Lymphoid Organs/The organs of the body which comprise the immune system and/or contribute to immune function include the bone marrow, spleen, thymus, lymph nodes, a network of lymphoid tissue along secretory surfaces (i.e., the so-called mucosa-associated lymphoid tissue, MALT), and the skin. Lymphoid organs can be classified in two ways. The first classification is based on the role that organs play in the development of the immune system and/or its ability to elicit a response.
Primary and Secondary Lymphoid Organs
Primary lymphoid organs are those organs in which the production of the cells of the immune system takes place. For example, bone marrow is a primary organ and contains a pluripotent stem cell which serves as the precursor to red blood cells (i.e., erythrocytes) and myeloid progenitors (which ultimately differentiate into granulocytes, mast cells, monocytes, and platelets), in addition to lymphoid progenitors (which ultimately differentiate into the various types of lymphocytes). Hematopoiesis is a general term used to refer to the production of the cells of the blood, and it can be subdivided into erythropoiesis, myelopoiesis, and lymphopoiesis, respectively, based on the cell lineages described previously. Lymphoid progenitors will emerge from the bone marrow and travel to other primary lymphoid organs where the final stages of lymphocyte maturation take place. As described later, mature lymphocytes play a major role in discriminating between self and nonself because they are endowed with surface receptors characterized by tremendous specificity. Lymphoid progenitors which receive their final education in the thymus are called thymus-derived lymphocytes or T cells. The other major subtype of lymphocyte is the B cell, so named because it was originally characterized in the chicken as a lymphoid progenitor which receives its final education in a primary lymphoid organ called the Bursa of Fabricius, an out pocket of the gastrointestinal epithelium. Although there is no Bursa in mammals, fetal liver, spleen, and adult bone marrow are considered the ‘bursal equivalents’ and function as the primary lymphoid organs for the production of B cells. The process of lymphopoiesis takes place within specific regions of the thymus and bursal equivalents called microenvironments and is regulated by specialized cells (bone marrow stromal cells and thymic epithelial cells) and their soluble factors (including the interleukins IL-3, IL-7, IL-9, and IL-12; see Table 1), which comprise the microenvironments. The stages of lymphopoiesis are generally believed to be antigen-independent, where the antigen is defined as any substance which can stimulate a specific immunological reaction. The surface receptors of lymphocytes mentioned previously are directed toward ‘antigen’. Although lymphopoiesis is neither antigen-dependent nor antigen-driven, a role for antigen cannot be excluded because factors secreted during an antigen-specific reaction in the periphery can promote various forms of hematopoiesis in the bone marrow.
Secondary lymphoid organs
Secondary lymphoid organs are those organs in which the antigen-dependent proliferation and differentiation of specific lymphocytes takes place. These organs are responsible for the dissemination of an antigen-specific immune response and include lymph nodes, spleen, and the various types of MALT, which are further defined below. An appreciation for the role that secondary lymphoid organs play in the immune system can be derived from the fact that swollen lymph nodes (i.e., as a consequence of the antigen-specific lymphoproliferation) are a hallmark indicator of certain types of infections.
Internal and External Lymphoid Organs
The second classification of lymphoid organs is based on their location, with some being classified as internal organs and others being classified as external organs. The internal lymphoid organs include the bone marrow, thymus, spleen, and some lymph nodes. The external lymphoid organs include all the components of MALT as well as the lymph nodes draining MALT. As indicated previously, MALT is defined as lymphoid tissue associated with mucosa. This tissue can be subdivided into more specific regions based on the anatomical location, and includes gut-associated lymphoid tissue (including Peyer’s patches and the appendix) and bronchus-associated lymphoid tissue. The skin is another example of an external organ whose contribution to the immune system is sometimes underappreciated. Although the skin does not contain organized lymphoid tissue, there are immune components associated with the skin that are interconnected with other immune organs, leading to the concept of the so-called skin-associated lymphoid tissue. An appreciation for the important role that skin plays as a ‘first line of defense’ in the immune system can be derived from the fact that when this barrier is breached, as occurs following an abrasion and especially so after a severe burn, a serious consequence is an increase in the incidence and severity of infections.
