secondary lymphoid tissues, but they can also arise at sites of chronic inflammation. In addition to their characteristic cuboidal shape, features of HEV endothelial cells include the expression of various sets of sulfated and heavily glycosylated Cell-to-Cell Adhesion molecules that bind to circulating T cells, thereby directing them from the bloodstream into the lymphoid tissue. These adhesion molecules differ from those that regulate lymphocyte migration to sites of acute inflammation. Moreover, in different lymphoid tissues (Peyer's patches, mucosal lymph nodes, etc.), various cell adhesion molecules are expressed on the HEV endothelium. Previously, these adhesion molecules were termed vascular addressins; their expression on the endothelium of various HEVs ensures the homing of lymphocytes back to their resident lymphoid tissue.

Migration is regulated by a number of factors of both endothelial and leukocyte origin

Leukocyte migration depends on the presence of adhesion molecules on The surface of both the endothelium and leukocytes, on the motility of the cells themselves, and on the presence of chemotactic agents. To explain the complex and variable nature of cellular migration, it is necessary to consider the multitude of factors influencing it. These include:

✵ the state of activation of the migrating lymphocytes or phagocytes: the expression of adhesion molecules and their functional affinity vary depending on the cell type and whether they are activated by antigen, cytokines, or cell-to-cell interactions;

✵ the types of adhesion molecules expressed by the vascular endothelium: these are determined by the anatomical region where the vessel is located and whether the endothelium has been activated by cytokines;

✵ the presence of specific chemotactic molecules and cytokines in tissues: different leukocyte populations are characterized by distinct specialized receptors, so each chemotactic agent selectively attracts only a specific cell type.

Before examining The Role of adhesion molecules in leukocyte migration, it is necessary to become familiar with their diversity and intercellular distribution.