Section 9: Lymphatic System

Ronald A. Bergman, Ph.D., Adel K. Afifi, M.D., Paul M. Heidger, Jr., Ph.D.
Peer Review Status: Externally Peer Reviewed

Plates

The lymphatic system is responsible for the protection of the individual against a hostile external environment composed of foreign substances and organisms. Specific cells of this system can distinguish between ourselves specifically, "self," and seek out and inactivate or destroy many invasive foreign substances and organisms, "non-self." These cells are called immunocompetent cells, and the entire system is frequently termed the immune system. Lymphoid tissue consists of reticular cells and their secretory product, collagen Type 3 or reticular fibers, supporting masses of lymphocytes, macrophages, antigen-presenting cells, and plasma cells.

Lymphoid tissue is remarkably variable and may appear as a diffuse infiltration into the lamina propria of mucous membranes or as well-defined organs, such as the thymus. One classification of lymphoid tissue, based upon increasing structural/functional complexity, is (1) diffuse lymphoid tissue, (2) lymph nodules, (3) tonsils, (4) lymph nodes, (5) thymus, and (6) spleen.

The simplest form, diffuse lymphoid tissue, is found throughout the body but, in particular, in the alimentary and respiratory tracts. Located in the lamina propria, it underlies the surface epithelium, surrounds mucosal glands and their ducts, and is characterized by a loosely organized mass of lymphocytes. The diffuse form of lymphocytic tissue grades into a more dense form, termed lymph nodules, of circumscribed masses of densely packed lymphocytes, which may be considered the basic structural unit of lymphoid tissue. Each nodule may contain a light staining central area, termed the germinal center, the presence of which indicates a site of active lymphocyte proliferation. These "primary" nodules or lymph follicles are found in large numbers in the mucosa of the intestinal tract, notably in the ileum and vermiform appendix.

Groups of lymph nodules may be partially encapsulated as small organs with a definite lymphatic and blood vascular supply. Such is the case in the tonsils, found in the pharynx. The three distinct tonsillar masses include the palatine, lingual, and pharyngeal (clinically, the adenoids), which form an incomplete ring around the entrance to the throat. The palatine and lingual tonsils are covered with a stratified squamous epithelium, whereas the pharyngeal tonsil is covered with a pseudostratified columnar ciliated epithelium, with some goblet cells characteristic of the nasopharynx. In adults, the pharyngeal tonsil is covered by a stratified squamous epithelium. The palatine and lingual tonsils have numerous epithelium lined pits, referred to as crypts, which may bifurcate. Surrounding the crypts is a single layer of lymph nodules with germinal centers. The pharyngeal tonsil does not possess true crypts but rather widened ducts of underlying glands. The epithelium covering the tonsils is extensively infiltrated by lymphocytes, plasma cells, and polymorphonuclear leucocytes.

Lymph nodes are completely encapsulated ovoid structures, in contrast to the lymphatic tissue previously described, and are the immunologic filters of the lymph. The capsule admits afferent lymphatic vessels containing valves that provide one-way flow into the subcapsular sinus. The lymph circulates through sinuses located in the cortex (containing the lymph nodules) and the medulla (containing lymphatic cords), and leaves the node via larger but fewer efferent lymphatic vessels. These also contain valves and emerge from a specific region of the node, the hilus. Lymph nodes, which vary in size from 1 to 25 mm, receive their blood supply only at the hilus of the node. The arterial vessels enter both the trabeculae formed from the capsular connective tissue and the medullary cords, and they regionally supply the node by giving off capillaries; they continue to the cortex, where an arterial branch penetrates each cortical lymph nodule and forms a capillary plexus around the germinal center. From the capillary beds, blood is carried by veins, which follow a pathway similar to the arteries, leaving the node at the hilum along with efferent lymphatic vessels.