Thymus
The thymus is a specialized organ that “educates” T cells or T lymphocytes, which are part of the adaptive immune system.
Key Points
- Each T cell is specialized to attack a different antigen, but those that attack self-antigens are destroyed by the thymus during selection processes in lymphocyte proliferation and maturation.
- The organ enlarges during childhood, atrophies at puberty, and is generally replaced with fat. Residual T lymphopoiesis continues through adulthood.
- The thymus is composed of two identical lobes in the upper chest. Its main components are the the cortex, which is the site of lymphocyte maturation, and the medulla, which connects the thymus to venous circulation.
- One of the most important roles of the thymus is the maintenance of central tolerance, which works to prevent autoimmune disorders from occurring.
- T-cells are generated in the bone marrow and travel to the thymus in order to mature.
Key Terms
- thymus: A ductless gland consisting mainly of primary lymphatic tissue. It plays an important role in the development of the immune system and produces lymphocytes.
- Central tolerance: The ability for T-cells to avoid perceiving normal host molecules as foreign antigens.
- T lymphocytes: These cells, also called T cells, belong to a group of white blood cells known as lymphocytes and play a central role in cell-mediated immunity.
EXAMPLES
Thymectomy, the surgical removal of the thymus, is done most often to gain access to the heart in surgeries to correct congenital heart defects performed in the neonatal period. In neonates, the relative size of the thymus obstructs surgical access to the heart. Surprisingly, removal of the thymus does not result in a T cell immunodeficiency. This is because sufficient T cells are generated during fetal life prior to birth. These T cells are long-lived and can proliferate by homeostatic proliferation throughout the patient’s lifetime. However, there is evidence of premature immune aging in patients thymectomized during early childhood.
The thymus is a specialized organ of the immune system. It consists of primary lymphoid tissue, which provides a site for the generation and maturation of T lymphocytes, critical cells of the adaptive immune system.
Structure of the Thymus
The thymus is of a pinkish-gray color, soft, and lobulated on its surfaces. The organ enlarges during childhood into adolescence and begins to atrophy at puberty due to hormonal changes. After puberty, the thymus shrinks rapidly with age, eventually becoming almost indistinguishable from the surrounding fatty tissue.
The thymus consists of two lateral lobes placed in close contact along the middle line situated partly in the thorax, resting in the chest beneath the neck. The two lobes differ slightly in size, maybe united or separated, and maybe broken down into smaller lobules. It is covered with a capsule of connective tissue that provides structural support.
Histologically, the thymus contains mature lymphocytes, immature lymphocytes, and stroma, while lobule tissues consist of an inner medulla and an outer cortex. The cortex and medulla play different roles in the development of T cells. The cortex is the site of T cell generation and proliferation, while the medulla connects to the venous bloodstream and allows for transport of mature inactive T cells to the lymph nodes and transport of immature T cells from bone marrow tissue into the thymus cortex for proliferation and maturation.
The function of the Thymus
Thymus: The thymus is the site of T-cell generation and maturation.
The thymus provides an environment for T cells to mature and proliferate, a process called lymphopoiesis. First, immature T cells generated in bone marrow travel to the cortex tissues of the thymus through the bloodstream. Then the immature T cells undergo proliferative expansion, in which they are exposed to growth factors and antigen receptors are formed. Then the T cells are sorted by the thymus so that only T cells that express T-cell receptors (TcRs) and can bind to foreign MHC molecules will survive. The surviving cells will not mistake self-molecules for antigens. Only 2-4% of T cells survive this sorting process. The thymus is most active early in life for building a large reservoir of T cells. Though the removal of the thymus in childhood causes severe immunodeficiency, later in life this is not an issue because of the proliferation of thymus activity early in life.
Central tolerance is another function of the thymus. Autoimmune diseases occur when central tolerance is lost, which causes lymphocytes to recognize host molecules as antigens and attack them, even if those tissues otherwise function normally. The thymus sorts T cells so that they will be inactive towards host molecules, though sometimes a few T cells evade this sorting process and may initiate an autoimmune disease. Though the thymus is most effective at preventing this occurrence, those with certain genetic characteristics (such as altered MHC complexes) may be more likely to develop autoimmune diseases with the few T-cells that aren’t properly selected by the thymus.
