IMMUNOLOGY - Roit A. - Mir 2000

Chapter 3. The Lymphoid System

LYMPHOCYTE CIRCULATION

The migration of lymphocytes from primary to secondary lymphoid Tissues has been described above. Once in Secondary Lymphoid Organs and structures, many lymphocytes do not remain there, but instead move from one lymphoid organ to another via the Blood and Lymphatic vessels (Fig. 3.25).

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Fig. 3.25. Lymphocytes enter Lymph Nodes AND MALT from the bloodstream via specialized high endothelial venules (HEVs); they subsequently leave the lymphoid tissue through efferent Lymphatic vessels and, after passing through other lymph nodes, return to the bloodstream via the Thoracic duct, which empties into the left subclavian vein in humans. In the Spleen, lymphocytes enter the white pulp via the marginal zones; then, having reached the red pulp sinusoids, they leave the organ via the splenic vein.

Lymphocytes leave the bloodstream and enter lymphoid tissue through the walls of high endothelial venules. Although some lymphocytes pass from the blood into lymphoid tissue through ordinary postcapillary venules, in most mammals this passage occurs predominantly through specialized segments of the venous bed known as high endothelial venules, or HEVs (Figs. 3.26 and 3.27). In lymph nodes, these vessels are located mainly in the paracortical area and occasionally in the cortex, but are absent from the medulla. At the same time, some lymphocytes—primarily T Cells—enter regional lymph nodes from their drained area via afferent lymphatic vessels rather than through HEVs. Most Antigens reach the lymph nodes via this same route. High endothelial venules have been found not only in lymph nodes, but also in MALT and the Thymus.

Fig. 3.26. High endothelial venule (HEV) in the paracortical area of a lymph node. Lymphocytes exit the bloodstream through the high endothelium (HEV) and infiltrate the lymph node. Hematoxylin and eosin (H&E) stain. × 200. (Photographs kindly provided by Dr. A. Stevens and Prof. J. Lowe.)

Fig. 3.27. Transmission electron micrograph of a high endothelial venule in the paracortical area of a lymph node. Near the basement membrane, a lymphocyte (LYM) is visible leaving the lumen (Lum) of the venule, which is partially encircled on the outside by an adventitial Cell (AC). × 1600.

High endothelial venules regulate lymphocyte Circulation. These venules are lined by cuboidal endothelial cells which, unlike the resting flat cells lining ordinary venules, express a variety of Cell Adhesion molecules upon activation. One of the mechanisms of endothelial cell activation is mediated by locally synthesized cytokines such as IFNγ, IL-1, and TNF.

The endothelium of ordinary venules can transform into a cuboidal epithelium in areas of chronic inflammation, such as the Skin or synovial membranes, where HEVs are normally absent. These newly formed HEVs direct specialized subpopulations of T lymphocytes to the site of inflammation. Activated cuboidal endothelial cells express A number of cell adhesion molecules belonging either to the immunoglobulin superfamily [ICAM-1 (CD54), ICAM-2 (CD102), and VCAM-1 (CD106)] or the selectin family, including E-selectin [ELAM-1 (CD62E)] and P-selectin (CD62P). P-selectin is stored in the Weibel-Palade bodies of blood capillary endothelial cells and is rapidly translocated to the endothelial cell surface upon activation (see Chapter 5). The leading role in lymphocyte adhesion to the endothelium belongs to CD44, a 90 kDa protein expressed by all leukocytes. Presumably, specific Ligand-receptor interactions arise between lymphocytes and the endothelium, directing the lymphocytes to specific target tissues. This is achieved through the endothelial expression of organ-specific "addressins," such as MAdCAM-1 on intestinal endothelial cells and VCAM-1 on endothelial cells in other organs. Specialized homing molecules are also crucial for the selective, organ-specific distribution of lymphocytes. For instance, their Integrins α₄β₇, which bind to the addressin MAdCAM-1 on HEV endothelial cells in Peyer's patches, are critically important for the return of lymphocytes to intestinal lymphoid tissue. In β₇-Gene-deficient mice, The formation of intestinal lymphoid tissue is significantly impaired.

