What is the lymphatic system?

Structure and Functions

The lymphatic system is a complex of capillaries, ducts, nodes, and organs that filters and maintains interstitial fluid—that is, fluid from body tissues. Fluid is collected from body tissues and returned to the bloodstream. In addition, the system functions as a site of the immune response, primarily in the spleen and the lymph nodes, and transports fat and protein to the bloodstream.

The organs of the lymphatic system are divided into primary lymphoid organs and secondary organs. The primary organs include the thymus and the bone marrow, which are sites where lymphocytes are produced and mature. Secondary lymphoid organs are those in which the immune response is carried out. These include both encapsulated organs such as the spleen and lymph nodes and unencapsulated organs such as the mucosal associated lymphoid tissue, which includes Peyer’s patches in the intestine and Waldeyer’s ring in the throat (the tonsils and adenoids), which encircles the pharnyx. Lymph nodes are found throughout the body, but they occur in large numbers in the head, neck, armpits (the axillary nodes), and abdomen and groin (the inguinal nodes).

The lymphatic vessels essentially parallel those of the bloodstream. The system originates in peripheral tissue as small openings, or sinuses, within the tissue. Fluid that drains from the tissue collects in these sinuses and forms lymph. In addition, a significant amount of liquid (1 to 2 liters) that is lost from blood capillaries each day also collects in the interstitial fluid. The lymph is physiologically similar to blood plasma in that it is a balanced solution of
electrolytes containing some carbohydrates, lipids, and proteins. In general, the protein level is about half that found in blood, since most blood proteins are too large to pass through the endothelial walls of blood capillaries. Arguably, the major function of the lymphatic system is the return of this fluid, and its constituent materials, to the blood. The buildup of abnormal amounts of fluid in tissue results in swelling, or edema. Approximately 60 percent of lost fluid is returned to the blood through the lymphatics, and the remainder is collected directly into small blood capillaries.

Generally speaking, the peripheral portion of the lymphatic system is completely separate from that of the blood. Once the interstitial fluid is collected, it begins to move toward the thoracic duct. Since the duct is found in the neck region, this movement is primarily in an upward direction. The fluid moves through regional lymph nodes, such as those found in the groin or armpits, and gradually collects in the larger ducts of the major lymphatics. Though an extensive system of valves is found in the lymphatic system to prevent the movement of lymph in the wrong direction, no internal pumping mechanism analogous to the heart exists. The movement of the lymph is mediated by the musculature of the body: respiratory pressure, muscular movement, and the pulsing or motion of nearby organs. Lymphatic fluids from all portions of the body, except for the upper-right quadrant, eventually collect in the thoracic duct. Lymph from the upper-right quadrant of the body collects in the right lymphatic duct. The endothelia of these major lymphatic ducts are contiguous with those of the veins in the neck, and it is here that the fluid is returned to the bloodstream. Valves present in the lymphatic ducts serve to prevent the backup of blood from the bloodstream into the lymphatic system.

In addition to the electrolytes and proteins that collect in lymph, foreign materials such as infectious agents may also penetrate the skin or internal surfaces of the body. These materials pass into tissue fluids and also collect in the lymphatic system. From here, they travel to regional lymph nodes, where they are filtered out by phagocytic cells such as macrophages. In addition, antigen-collecting cells in the skin, including dendritic cells, may transport foreign materials such as bacteria to these regional nodes. These cells may intercalate, or interdigitate, among the lymphocytes of the lymph nodes and, along with the macrophages, “present” antigen to B and T cells. In this manner, the immune response is initiated.

An analogous situation exists in the blood system. In this case, however, it is the macrophages of the spleen that serve to filter foreign material, such as infectious agents, from the blood. Damaged or old red blood cells are removed in a similar manner. The macrophages then degrade the foreign material and “present” it to B and T lymphocytes in the spleen.

Most of the immune response occurs in the lymph nodes and the spleen. Once the interaction has occurred between the APCs and the lymphocytes, differentiation of the B and T cells begins. The B cells develop into plasma cells, which are essentially antibody-producing factories, while T cells may undergo proliferation. Within the nodes, B and T cells are generally confined to specific areas: the outer cortex for B cells and the underlying paracortex for T cells. Embedded within the cortex are collections of primary nodules, which consist primarily of B cells. Once antigenic stimulation occurs, the cells within the nodules enlarge and proliferate, forming secondary follicles that surround germinal centers. These germinal centers enlarge as B lymphocytes mature and proliferate, and they account for the enlargement of regional lymph nodes in the event of infection. In addition, blood vessels within the node may become enlarged, increasing blood flow. Though some of the activated lymphocytes eventually find their way to the bloodstream, most remain within the lymphatic system. Antibodies produced in response to an infection, however, are transported to the blood.