The thymus varies in size and undergoes structural alterations with age. It undergoes rapid growth until the end of the second year, after which time the rate of growth slows until approximately the fourteenth year. After this, the thymus begins to involute or decrease in size, and, gradually, the lymphatic tissue is largely replaced by fat and connective tissue. In old age, very little thymic tissue may be present. The thymus consists of two lobes joined by connective tissue. Each lobe contains many lobules, which are 0.5 to 2 mm in diameter and which are incompletely separated from each other. A lobule is composed of a cortex and a medulla, which sends a projection to join with the medullae of adjacent lobules. The cortex consists of lymphocytes, which are densely and uniformly packed, obscuring the sparse reticular framework. The cortex lacks lymph nodules. The medulla stains less intensely as a result of thinning of the concentration of lymphocytes, and it is here that reticular cells can be recognized. Hassall's thymic corpuscles, located in the medulla, are diagnostic for identifying the thymus. The diameter of Hassall's corpuscles varies from 20 to 150 µm. The origin and nature of Hassall's corpuscles is unknown but may represent degeneration residue.

Arteries supplying the thymus follow the connective tissue septa and give off branches that enter the lobular cortex and break up into capillaries, which supply the cortex. Epithelial reticular cells sequester developing lymphocytes and form a sheath covering capillaries and lymphatic vessels. The sheathing forms what is called the blood-thymus barrier, preventing antigen contamination of developing and programmed T lymphocytes. The blood-thymus barrier is not found in the medulla, which appears to have a richer blood supply than the cortex. The capillaries terminate in thin-walled veins located in the connective tissue septa along with arteries. Lymphatic vessels arise within the thymic lobule and join to form larger vessels, which accompany the arteries and veins in the septa. In contrast to lymph nodes, the thymus contains no lymph sinuses or afferent lymphatic vessels.

The spleen is the largest lymphatic organ in the body and is the immunologic filter for the blood. Like the thymus, it has no afferent lymphatic vessels and no lymph sinuses. Splenic vessels enter and leave the spleen at the hilum of the organ and are located in thick trabeculae, which extend inward from the capsule. The capsule and trabeculae are composed of collagen and elastic fibers and some smooth muscle fibers. A reticular fiber network and lymphocytes are found between the trabeculae.

Sections of fresh spleen reveal two different regions, the so-called red and white pulps. The red pulp is traversed by a plexus of venous sinuses separated by lymphatic splenic cords. The venous sinuses contain tightly packed red blood corpuscles when they perform a storage function. The white pulp is composed of compact lymphoid tissue arranged in spherical or ovoid aggregations around arterioles (central arterioles). These aggregations are called splenic, or Malpighian corpuscles, and bear a resemblance to lymph nodules.

The vascular supply is critical for an understanding of the spleen. The arteries enter at the hilus and are carried in, and branch with, the trabeculae. Arterioles emerge from the trabeculae and pass into the splenic parenchyma, where the adventitia of the arterioles is infiltrated by lymphocytes to form splenic corpuscles. These arterioles supply the capillaries for the white pulp and continue their course, lose their lymphatic investment, and enter the red pulp, where they subdivide into several branches called penicilli. These branches become smaller and are differentiated into three distinct regions: pulp arterioles, sheathed arterioles, and terminal capillaries. The nature of the termination of these capillaries and their ultimate union with venous sinuses is controversial. A discussion of this point can be found in comprehensive textbooks of histology. The venous sinuses are lined not by endothelium but by specialized reticular cells, which are fixed macrophages. The reticular cells are encircled by reticular fibers. The venous sinuses unite to form pulp veins, which are lined by endothelial cells. The pulp, or collecting, veins enter the trabeculae and leave the spleen at the hilum.

Lymphocytes and monocytes develop in both the red and white pulp, the primary source, however, being the white pulp. They migrate to the white pulp to gain access to the venous sinuses. Although the spleen is not essential for life, it carries out several very important functions, including (1) filtering the blood by removing from the circulation foreign particles and aging red blood corpuscles and leucocytes; (2) conserving and temporarily storing iron recovered from hemoglobin of removed corpuscles; (3) storing normal red blood corpuscles within the splenic sinuses; (4) playing a key role in antibody formation; and (5) generating lymphocytes and monocytes, which enter the general circulation.