Spleen
The spleen, similar to a large lymph node, acts primarily as a blood filter in the mononuclear phagocyte system of the immune system.
Key Points
The primary function of the spleen is to filter old blood cells out of the bloodstream.
Structurally, the spleen is similar to a massive lymph node; however, it filters blood instead of lymph and therefore contains only efferent lymph vessels.
Red pulp mechanically filters old blood using macrophage activity. White pulp is responsible for active immune response by synthesizing antibodies.
The spleen removes some bacteria from the bloodstream, particularly those that cause pneumonia.
The spleen holds extra blood that can help during hypovolemic shock.
Survival is possible with removal of the spleen because the lymph nodes and liver can perform most of the same functions.
Key Terms
- spleen: A ductless vascular gland that destroys old red blood cells, removes debris from the bloodstream, acts as a reservoir of blood, and produces lymphocytes.
- white pulp: The part of the spleen where lymphocytes are maintained in a similar way as in lymph nodes.
- red pulp: The site of blood filtration in the spleen.
EXAMPLES
Survival is possible without a spleen. However, retrospective epidemiological studies of World War II veterans found that those who had their spleens removed on the battlefield showed significant mortality risk from pneumonia and a significant excess of mortality from ischemic heart disease, but not from other conditions.
The spleen is the largest distinct organ of the lymphatic system. Similar in structure to a large lymph node, it acts primarily as a blood filter. Despite this important function, healthy life is possible after removal. The spleen plays important role in regards to red blood cells and the immune system.
Structure of the Spleen
The spleen is located in the left upper quadrant of the abdomen. It is similar to an enlarged lymph node but is a bit more complex. The spleen is made up of two distinct tissue types:
- The red pulp is the site of blood filtration in the spleen. It is made of connective tissue called the cord of Billroth that can fill with blood and contains many macrophages.
- White pulp is secondary lymphoid tissue that is similar to that in the adenoid tonsils. They contain large amounts of lymphocytes and antigen-presenting cells.
Unlike lymph nodes, the spleen possesses only efferent lymphatic vessels, because it only filters blood instead of lymph fluid. The splenic artery forms its primary blood supply. The spleen is unique in respect to its development within the gut because it is derived from mesenchymal tissue rather than endoderm tissue during embryonic development. However, it still shares the same blood supply as the foregut organs in the abdominal cavity.
The function of the Spleen
Spleen: This diagram of the spleen indicates the vein, artery, white pulp, red pulp, and capsule.
The primary function of the spleen is blood filtration. Blood cells have a lifespan of roughly 120 days. When blood passes through the red pulp of the spleen, healthy blood cells easily pass, while older red blood cells are caught phagocytized by the macrophages within. The macrophages also remove pathogens, denatured hemoglobin, and other cellular debris. Iron from old or damaged hemoglobin content in the blood is filtered out and sent to the liver so that new red blood cells can be created. Antigens are also filtered by the red pulp, which may be presented to naive lymphocytes in the white pulp of the spleen. This stimulates the same type of adaptive immune response that occurs in the lymph nodes.
The spleen is also important for generating new red blood cells early in embryonic development, but this function stops after birth. The spleen may also function as a reservoir of blood and platelets during hypovolemic shock, which occurs when overall tissue perfusion falls due to severe dehydration or severe bleeding or hemorrhage. During hypovolemic shock, the spleen can release up to a cup of extra blood to help mitigate the complications of fluid loss.
The spleen is often removed surgically if it becomes damaged or infected. This causes modest increases in circulating white blood cells and platelets, diminished responsiveness to some vaccines, and increased susceptibility to infection by bacteria and protozoa. In particular, there is an increased risk to infection from gram negative bacteria that cause pneumonia. Besides these increased risks, the loss of the spleen does not cause major immune system impairment, and most people will still live normal and healthy lives because the lymph nodes and liver perform the same functions as the spleen. In particular, those with splenomegaly (an enlarged spleen that could rupture) or splenic cancers are typically better off living without their spleen than living with the risk of severe bleeding from a ruptured spleen or the plethora of symptoms caused by splenic cancer and its metastases.
