| Lymphatic system | |
|---|---|
Human lymphatic system
| |
| Details | |
| Identifiers | |
| Latin | systema lymphoideum |
| MeSH | D008208 |
| TA | A13.0.00.000 |
| FMA | 74594 |
The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the circulatory system and the immune system. It is made up of a large network of lymphatic vessels, lymphatic or lymphoid organs, and lymphoid tissues. The vessels carry a clear fluid called lymph (the Latin word lympha refers to the deity of fresh water, "Lympha") towards the heart.
Unlike the circulatory system, the lymphatic system is not a closed system. The human circulatory system processes an average of 20 litres of blood per day through capillary filtration, which removes plasma from the blood. Roughly 17 litres of the filtered plasma is reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymphatic system is to provide an accessory return route to the blood for the surplus three litres.
The other main function is that of immune defense. Lymph is very similar to blood plasma, in that it contains waste products and cellular debris, together with bacteria and proteins. The cells of the lymph are mostly lymphocytes. Associated lymphoid organs are composed of lymphoid tissue, and are the sites either of lymphocyte production or of lymphocyte activation. These include the lymph nodes (where the highest lymphocyte concentration is found), the spleen, the thymus, and the tonsils. Lymphocytes are initially generated in the bone marrow. The lymphoid organs also contain other types of cells such as stromal cells for support. Lymphoid tissue is also associated with mucosas such as mucosa-associated lymphoid tissue (MALT).
Fluid from circulating blood leaks into the tissues of the body by capillary action, carrying nutrients to the cells. The fluid bathes the tissues as interstitial fluid, collecting waste products, bacteria, and damaged cells, and then drains as lymph into the lymphatic capillaries and lymphatic vessels. These vessels carry the lymph throughout the body, passing through numerous lymph nodes which filter out unwanted materials such as bacteria and damaged cells. Lymph then passes into much larger lymph vessels known as lymph ducts. The right lymphatic duct drains the right side of the region and the much larger left lymphatic duct, known as the thoracic duct, drains the left side of the body. The ducts empty into the subclavian veins to return to the blood circulation. Lymph is moved through the system by muscle contractions. In some vertebrates, a lymph heart is present that pumps the lymph to the veins.
The lymphatic system was first described in the 17th century independently by Olaus Rudbeck and Thomas Bartholin.
Structure
Diagram of vessels and organs in the lymphatic system
The lymphatic system consists of a conducting network of lymphatic
vessels, lymphoid organs, lymphoid tissues, and the circulating lymph.
Primary lymphoid organs
The primary (or central) lymphoid organs generate lymphocytes from immature progenitor cells. The thymus and the bone marrow constitute the primary lymphoid organs involved in the production and early clonal selection of lymphocyte tissues.
Bone marrow
Bone marrow is responsible for both the creation of T cells and the production and maturation of B cells,
which are important cell types of the immune system. From the bone
marrow, B cells immediately join the circulatory system and travel to
secondary lymphoid organs in search of pathogens. T cells, on the other
hand, travel from the bone marrow to the thymus, where they develop
further and mature. Mature T cells then join B cells in search of
pathogens. The other 95% of T cells begin a process of apoptosis, a form of programmed cell death.
Thymus
The thymus increases in size from birth in response to postnatal
antigen stimulation. It is most active during the neonatal and
pre-adolescent periods. At puberty, by the early teens, the thymus
begins to atrophy and regress, with adipose tissue mostly replacing the
thymic stroma. However, residual T lymphopoiesis continues throughout
adult life. The loss or lack of the thymus results in severe
immunodeficiency and subsequent high susceptibility to infection. In
most species, the thymus consists of lobules divided by septa which are
made up of epithelium; it is therefore often considered an epithelial
organ. T cells mature from thymocytes, proliferate, and undergo a
selection process in the thymic cortex before entering the medulla to
interact with epithelial cells.
The thymus provides an inductive environment for the development
of T cells from hematopoietic progenitor cells. In addition, thymic
stromal cells allow for the selection of a functional and self-tolerant T
cell repertoire. Therefore, one of the most important roles of the
thymus is the induction of central tolerance.
Secondary lymphoid organs
The secondary (or peripheral) lymphoid organs (SLO), which include lymph nodes and the spleen, maintain mature naive lymphocytes and initiate an adaptive immune response. The peripheral lymphoid organs are the sites of lymphocyte activation by antigens.