There are two classes of lymphocytes: T lymphocytes and B lymphocytes. These cells are functionally different but structurally similar, at least at the level of the light microscope. T lymphocytes are thymus-derived and are involved in cellular immunity, in which they interact with and destroy foreign or "non-self" cells. The B lymphocytes are involved with humoral immunity. These cells interact with foreign substances, then differentiate into plasma cells and synthesize and secrete immunoglobulins. The two immune systems are assisted by macrophages and certain other cells known as antigen-presenting cells (e.g., Langerhans cells of the skin and Kupffer's cells of the liver). Both the T and B lymphocytes have subpopulations that play a role in the immune system. The major T cell subgroups are the helper, suppressor, and killer cells. Helper cells are necessary in the initial antigen responses, especially to generate IgG and IgA responses. The immune response has potentially good as well as harmful effects and should be modulated to prevent a hyperimmune response. The T-suppressor cell serves this purpose. The T-killer cells are the effector cells of the thymus-dependent system. They combine with the antigen to initiate the cytotoxic mechanisms, which kill the invading organism. T cells are the major immune factor involved in the rejection of organ transplants and are the responsible culprits in the process known as graft/host reaction. In addition, T cells are involved in the immune response to acid- fast bacteria, certain viral infections, and fungi. They are also the main mediators of the immunopathological mechanisms in contact dermatitis.

Subpopulations of the B lymphocytes have not been as well defined as those of the T cells but are believed to exist on the basis of surface marker analysis. B cell products, the immunoglobulins, are divided into five major classes, each of which is produced by a different cell line.

Plasma cells produce five kinds of immunoglobulins, which have the following characteristics:

1. IgG constitutes about 75 per cent of serum immunoglobulin, which provides binding sites for antigens. This immunoglobulin, produced by a mother, also provides protection for her newborn against infection because it can cross the placenta.
2. IgA is found in colostrum, saliva, tears, and nasal, bronchial, intestinal, prostatic, and vaginal secretions. It is synthesized by the mucosal epithelial cells. Another type of IgA and associated proteins are synthesized by plasma cells located in the mucosa of the digestive, respiratory, and urinary tracts.
3. IgM is important for early immune responses and may be bound to B lymphocytes, or it may circulate in the blood. The bound form (along with IgD) is a receptor for antigens, which leads to the differentiation of anti body- producing plasma cells. IgM can activate a group of plasma enzymes (complement) capable of lysing bacteria and other cells.
4. IgE is secreted by plasma cells and attaches itself to basophils and mast cells. When the antigen that induced IgE synthesis and secretion is once again encountered, the basophils and mast cells release their stored histamine, heparin, leucotrienes, and eosinophil chemotactic factor, resulting in an allergic reaction. Leucotrienes are important compounds mediating allergic reactions, such as in asthma, which are produced by mast and perhaps, other cells.
5. IgD is found on the surface membrane of B lymphocytes with IgM, but its function is uncertain.

Thus, of the immunoglobulins, IgM is considered the first line of defense. IgG has a long half-life and can cross the placenta, thus is ideally suited for passive immunization. IgA protects mainly the secretory surfaces (gastrointestinal tract and eyes) where there are nonvascular exposures to antigens and conditions that may interfere with the usual antibody activity, such as acid secretion, intestinal motility, and proteolytic enzymes. IgE is important in the release of pharmacologically active agents from mast cells and thus causes asthma and hayfever. It is also the major mechanism in the elimination of parasites. IgD is primarily a lymphocyte receptor, is the strongest binding antibody, and is important in directing antigen to B cell surfaces to accomplish initial immunization.

T lymphocytes that migrate into other lymphoid tissues are located in so-called thymus-dependent areas such as the paracortical zone of lymph nodes and periarterial sheaths of the white pulp of the spleen. The paracortical area is an ill-defined band or zone that lies between the cortex and medulla. T lymphocytes are long-lived and constitute most of the lymphocytes in lymph and blood. B lymphocytes are located in the nodules of the spleen, lymph nodes, and lymphatic aggregations of the ileum (Peyer's patches).

When a microbe or a virus invades the body, white cells (including neutrophils) are among the first of the body's defenses to attack the invading organisms. White cells are short-lived scavengers and survive only a few days. Macrophages, however, are long-lived scavengers that engulf cellular debris and foreign matter. Macrophages display specific markers from the invading organisms on their surface known as antigens. Antigens signal helper T cells, which begin reproducing themselves. The helper T cells in turn produce chemicals (interleukins) to activate B cells. The B cells begin reproducing themselves and mature into plasma cells. Plasma cells produce antibodies, which are specifically intended to destroy the invading organism either directly by binding to it or by making it more vulnerable to macrophages and neutrophils. After the invader has been destroyed, suppressor T cells chemically notify B cells and helper T cells to return to a dormant state.

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