Tonsils
The tonsils are one of the immune system’s first lines of defense against ingested or inhaled foreign pathogens.
Key Points
The four sets of tonsils are the adenoids, palatine tonsils, tubal tonsils,and the lingual tonsils.
Tonsils consist of epithelial tissue with narrow folds called crypts, secondary lymphoid tissue that contains lymphocytes, and M cells that capture antigens in the respiratory tract.
Tonsils tend to reach their largest size near puberty and gradually atrophy thereafter.
Tonsils can become enlarged or inflamed and may be surgically removed in tonsillectomy. Chronic inflammation of the tonsils can cause their cells to increase in size ( hypertrophy ).
Enlarged tonsils can make breathing more difficult and disrupt mucus drainage in the pharynx.
Those with a tonsillectomy show no significant long-term difference in immune system function, though minor changes in immune cell and antibody levels do occur.
Key Terms
- tonsillitis: Inflammation of the tonsils.
- tonsillectomy: The surgical removal of the tonsils, especially the palatine tonsils. Frequently accompanied by an adenoidectomy.
- squamous cell carcinoma: a cancer of squamous cell epithelial tissue.
- tonsils: Paired masses of secondary lymphoid tissue and epithelial tissue found in the pharynx.
The tonsils are small masses of secondary lymphoid tissue located in the pharynx. They function similarly to other types of secondary lymphoid organs and also capture antigens from respiratory tract pathogens.
Location and Structure of the Tonsils
There are four pairs of tonsils located within the pharynx. They function similarly but have a few structural differences.
- The adenoids are located in the wall of the nasopharynx.
- The palatine tonsils are located in the sides of the oropharynx.
- The tubal tonsils are located in the wall of the nasopharynx near the entrance to each Eustachian tube.
- The lingual tonsils are located behind the tongue.
The tonsils are made of secondary lymphoid tissue and covered with an epithelium characteristic of the part of the body where they are located. For example, the adenoids and tubal tonsils are covered with the ciliated pseudostratified columnar epithelium of the nasopharynx, while the palatine and lingual tonsils are made up of the non-keratinized stratified squamous epithelium of the oropharynx. The tonsils also contain very deep and narrow folds in their tissues called crypts. Like the thymus, the tonsils reach their largest size near puberty and gradually atrophy thereafter.
The function of the Tonsils
Tonsils: Palatine tonsils can be seen on the left and right sides at the back of the throat.
The tonsils primarily facilitate adaptive immune responses in the upper respiratory tract, one of the most common pathways for pathogen entry in the body. In a way, the tonsils are the “first line of defense” against potential respiratory pathogens. They contain specialized M cells that collect antigens produced by respiratory tract pathogens. The secondary lymphoid tissue within the tonsils functions like the same type of the tissue in lymph nodes. Captured antigens are presented to B and T cells within the tonsil, then the B cells migrate to germinal centers within the tonsil as an adaptive immune response is initiated. Additionally, evidence exists that suggests that tonsils may play a role in T cell maturation and development like the thymus does, but more research is needed.
Tonsil removal (tonsillectomy) is a common procedure to treat swollen and infected lymph nodes (tonsillitis). It does not appear to cause weakened immune function. Chronic infection of the adenoids can cause adenoid hypertrophy, increases in cell size from repeated damage. Enlarged tonsils can make it more difficult to breath and disrupt normal mucus drainage in the pharynx, so removal is generally recommended in those cases. Squamous cell carcinomas (epithelial tumor) and lymphomas (lymphocyte tumor) can also develop in the tonsillar tissue, and removal is a key treatment. Epidemiological studies show no significant change in immune system function in those that have a tonsillectomy, but minor increases in helper T cell levels and minor decreases in IgA levels (an antibody produced by B cells) were observed.