Through recirculation, any antigen is exposed to a vast array of lymphocytes. Lymphocytes return from lymph nodes to the bloodstream via efferent lymphatic vessels, the thoracic duct, and the subclavian vein. Every hour, 1–2% of the lymphocyte pool undergoes recirculation. Ultimately, this process allows numerous antigen-specific lymphocytes to encounter their corresponding antigens upon entering the microenvironment of peripheral lymphoid organs. The critical importance of recirculation becomes evident when we recall that lymphoid cells are monospecific, and only a limited number of lymphocytes are capable of recognizing any given antigen.

Normally, lymphocyte recirculation through lymph nodes is continuous; however, if an animal previously sensitized to a particular antigen is re-exposed to it, recirculation halts for approximately 24 hours. This temporary arrest is caused by the selective retention of antigen-specific lymphocytes within the lymph nodes draining the site of antigen entry. For instance, lymphoblasts generated As a result of antigen contact no longer recirculate, apparently remaining localized at the site of antigenic encounter.

Mucosa-associated lymphoid tissue (MALT) differs as a system from other lymphoid organs partly because MALT lymphocytes return predominantly to this same tissue during recirculation. Thus, lymphocytes stimulated in Peyer's patches pass through regional lymph nodes into the bloodstream and then return "home" to the lamina propria of the intestinal mucosa (Fig. 3.28). This specific recirculation pattern is explained by the fact that these lymphocytes express homing molecules that bind to specific adhesion molecules—addressins—On the surface of endothelial cells. These addressins are expressed exclusively by the venular endothelium of mucosa-associated lymphoid tissue, but not by HEVs of ordinary lymph nodes (see above), thereby ensuring selective recirculation. For the same reason, antigenic stimulation in a mucosal area (at any site in the body) elicits a systemic antibody response predominantly within MALT.

Fig. 3.28. Lymphoid cells activated by antigen in Peyer's patches (or in bronchus-associated and other mucosa-associated lymphoid structures) migrate via regional lymph nodes and the thoracic duct into the bloodstream, from which they return to the lamina propria (LP) of the epithelium of the intestine and other mucosal surfaces, either near or far from the site of initial antigenic priming. Thus, lymphocytes stimulated at a mucosal site in one part of the body can be selectively distributed throughout the MALT system. This selective homing is achieved through the expression of specific cell adhesion molecules on lymphocytes and mucosal HEV cells.

Questions for Thought

■ Why do mammals require such a highly specialized lymphoid system, whereas more primitive animals are able to survive without it?

■ How critical is lymphocyte recirculation within the mucosa-associated lymphoid tissue system, and which molecules ensure its selectivity?

■ What are the Similarities and differences between mucosa-associated lymphoid tissue and the other Organs of the lymphoid system? Is one of these PARTS OF THE lymphoid system more vital for survival than the other?

■ How does the lymphoid system differ from any other body system, such as the respiratory or Reproductive System? (You may need to review various body systems in a physiology textbook to answer this.)

■ What accessory cells are present in lymphoid tissues, and what are their functions? What are the functions of Primary and secondary lymphoid organs and structures?

Introduction/47.html">Further Reading

Butcher Е.С., Picker L.J. 1996. Lymphocyte homing and Homeostasis. Science 272: 6—66.

Hogg N., Berlin C. 1995. Structure and function of adhesion receptors in leukocyte trafficking. Immunol. Today 16: 327-330.

Kuby J. 1997. Immunology. 3rd edn. Cells and Organs of The Immune System. New York: W.H. Freeman and Co. 47-83.

Playfair J.H.L. Immunology at a Glance. 6th edn.

Oxford: Blackwell Scientific Publications. 1996.

Roitt I.M. Essential Immunology. 9th edn. Oxford: Blackwell Scientific Publications, 1997.