Activation leads to clonal expansion and affinity maturation. Mature
lymphocytes recirculate between the blood and the peripheral lymphoid
organs until they encounter their specific antigen.
Spleen
The main functions of the spleen are:
- to produce immune cells to fight antigens
- to remove particulate matter and aged blood cells, mainly red blood cells
- to produce blood cells during fetal life.
The spleen synthesizes antibodies in its white pulp and removes antibody-coated bacteria and antibody-coated blood cells by way of blood and lymph node circulation. A study published in 2009 using mice found that the spleen contains, in its reserve, half of the body's monocytes within the red pulp. These monocytes, upon moving to injured tissue (such as the heart), turn into dendritic cells and macrophages while promoting tissue healing. The spleen is a center of activity of the mononuclear phagocyte system and can be considered analogous to a large lymph node, as its absence causes a predisposition to certain infections.
Like the thymus, the spleen has only efferent lymphatic vessels. Both the short gastric arteries and the splenic artery supply it with blood. The germinal centers are supplied by arterioles called penicilliary radicles.
Until the fifth month of prenatal development, the spleen creates red blood cells; after birth, the bone marrow is solely responsible for hematopoiesis.
As a major lymphoid organ and a central player in the
reticuloendothelial system, the spleen retains the ability to produce
lymphocytes. The spleen stores red blood cells
and lymphocytes. It can store enough blood cells to help in an
emergency. Up to 25% of lymphocytes can be stored at any one time.
Lymph nodes
A lymph node showing afferent and efferent lymphatic vessels
Regional lymph nodes
A lymph node
is an organized collection of lymphoid tissue, through which the lymph
passes on its way back to the blood. Lymph nodes are located at
intervals along the lymphatic system. Several afferent lymph vessels bring in lymph, which percolates through the substance of the lymph node, and is then drained out by an efferent lymph vessel. Of the nearly 800 lymph nodes in the human body, about 300 are located in the head and neck.
Many are grouped in clusters in different regions, as in the underarm
and abdominal areas. Lymph node clusters are commonly found at the
proximal ends of limbs (groin, armpits) and in the neck, where lymph is
collected from regions of the body likely to sustain pathogen
contamination from injuries. Lymph nodes are particularly numerous in
the mediastinum in the chest, neck, pelvis, axilla, inguinal region, and in association with the blood vessels of the intestines.
The substance of a lymph node consists of lymphoid follicles in an outer portion called the cortex. The inner portion of the node is called the medulla, which is surrounded by the cortex on all sides except for a portion known as the hilum.
The hilum presents as a depression on the surface of the lymph node,
causing the otherwise spherical lymph node to be bean-shaped or ovoid.
The efferent lymph vessel directly emerges from the lymph node at the
hilum. The arteries and veins supplying the lymph node with blood enter
and exit through the hilum. The region of the lymph node called the
paracortex immediately surrounds the medulla. Unlike the cortex, which
has mostly immature T cells, or thymocytes, the paracortex has a mixture of immature and mature T cells. Lymphocytes enter the lymph nodes through specialised high endothelial venules found in the paracortex.
A lymph follicle is a dense collection of lymphocytes, the
number, size, and configuration of which change in accordance with the
functional state of the lymph node. For example, the follicles expand
significantly when encountering a foreign antigen. The selection of B cells, or B lymphocytes, occurs in the germinal centre of the lymph nodes.
Secondary lymphoid tissue provides the environment for the
foreign or altered native molecules (antigens) to interact with the
lymphocytes. It is exemplified by the lymph nodes, and the lymphoid follicles in tonsils, Peyer's patches, spleen, adenoids, skin, etc. that are associated with the mucosa-associated lymphoid tissue (MALT).
In the gastrointestinal wall, the appendix has mucosa resembling that of the colon, but here it is heavily infiltrated with lymphocytes.