Cytokine network
| Cytokine | Other names | Cell source | Cell target and actions |
|---|---|---|---|
| Interferon-α (IFN-α) | Leukocytes | B cells: proliferation and differentiation | |
| NK cells: stimulates cytolytic activity | |||
| TC cells: increases generation | |||
| APCs: increases MHC I and II expression | |||
| Others: increases MHC I and FcR expression; induces antiviral state | |||
| IFN-β | Fibroblasts | Similar to IFN-α | |
| IFN-γ | TH cells | B cells: stimulates IgG2a synthesis and inhibits IL-4-induced IgE/IgG1 synthesis | |
| APCs: increases MHC I and II expression | |||
| Macrophages (macs): activates cytolytic activity | |||
| NK cells: stimulates cytolytic activity | |||
| Others: increases MHC I expression; induces antiviral state | |||
| Interleukin 1 (IL-1) | Endogenous pyrogen | Monocytes/macs | TH cells: stimulates production of lymphokines, especially IL-2 and expression of IL-2R |
| B cells: proliferation and differentiation | |||
| Macs: stimulates production of cytokines, IL-1, IL-6, and tumor necrosis factor-α (TNF-α) | |||
| Brain: fever response | |||
| IL-2 | T cell growth factor (GF) | TH cells | TH cells: stimulates proliferation and release of lymphokines (especially TH1 cells) |
| B cells: proliferation and differentiation | |||
| NK cells: activates | |||
| IL-3 | Multicolony stimulating factor (MSF) | TH cells | Bone marrow (BM): promotes growth of stem cells to granulocytes, macs, and mast cells |
| IL-4 | BCGF; B-cell-stimulating factor (BSF) | TH cells (B cells) | B cells: stimulates IgE and IgG1 production and increases MHC II expression |
| TH cells: promotes generation; synergizes with IL-2 | |||
| IL-5 | T-cell-replacing factor (TRF); BCGF II | TH cells | B cells: proliferation and differentiation; stimulates IgA production |
| IL-6 | IFN-γ2 | TH cells | T cells: proliferation and differentiation |
| Monocytes | B cells: proliferation and differentiation | ||
| Endothelial cells | Others: similar profile of activity to IL-1; synergizes with IL-1 | ||
| Fibroblasts | |||
| IL-7 | Lymphopoietin | BM stroma | T cells: induces growth of immature cells |
| B cells: induces growth of immature cells | |||
| IL-8 | Neutrophil-activating factor (NAF) | Monocytes | Neutrophils: chemotaxis; granular exocytosis; respiratory burst |
| IL-9 | TH cells | BM: stimulates growth of erythroid and megakaryocyte precursors | |
| Others: promotes mast cell growth | |||
| B cells: acts synergistically with IL-4 in production of IgE and IgG1 | |||
| IL-10 | TH cells (B cells) | TH1 cells: inhibits lymphokine synthesis | |
| TH2 cells: promotes generation | |||
| Monocytes: inhibits cytokine synthesis | |||
| TC cells: stimulates IL-2-dependent growth | |||
| Mast cells: stimulates growth | |||
| IL-11 | Fibroblasts | BM: stimulates T-dependent antibody response; resembles IL-6 | |
| BM stroma | |||
| IL-12 | NK cell stimulatory factor (NKSF) | Monocytes/macs | NK cells: activates cytotoxicity |
| B cells | TH1 cells: stimulates proliferation and lymphokine production, especially IFN-γ | ||
| TH2 cells: inhibits generation (negative feedback) | |||
| TC cells: activates; synergizes with IL-2 | |||
| IL-13 | P600 | T cells | B cells: promotes growth and differentiation macrophages; inhibits inflammatory cytokine production TH1 cells; inhibits cytokine release |
| IL-15 | T-cell growth factor | T cells | T cells: stimulates growth NK cells; stimulates growth epithelial cells; stimulates growth |
| IL-16 | T cells; mast cells; eosinophils | CD4+ T cells: chemoattractant monocytes; chemoattractant eosinophils; chemoattractant T cells, anti-apoptotic for IL-2-activated cells | |
| IL-17 | MCTLA-8 | CD4+ memory cells | Epithelial cells: induces cytokine production endothelial cells; induces cytokine production fibroblasts; induces cytokine production |
| IL-18 | Interferon-γ inducing factor | ||
| Lymphotoxin | Tumor necrosis factor-β (TNF-β) | T cells | Target cells: kills |
| Macrophage-activating factor | MAF | TD cells | Macs: activates cytotoxicity and proinflammatory actions |
| Macrophage-inhibiting factor | MIF | TD cells | Macs: inhibits migration |
| Transforming growth factor-β (TGF-β) | TGF-β | Lymphocytes | B cells: suppresses growth; inhibits IgM and IgG production; decreases MHC II expression |
| Macs | T cells: suppresses growth | ||
| Monocytes: inhibits TNF production; chemotaxis; induces IL-1 and IL-6 expression | |||
| Tumor necrosis factor-α (TNF-α) | Cachectin (TNF-α) | Monocytes/macs | Tumor cells: cytotoxicity |
| Others: similar profile of activity of IL-1; promotes antiviral state |
Organs that function as barriers
Your skin and mucous membranes are the first line of defense against germs entering from outside the body. They act as a physical barrier with support from the following:
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Antibacterial substances can kill germs right from the start. A certain enzyme found in saliva, the airways and tear fluid destroys the cell walls of bacteria.