Since lymph nodes serve as regions of drainage for local tissue, they also represent a route through the body for cancer cells that break away from a tumor. For example, cells from a breast cancer may lodge in regional lymph nodes of the neck or armpit and travel from there to other areas of the body. Although specialized types of lymphocytes capable of killing tumor cells are found in the nodes, some cancer cells may survive. It is for this reason that, during the removal of tumors, localized nodes are examined for evidence of metastasis. If no cancer cells are observed in the nodes, the chances are high that the cancer has not spread.

Mucosal associated lymphatic tissue (MALT) is found along mucosal membranes in regions of the intestines (Peyer’s patches and the appendix) and the throat (tonsils). The tonsils actually consist of a network of three groups of tissues that are located at the base of the tongue, at the back of the throat, and at the roof of the nasopharynx (adenoids). Like the spleen and the lymph nodes, MALT tissues may be sites of germinal centers. Unlike the spleen and lymph nodes, however, these tissues are not enclosed by defined capsules of connective tissue. They may be loosely organized, like the mucosa of the intestinal villi, or they may form organized regions like those of the tonsils and adenoids.

MALT appears to function to protect the body against respiratory or gastrointestinal agents. For example, agents such as bacteria or viruses that enter through the oral or respiratory route may stimulate an immune response by the tonsils. The swelling of the tonsils, tonsillitis, is the result of a localized immune response much like that found in the spleen or the lymph nodes. Germinal centers within the tissue represent areas of B cell maturation and proliferation. In the same way, the Peyer’s patches consist of approximately thirty to forty nodules along the wall of the intestines. Gastrointestinal antigens that penetrate the intestinal wall stimulate germinal centers in these regions.

Digestion products of carbohydrates and proteins are actively transported into the villi of the small intestine and enter the bloodstream directly. Fats, however, enter the blood in a more roundabout way through the lymphatic system. Fats are digested in the small intestine and diffuse into underlying cells. There they are assembled into triglycerides and, along with cholesterol, are enclosed in protein envelopes; the resulting bodies are called chylomicrons. Once these bodies pass into the lacteals of the lymphatic system, the whitish fluid, chyle, is transported to a region at the beginning of the thoracic duct called the cisterna chyli. It is here that the fat enters the bloodstream.

Disorders and Diseases

If the interstitial fluid—that is, the fluid in the tissues—increases beyond the capacity of the lymphatic system to handle the situation, an abnormal accumulation of fluid will build up in the tissue. This creates a situation known as edema. A variety of etiological factors can cause edema. For example, burns, inflammation, and certain allergic reactions may increase the level of capillary permeability. This is particularly true if a large amount of protein is lost as the result of a serious burn.

An increase in capillary hydrostatic pressure may also increase the rate of fluid buildup in the tissues. This may be a by-product of several conditions: congestive heart failure, renal failure, or the use of a variety of drugs (estrogen, phenylbutazone). For example, an increase in the sodium concentration of the blood caused by retention resulting from
renal failure or simply an excess of salt in the diet may cause water retention and increased blood volume. The sequelae include increased fluid leakage and edema. It is for this reason that a reduction in sodium intake is often recommended for those who suffer from this problem. Diuretics may be prescribed to promote the excretion of sodium and water. Similarly, venous obstruction as serious as phlebitis or as minor as the pressure from a tight bandage or clothing may increase hydrostatic pressure and lead to edema.

A buildup of fluid in the lungs, or
pulmonary edema, may occur as a result of congestive heart failure. Hydrostatic pressure in the capillaries of the lungs is relatively low when compared with that of the circulation elsewhere. As a result, the “wetness” of lung tissue is minimal. In patients with serious congestive heart disease, capillary fluid is backed up into the lung (and, indeed, in tissues of the extremities). The result is fluid leakage into the alveoli and bronchioles. Though the lymphatics are capable of removing small amounts of excess fluids, at some point the leakage of plasma and dissolved proteins exceeds the capacity of the lymphatic system to handle the problem. The result is a vicious circle. Since less oxygen is taken up through the lungs, capillary permeability increases. More fluid and protein are then lost. Unless intervention is carried out, the patient may eventually drown in his or her own fluids.

Intervention for pulmonary edema generally involves elevating the head and knees of the patient (Fowler’s position) and the administration of diuretics. A low-sodium diet, allowing for decreased fluid retention, may also relieve some of the stress on the lymphatic system. With time, the number of lymphatic vessels in the lungs may increase, allowing for a greater capacity to remove fluids.

A variety of disorders may directly involve the lymphatic system itself. Lymphedema, or the accumulation of lymph in tissue with subsequent swelling, may result from the absence of lymphatic vessels or from obstructions within the vessels. The symptoms of lymphedema, particularly in the lower extremities, include mild swelling that becomes increasingly severe with time. The problem may be exacerbated by menstruation or pregnancy. In some instances, lymphatic vessels may be absent, either congenitally or because of surgical removal. Diagnosis of the problem often requires the use of lymphangiography (lymphography). In this procedure, a contrast medium is injected, and the lymphatic vessels are examined by means of x-rays.