Tertiary lymphoid organs
Tertiary lymphoid organs (TLOs) are abnormal lymph node-like structures that form in peripheral tissues at sites of chronic inflammation, such as chronic infection, transplanted organs undergoing graft rejection, some cancers, and autoimmune and autoimmune-related diseases. TLOs are regulated differently from the normal process whereby lymphoid tissues are formed during ontogeny, being dependent on cytokines and hematopoietic cells, but still drain interstitial fluid and transport lymphocytes in response to the same chemical messengers and gradients. TLOs typically contain far fewer lymphocytes, and assume an immune role only when challenged with antigens that result in inflammation. They achieve this by importing the lymphocytes from blood and lymph.
Other lymphoid tissue
Lymphoid tissue associated with the lymphatic system is concerned with immune functions in defending the body against infections and the spread of tumours. It consists of connective tissue formed of reticular fibers, with various types of leukocytes (white blood cells), mostly lymphocytes enmeshed in it, through which the lymph passes. Regions of the lymphoid tissue that are densely packed with lymphocytes are known as lymphoid follicles.
Lymphoid tissue can either be structurally well organized as lymph
nodes or may consist of loosely organized lymphoid follicles known as
the mucosa-associated lymphoid tissue.
The central nervous system also has lymphatic vessels. The search for T cell gateways into and out of the meninges uncovered functional meningeal lymphatic vessels lining the dural sinuses, anatomically integrated into the membrane surrounding the brain.
Lymphatic vessels
Lymph capillaries in the tissue spaces
The lymphatic vessels, also called lymph vessels, are thin-walled vessels that conduct lymph between different parts of the body. They include the tubular vessels of the lymph capillaries, and the larger collecting vessels–the right lymphatic duct and the thoracic duct
(the left lymphatic duct). The lymph capillaries are mainly responsible
for the absorption of interstitial fluid from the tissues, while lymph
vessels propel the absorbed fluid forward into the larger collecting
ducts, where it ultimately returns to the bloodstream via one of the subclavian veins.
The tissues of the lymphatic system are responsible for maintaining the balance of the body fluids.
Its network of capillaries and collecting lymphatic vessels work to
efficiently drain and transport extravasated fluid, along with proteins
and antigens, back to the circulatory system. Numerous intraluminal
valves in the vessels ensure a unidirectional flow of lymph without
reflux. Two valve systems, a primary and a secondary valve system, are used to achieve this unidirectional flow.
The capillaries are blind-ended, and the valves at the ends of
capillaries use specialised junctions together with anchoring filaments
to allow a unidirectional flow to the primary vessels. The collecting
lymphatics, however, act to propel the lymph by the combined actions of
the intraluminal valves and lymphatic muscle cells.
Development
Lymphatic tissues begin to develop by the end of the fifth week of embryonic development. Lymphatic vessels develop from lymph sacs that arise from developing veins, which are derived from mesoderm.
The first lymph sacs to appear are the paired jugular lymph sacs at the junction of the internal jugular and subclavian veins. From the jugular lymph sacs, lymphatic capillary plexuses spread to the thorax, upper limbs, neck and head.
Some of the plexuses enlarge and form lymphatic vessels in their
respective regions. Each jugular lymph sac retains at least one
connection with its jugular vein, the left one developing into the
superior portion of the thoracic duct.
The next lymph sac to appear is the unpaired retroperitoneal
lymph sac at the root of the mesentery of the intestine. It develops
from the primitive vena cava and mesonephric veins. Capillary plexuses
and lymphatic vessels spread from the retroperitoneal lymph sac to the
abdominal viscera and diaphragm. The sac establishes connections with
the cisterna chyli but loses its connections with neighbouring veins.
The last of the lymph sacs, the paired posterior lymph sacs,
develop from the iliac veins. The posterior lymph sacs produce capillary
plexuses and lymphatic vessels of the abdominal wall, pelvic region,
and lower limbs. The posterior lymph sacs join the cisterna chyli and lose their connections with adjacent veins.
With the exception of the anterior part of the sac from which the
cisterna chyli develops, all lymph sacs become invaded by mesenchymal
cells and are converted into groups of lymph nodes.
The spleen develops from mesenchymal cells between layers of the dorsal mesentery of the stomach. The thymus arises as an outgrowth of the third pharyngeal pouch.
Function
The lymphatic system has multiple interrelated functions:
- It is responsible for the removal of interstitial fluid from tissues
- It absorbs and transports fatty acids and fats as chyle from the digestive system
- It transports white blood cells to and from the lymph nodes into the bones
- The lymph transports antigen-presenting cells, such as dendritic cells, to the lymph nodes where an immune response is stimulated.