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Mucus in the bronchi helps trap many of the germs we breathe in so they can be moved out of the airways by hair-like structures called cilia.
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Stomach acid stops most of the germs that enter the body in the food we eat.
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Harmless bacteria on our skin and many of the mucous membranes in our body also act as part of the immune system.
In addition, the reflexes that cause us to cough and sneeze help to free our airways of germs.
The parts of the immune system
Lymphoid organs
The lymphatic system is composed of:
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Primary lymphoid organs: These organs include the bone marrow and the thymus. They create special immune system cells called lymphocytes.
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Secondary lymphoid organs: These organs include the lymph nodes, the spleen, the tonsils and certain tissue in various mucous membrane layers in the body (for instance in the bowel). It is in these organs where the cells of the immune system do their actual job of fighting off germs and foreign substances.
Bone marrow
Bone marrow is a sponge-like tissue found inside the bones. That is where most immune system cells are produced and then also multiply. These cells move to other organs and tissues through the blood. At birth, many bones contain red bone marrow, which actively creates immune system cells. Over the course of our life, more and more red bone marrow turns into fatty tissue. In adulthood, only a few of our bones still contain red bone marrow, including the ribs, breastbone and the pelvis.
Thymus
The thymus is located behind the breastbone above the heart. This gland-like organ reaches full maturity only in children, and is then slowly transformed to fatty tissue. Special types of immune system cells called thymus cell lymphocytes (T cells) mature in the thymus. Among other tasks, these cells coordinate the processes of the innate and adaptive immune systems. T cells move through the body and constantly monitor the surfaces of all cells for changes.
Lymph nodes
Lymph nodes are small bean-shaped tissues found along the lymphatic vessels. The lymph nodes act as filters. Various immune system cells trap germs in the lymph nodes and activate the creation of special antibodies in the blood. Swollen or painful lymph nodes are a sign that the immune system is active, for example to fight an infection.
Spleen
The spleen is located in the left upper abdomen, beneath the diaphragm, and is responsible for different kinds of jobs:
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It stores various immune system cells. When needed, they move through the blood to other organs. Scavenger cells (phagocytes) in the spleen act as a filter for germs that get into the bloodstream.
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It breaks down red blood cells (erythrocytes).
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It stores and breaks down platelets (thrombocytes), which are responsible for the clotting of blood, among other things.
There is always a lot of blood flowing through the spleen tissue. At the same time this tissue is very soft. In the event of severe injury, for example in an accident, the spleen may rupture easily. Surgery is then usually necessary because otherwise there is a danger of bleeding to death. If the spleen needs to be removed completely, other immune system organs can carry out its roles.
Mucous membranes
The bowel plays a central role in defending the body against germs: More than half of all the body’s cells that produce antibodies are found in the bowel wall, especially in the last part of the small bowel and in the appendix. These cells detect foreign substances, and then mark and destroy them. They also save information about the substances in order to be able to react more quickly the next time. The large bowel also contains harmless bacteria called gastrointestinal or gut flora. Healthy gut flora make it difficult for germs to spread and enter the body.
Mucous membranes support the immune system in other parts of the body, too, such as the respiratory and urinary tracts, and the lining of the vagina. The immune system cells are directly beneath the mucous membranes, where they prevent bacteria and viruses from attaching.
References
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