Your browser is too old
We can't provide a great video experience on old browserUpdate now
Lymphocytes, which circulate continually in the blood and lymph and, in common with other types of leukocytes, migrate into the tissues at sites of infection or tissue injury. Inflammation is a complex response to local injury or other trauma; it is characterized by redness, heat, swelling, and pain. Inflammation involves various immune-system cells and numerous mediators. Assembling and regulating inflammatory responses would be impossible without the controlled migration of leukocyte populations. After a brief transit time of approximately 30 min in the bloodstream, nearly 45% of all lymphocytes are carried from the blood directly to the spleen, where they reside for approximately 5 h. Almost equal numbers (42%) of lymphocytes exit from the blood into various peripheral lymph nodes, where they reside for about 12 h. A smaller number of lymphocytes (10%) migrate to tertiary extra lymphoid tissues by crossing between endothelial cells that line the capillaries. These tissues normally have few, if any, lymphoid cells but can import them during an inflammatory response. The likelihood of such contacts is profoundly increased also by factors that regulate, organize, and direct the circulation of lymphocytes and antigen presenting cells.
The vascular endothelium serves as an important “gatekeeper,” regulating the movement of blood-borne molecules 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). Most of these CAMs belong to four families of proteins: the selectin family, the mucin-like family, the integrin family, and the immunoglobulin (Ig) superfamily. The selectin family of membrane glycoproteins has a distal lectin-like domain that enables binding to specific carbohydrate groups. The mucins are a group of serine and threonine rich proteins that are heavily glycosylated. The integrins are heterodimeric proteins that are expressed by leukocytes and facilitate both adherence to the vascular endothelium and other cell-to-cell interactions. 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.
As an inflammatory response develops, various cytokines and other inflammatory mediators act upon the local blood vessels, inducing increased expression of endothelial CAMs. The vascular endothelium is then said to be activated or inflamed. Neutrophils are generally the first cell type to bind to inflamed endothelium and extravasate into the tissues. To accomplish this, neutrophils must recognize the inflamed endothelium and adhere strongly enough so that they are not swept away by the flowing blood. The process of neutrophil extravasation can be divided into four sequential steps:
- Activation by Chemoattractant Stimulus
- Arrest and Adhesion
- Trans-endothelial Migration
Lymphocyte Extravasation - I
Some regions of vascular endothelium in postcapillary venules of various lymphoid organs are composed of specialized cells with a plump, cuboidal (“high”) shape; such regions are called high-endothelial venules, or HEVs. The development and maintenance of HEVs in lymphoid organs is influenced by cytokines produced in response to antigen capture. The different trafficking patterns of lymphocyte subsets are mediated by unique combinations of adhesion molecules and chemokines; receptors that direct the circulation of various populations of lymphocytes to particular lymphoid and inflammatory tissues are called homing receptors. A naive lymphocyte is not able to mount an immune response until it has been activated to become an effector cell. Rapid proliferation and differentiation of naive cells occurs during the shut-down phase. The effector and memory cells that are generated by this process then leave the lymphoid tissue and begin to recirculate.
Lymphocyte Extravasation - II
The trafficking patterns of effector and memory lymphocytes differ from those of naive lymphocytes. Memory lymphocytes, on the other hand, home selectively to the type of tissue in which they first encountered antigen. Effector and memory cells express increased levels of certain cell-adhesion molecules, such as LFA-1, that interact with ligands present on tertiary extra lymphoid tissue (such as skin and mucosal epithelia) and at sites of inflammation, allowing effector and memory cells to enter these sites. A second subset of memory/effector cells displays preferential homing to the skin. This subset also expresses low levels of L-selectin but displays high levels of cutaneous lymphocyte antigen (CLA) and LFA-1, which bind to E-selectin and ICAMs on dermal venules of the skin. Although effector and memory cells that express reduced levels of L-selectin do not tend to home through HEVs into peripheral lymph nodes, they can enter peripheral lymph nodes through the afferent lymphatic vessels.