Fat absorption
Nutrients in food are absorbed via intestinal vili (greatly enlarged in the picture) to blood and lymph. Long-chain fatty acids (and other lipids with similar fat solubility like some medicines) are absorbed to the lymph and move in it enveloped inside chylomicrons.
They move via the thoracic duct of the lymphatic system and finally
enter the blood via the left subclavian vein, thus bypassing the liver's
first-pass metabolism completely.
Lymph vessels called lacteals are at the beginning of the gastrointestinal tract, predominantly in the small intestine. While most other nutrients absorbed by the small intestine are passed on to the portal venous system to drain via the portal vein into the liver for processing, fats (lipids) are passed on to the lymphatic system to be transported to the blood circulation via the thoracic duct. (There are exceptions, for example medium-chain triglycerides
are fatty acid esters of glycerol that passively diffuse from the GI
tract to the portal system.) The enriched lymph originating in the
lymphatics of the small intestine is called chyle. The nutrients that are released into the circulatory system are processed by the liver, having passed through the systemic circulation.
Immune function
The lymphatic system plays a major role in the body's immune system, as the primary site for cells relating to adaptive immune system including T-cells and B-cells. Cells in the lymphatic system react to antigens presented or found by the cells directly or by other dendritic cells.
When an antigen is recognized, an immunological cascade begins
involving the activation and recruitment of more and more cells, the
production of antibodies and cytokines and the recruitment of other immunological cells such as macrophages.
Clinical significance
The study of lymphatic drainage of various organs is important in the
diagnosis, prognosis, and treatment of cancer. The lymphatic system,
because of its closeness to many tissues of the body, is responsible for
carrying cancerous cells between the various parts of the body in a
process called metastasis.
The intervening lymph nodes can trap the cancer cells. If they are not
successful in destroying the cancer cells the nodes may become sites of
secondary tumours.
Enlarged lymph nodes
Lymphadenopathy refers to one or more enlarged lymph nodes. Small groups or individually enlarged lymph nodes are generally reactive in response to infection or inflammation. This is called local lymphadenopathy. When many lymph nodes in different areas of the body are involved, this is called generalised lymphadenopathy. Generalised lymphadenopathy may be caused by infections such as infectious mononucleosis, tuberculosis and HIV, connective tissue diseases such as SLE and rheumatoid arthritis, and cancers, including both cancers of tissue within lymph nodes, discussed below, and metastasis of cancerous cells from other parts of the body, that have arrived via the lymphatic system.
Lymphedema
Lymphedema is the swelling
caused by the accumulation of lymph, which may occur if the lymphatic
system is damaged or has malformations. It usually affects limbs, though
the face, neck and abdomen may also be affected. In an extreme state,
called elephantiasis, the edema progresses to the extent that the skin becomes thick with an appearance similar to the skin on elephant limbs.
Causes are unknown in most cases, but sometimes there is a previous history of severe infection, usually caused by a parasitic disease, such as lymphatic filariasis.
Lymphangiomatosis is a disease involving multiple cysts or lesions formed from lymphatic vessels.
Lymphedema can also occur after surgical removal of lymph nodes
in the armpit (causing the arm to swell due to poor lymphatic drainage)
or groin (causing swelling of the leg). Conventional treatment is by manual lymphatic drainage and compression garments. Two drugs for the treatment of lymphedema are in clinical trials: Lymfactin and Ubenimex/Bestatin.
There is no evidence to suggest that the effects of manual lymphatic drainage are permanent.
Cancer
Cancer of the lymphatic system can be primary or secondary. Lymphoma refers to cancer that arises from lymphatic tissue.
Lymphoid leukaemias and lymphomas are now considered to be tumours of
the same type of cell lineage. They are called "leukaemia" when in the
blood or marrow and "lymphoma" when in lymphatic tissue. They are
grouped together under the name "lymphoid malignancy".
