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Home , Lymphatic system, Red pulp, Thymic involution, White pulp

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Clinical Practice Keywords Immunity//Stem cell production/ Systems of life This article has been Lymphatic system double-blind peer reviewed In this article... ● How and immune cells are produced and developed by the lymphatic system ● Clinical significance of the primary and secondary lymphoid organs ● How the lymphatic system mounts an immune response and filters pathogens

The lymphatic system 2: structure and function of the lymphoid organs

Key points Authors Yamni Nigam is professor in biomedical science; John Knight is associate The lymphoid professor in biomedical science; both at the College of and Health Sciences, organs include the Swansea University. red , , Abstract This article is the second in a six-part series about the lymphatic system. It and clusters of discusses the role of the lymphoid organs, which is to develop and provide immunity nodes for the body. The primary lymphoid organs are the red bone marrow, in which blood and immune cells are produced, and the thymus, where T- mature. The Blood and immune lymph nodes and spleen are the major secondary lymphoid organs; they filter out cells are produced pathogens and maintain the population of mature lymphocytes. inside the red bone marrow, during a Citation Nigam Y, Knight J (2020) The lymphatic system 2: structure and function of process called the lymphoid organs. Nursing Times [online]; 116: 11, 44-48.

The thymus secretes his article discusses the major become either erythrocytes, leucocytes or hormones that are lymphoid organs and their role . Stem cells rapidly multiply to essential for normal in developing and providing make billions of blood cells each day; this immune function Timmunity for the body. The lym- process is known as haematopoiesis and is and develops phoid organs include the red bone marrow, outlined in Fig 2. T-lymphocytes thymus, spleen and clusters of lymph To ensure there is a continuous produc- nodes (Fig 1). They have many functional tion and differentiation of blood cells to The spleen mounts roles in the body, most notably: replace those lost to function or age, hae- the immune l Production of blood cells, including red matopoietic stem cells are present through response and blood cells (erythrocytes), white blood adulthood. In the embryo, blood cells are removes micro- cells (leucocytes) and platelets initially made in the yolk sac but, as devel- organisms and (thrombocytes); opment of the embryo proceeds, this func- damaged red blood l Removal of damaged red blood cells; tion is taken over by the spleen, lymph cells from circulation l Maturation of immune cells; nodes and . Later in gestation, the l Trapping foreign material. bone marrow takes over most haematopoi- Lymph nodes are The red bone marrow and thymus are etic functions so that, at birth, the whole clustered considered to be primary lymphoid skeleton is filled with red bone marrow. throughout the body organs, because the majority of immune Red bone marrow produces all erythro- and filter pathogens cells originate in them. cytes, leucocytes and platelets. Haemat- from lymph, swelling opoietic stem cells in the bone marrow when mounting an The red bone marrow follow either the myeloid or lymphoid lin- immune response Bone marrow is a soft, gelatinous tissue eages to create distinct blood cells (Fig 2); present in the central cavity of long bones these include myeloid progenitor cells such as the femur and humerus. Blood (, , neutrophils, cells and immune cells arise from the bone basophils, eosinophils, erythrocytes, den- marrow; they develop from immature dritic cells and platelets), and lymphoid stem cells (haemocytoblasts), which progenitor cells (T-lymphocytes, B-lym- follow distinct developmental pathways to phocytes and natural killer cells).

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Fig 1. The lymphoid organs in adults weighs around 40g, but in a middle-aged adult it may have shrunk sufficiently to be difficult to locate. By 20 years of age, the Primary lymphoid organs Secondary lymphoid organs thymus is 50% smaller than it was at birth, and by 60 years of age it has shrunk to a sixth of its original size (Bilder, 2016); this Neck (cervical) lymph nodes is called thymic Each of the two lobes of the thymus is surrounded by a capsule, within which are numerous small lobules – typically meas- Thymus uring 2-3mm in width – which are held Armpit (axillary) together by loose . Each lymph nodes lobule consists of follicles that are com- posed of a framework of thyomsin- secreting epithelial cells and a population of T-lymphocytes; these cells are com- Spleen monly referred to as T-cells (the ‘T’ denotes their origin as mature cells from the thymus). Lobules have two distinct areas: l A dense outer cortex that is rich in Peyer’s patches actively dividing T-cells; l An inner medulla, which is much paler in colour and functions as an area of T-cell maturation. In addition to being a major lymphoid Red bone , the thymus is also recognised as marrow (inguinal) part of the because it secretes a family of hormones collectively referred to as thymosin; this is a group of several structurally related hormones secreted by the thymic epithelial cells. These hormones are essential for normal immune function and many members of the thymosin family are used therapeuti- cally to treat , and dis- Some lymphoid cells (lymphocytes) Bone marrow diseases and transplants eases such as multiple sclerosis (Severa et begin life in the red bone marrow and Any disease or disorder that poses a threat al, 2019). become fully formed in the lymphatic to the bone marrow can affect many body organs, including the thymus, spleen and systems, especially if it prevents stem cells Role in T-cell maturation lymph nodes. As is reached and from turning into essential cells. Those T-cells originate as haematopoietic stem growth slows down, physiological conver- known to damage the marrow’s productive cells from the red bone marrow (Fig 2). A sion occurs, changing red bone marrow to ability and destroy stem cells include: population of these haematopoietic stem yellow bone marrow. This entire process is l Leukaemia; cells infiltrate the thymus, dividing fur- completed by the age of 25 years, when red l Hodgkin’s ; ther within the cortical regions of the lob- bone marrow distribution shows its adult l Other . ules then migrating into the medullary pattern in the bones. A growing number of diseases can be regions to mature into active T-cells; this The pattern is characterised by: treated with a bone marrow transplant or process of T-cell maturation is controlled l The presence of red bone marrow in the haematopoietic stem cell transfer; this is by the hormone thymosin. A proportion of axial skeleton (the vertebral bodies, often achieved by harvesting suitable these mature T-cells continually migrate sacral bone and medial parts of the hip donor stem cells from the posterior iliac from the thymus into the blood and other bones) and articular ends of the crests of the hip bone, where the concen- lymphoid organs (spleen and lymph humeral and femoral bones; tration of red bone marrow is highest. nodes), where they play a major role in the l The most distal parts of the skeleton body’s specific immune responses (which being filled with yellow bone marrow The thymus will be discussed in detail in part 3 of this only, which mainly acts as a store for The thymus gland is a bi-lobed, pinkish- series). The importance of these cells is , providing sustenance and grey organ located just above the in apparent in patients who have depleted maintaining the correct environment the , where it rests below the T-cell populations, such as those infected for the bone to function. sternum (breastbone). Structurally, the with HIV. However, under particular conditions, thymus resembles a small bow tie, which One of the most important functions of such as severe blood loss or fever, the gradually atrophies (shrinks) with age. In the thymus is programming T-cells to rec- yellow marrow may revert back to red pre-pubescents, the thymus is a relatively ognise ‘self’ through a process