The etiologic factors associated with lymphatic obstruction may either be congenital or have external causes. Milroy disease is a hereditary lymphedema characterized by chronic obstructions. The obstruction of lymphatic vessels may also be caused by the presence of tumor cells or the infiltration of parasites. For example,
elephantiasis is caused by an infestation of a parasitic worm that obstructs the flow of fluid. The affected limb or region of the body may swell to an astounding degree.

The treatment of most of these disorders is essentially symptomatic. An obstruction may be treated or removed. Often, lymphedema may be treated by having the patient sleep with the feet elevated. A low-salt diet or diuretics may be indicated, and a light massage in the direction of lymph flow may also be helpful.

As is true for all tissues in the body, the cells and organs of the lymphatic system may also undergo malignant transformation. Any neoplasm of lymphoid tissue is referred to as a lymphoma. In general, these are malignant. Though lymphomas may be of different forms and involve different types of cells, they are characterized by enlarged lymph nodes (generally in the neck), fever, and weight loss. Among the more common forms of lymphomas are Hodgkin’s disease and non-Hodgkin lymphomas, a mixed collection of malignant solid tumors originating among the secondary lymphoid tissues of the lymph nodes. Hodgkin disease generally appears first among the cervical or axillary lymph nodes. Its manner of presentation usually allows for early diagnosis and treatment. As a result, the prognosis with early intervention has significantly improved since the 1960s.

Non-Hodgkin lymphomas often develop in less obvious areas of the lymphatic system, such as the gastrointestinal tract, the central nervous system, and the oral and nasal pharynx. The result is that diagnosis is often delayed until the disease has spread, and therefore the prognosis is less optimistic. According to the Lymphoma Research Foundation, 85 percent of non-Hodgkin lymphomas are of B-lymphocyte origin; they often arise within the follicles of the lymph node. There is some evidence that neoplastic transformation may be related to antigen exposure. In some instances, molecular defects of the cell DNA may result in the neoplastic event. Non-Hodgkin lymphomas may also be of T-lymphocyte or, less commonly, macrophage origin. Most treatments of lymphomas include both radiation therapy and chemotherapy.

Perspective and Prospects

The first description of the lymphatic system was made by the Italian anatomist Gasparo Aselli in 1622. Aselli observed the lacteals in the intestinal walls of dogs that he had dissected, and he included diagrams of the lacteals in his text De Lactibus (1627), the first anatomical medical text with color plates.

The role of the lymphatic system in maintaining the fluid dynamics of the body was understood by the beginning of the twentieth century. Much of this knowledge resulted from the early work of the British physiologist Ernest Henry Starling.

Beginning about 1900, Starling’s research centered on the secretion and circulation of lymph. It was known that the lymphatic system as a parallel to blood circulation was found only among the higher vertebrates. This indicated that it had developed relatively late during the course of evolution. There occurred, along with the increasing development of the body’s circulatory system as organisms evolved, an increase in the hydrostatic pressure within the system—that is, as the circulatory system became more complex, blood vessels branched into smaller and thinner capillaries. The pressure within those capillaries became higher. Starling pointed out the significance of the hydrostatic pressures within the capillaries: Fluids and dissolved materials leak out of the capillaries into the tissues.

Starling did not believe, however, that protein was able to leak through the capillary walls. In the 1930s, Cecil Drinker demonstrated that protein is a major constituent of dissolved material in lymph and suggested that an important role of the lymphatic system is the return of this protein to the bloodstream. Drinker was unable to prove definitively that the protein in lymph originated with the blood, and it remained for H. S. Mayerson to confirm this point in the 1940s.

Lymphocytes had been observed in the blood as early as the nineteenth century. Their role in the immune process was not readily apparent, however, and various functions were assigned to them. In 1948, Astrid Fagraeus demonstrated that lymphocytes mature into antibody-producing plasma cells. It remained unclear whether this was the sole purpose of these cells.

In 1956, Bruce Glick and Timothy Chang, working with chickens, discovered that an organ called the bursa, found near the cloaca in the region of the tail, was the site of the production of antibody-producing cells. Their discovery, along with those of Robert Good and Jacques Miller some years later, showed that lymphocytes are not all identical; at least two distinct populations exist. It remained for Henry Claman and his coworkers, in 1966, to demonstrate that these two populations of lymphocytes act cooperatively in the production of antibodies.

In 1969, Ivan Roitt called those lymphocytes that mature in the thymus gland T cells. The lymphocytes that mature in the bursa, an organ found only in birds, were called B cells. Since mammals lack the bursa, B cells in these organisms mature within the bone marrow (considered a bursa equivalent). Once the cells are released from the marrow, they migrate into both the lymphatic system and the bloodstream.

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