Lymphoma is generally considered as either Hodgkin lymphoma or non-Hodgkin lymphoma. Hodgkin lymphoma is characterised by a particular type of cell, called a Reed–Sternberg cell, visible under microscope. It is associated with past infection with the Epstein–Barr virus, and generally causes a painless "rubbery" lymphadenopathy. It is staged, using Ann Arbor staging. Chemotherapy generally involves the ABVD and may also involve radiotherapy. Non-Hodgkin lymphoma is a cancer characterised by increased proliferation of B-cells or T-cells, generally occurs in an older age group than Hodgkin lymphoma. It is treated according to whether it is high-grade or low-grade, and carries a poorer prognosis than Hodgkin lymphoma.
Lymphangiosarcoma is a malignant soft tissue tumour, whereas lymphangioma is a benign tumour occurring frequently in association with Turner syndrome. Lymphangioleiomyomatosis is a benign tumour of the smooth muscles of the lymphatics that occurs in the lungs.
Lymphoid leukaemia is another form of cancer where the host is devoid of different lymphatic cells.
Other
History
Hippocrates, in the 5th century BC, was one of the first people to mention the lymphatic system. In his work On Joints, he briefly mentioned the lymph nodes in one sentence. Rufus of Ephesus,
a Roman physician, identified the axillary, inguinal and mesenteric
lymph nodes as well as the thymus during the 1st to 2nd century AD. The first mention of lymphatic vessels was in the 3rd century BC by Herophilos, a Greek anatomist living in Alexandria, who incorrectly concluded that the "absorptive veins of the lymphatics," by which he meant the lacteals (lymph vessels of the intestines), drained into the hepatic portal veins, and thus into the liver. The findings of Ruphus and Herophilos were further propagated by the Greek physician Galen,
who described the lacteals and mesenteric lymph nodes which he observed
in his dissection of apes and pigs in the 2nd century AD.
In the mid 16th century, Gabriele Falloppio (discoverer of the fallopian tubes), described what is now known as the lacteals as "coursing over the intestines full of yellow matter." In about 1563 Bartolomeo Eustachi, a professor of anatomy, described the thoracic duct in horses as vena alba thoracis. The next breakthrough came when in 1622 a physician, Gaspare Aselli, identified lymphatic vessels of the intestines in dogs and termed them venue alba et lacteal,
which is now known as simply the lacteals. The lacteals were termed the
fourth kind of vessels (the other three being the artery, vein and
nerve, which was then believed to be a type of vessel), and disproved
Galen's assertion that chyle was carried by the veins. But, he still
believed that the lacteals carried the chyle to the liver (as taught by
Galen). He also identified the thoracic duct but failed to notice its connection with the lacteals. This connection was established by Jean Pecquet in 1651, who found a white fluid mixing with blood in a dog's heart. He suspected that fluid to be chyle
as its flow increased when abdominal pressure was applied. He traced
this fluid to the thoracic duct, which he then followed to a
chyle-filled sac he called the chyli receptaculum, which is now known as the cisternae chyli; further investigations led him to find that lacteals' contents enter the venous system via the thoracic duct. Thus, it was proven convincingly that the lacteals did not terminate in the liver, thus disproving Galen's second idea: that the chyle flowed to the liver. Johann Veslingius drew the earliest sketches of the lacteals in humans in 1647.
The idea that blood recirculates through the body rather than
being produced anew by the liver and the heart was first accepted as a
result of works of William Harvey—a work he published in 1628. In 1652, Olaus Rudbeck
(1630–1702), a Swede, discovered certain transparent vessels in the
liver that contained clear fluid (and not white), and thus named them hepatico-aqueous vessels. He also learned that they emptied into the thoracic duct and that they had valves. He announced his findings in the court of Queen Christina of Sweden, but did not publish his findings for a year, and in the interim similar findings were published by Thomas Bartholin,
who additionally published that such vessels are present everywhere in
the body, not just in the liver. He is also the one to have named them
"lymphatic vessels." This had resulted in a bitter dispute between one of Bartholin's pupils, Martin Bogdan, and Rudbeck, whom he accused of plagiarism.
Galen's ideas prevailed in medicine until the 17th century. It
was thought that blood was produced by the liver from chyle contaminated
with ailments by the intestine and stomach, to which various spirits
were added by other organs, and that this blood was consumed by all the
organs of the body. This theory required that the blood be consumed and
produced many times over. Even in the 17th century, his ideas were
defended by some physicians.
Alexander Monro, of the University of Edinburgh Medical School, was the first to describe the function of the lymphatic system in detail.
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