JENNIFER N.R. SMITH JENNIFER marrow (Malkiewicz and Dziedzic 2012). large and very active organ that, typically, called thymic education. This process

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Fig 2. Haematopoiesis eventually becomes a tributary of the hepatic portal . The spleen is made up of two regions: Haematopoietic l Stroma – comprising the dense outer stem cells capsule with its trabeculae, some fibres and fibroblasts (cells that secrete connective tissue collagen); Eosinophils l Parenchyma – composed of two types Lymphoid Myeloid of intermingling tissue called white progenitor cells progenitor cells pulp and . is a mass of germinal centres Basophils of dividing B-lymphocytes (B-cells), sur- rounded by T-cells and accessory cells, including macrophages and dendritic cells; T-lymphocytes Platelets these cells are arranged as lymphatic nod- Neutrophils ules around branches of the splenic . Monocytes As blood flows into the spleen via the splenic artery, it enters smaller, central of B- lymphocytes Erythrocytes the white pulp, eventually reaching the red pulp. The red pulp is a spongy tissue, accounting for 75% of the splenic volume (Pivkin et al, 2016); it consists of blood-filled venous sinuses and splenic cords. allows mature T-cells to distinguish for- lymphocytes (which are white blood Splenic cords are made up of red and eign, and therefore potentially pathogenic, cells) to enable the adaptive immune white blood cells and plasma cells (anti- material from antigens that belong to the response to begin. body-producing B-cells); therefore, the red body. It has been demonstrated that When foreign antigens reach these pulp primarily functions as a filtration removal of the thymus may lead to an organs, they initiate activa- system for the blood, whereas the white increase in autoimmune diseases, as this tion and subsequent clonal expansion and pulp is where adaptive T- and B-cell ability to recognise self is diminished maturation of these important white blood responses are mounted. The colour of the (Sherer et al, 1999). cells. Mature lymphocytes can then leave white pulp is derived from the closely the secondary organs to enter the circula- packed lymphocytes and the red pulp’s Clinical significance tion, or travel to other areas, and target colour is due to high numbers of erythro- Diseases of the thymus include thymic foreign antigens. cytes (Stewart and McKenzie, 2002). and myasthenia gravis (MG). MG The spleen is the largest lymphoid occurs when the thymus produces anti- organ. Situated in the upper left hypo- Functions bodies that block or destroy the muscle- chondriac region of the abdominal cavity, The spleen has three major functions: receptor sites, causing the muscles to between the diaphragm and the fundus of l To mount an immune response and become weak and easily tired. It most com- the stomach, it primarily functions as a remove micro-organisms from monly affects muscles that control the filter for the blood, bringing it into close circulation; eyes and eyelids, resulting in droopy eye- contact with scavenging l To destroy damaged and worn-out red lids and difficulty making facial expres- (white blood cells in the spleen that will blood cells; sions; chewing, swallowing and speaking seek out and ‘eat’ any pathogens in the l To store platelets (and blood). also become difficult. MG can affect people blood) and lymphocytes. The spleen’s main immunological func- of any age, but typically starts in women Due to its extensive vascularisation, the tion is to remove micro-organisms from aged <40 years and men aged >60 years. spleen is a dark-purplish oval-shaped circulation. The lymphatic nodules are In most cases of either MG or thymic organ; in adults it is approximately 12cm arranged as sleeves around the blood ves- cancer, is recommended. long, 7cm wide and weighs around 150g. sels, bringing blood into the spleen. Within Patients who have had a thymectomy may However, the size of the spleen can vary the white pulp are splenic nodules called develop an known as with circumstance: it diminishes in starva- Malpighian corpuscles, which are rich in Good syndrome, which increases their tion, after heavy exercise and following B-cells, so this portion of lymphoid tissue is susceptibility to bacterial, fungal and viral severe haemorrhage (Gujar et al, 2017), and quick to respond to foreign antigenic stim- opportunistic pathogens; this condition recent investigations indicate an increase in ulation by producing . The walls is, however, relatively rare. size in well-fed individuals and during the of the meshwork of sinuses in the red pulp ingestion of food (Garnitschnig et al, 2020). also contain phagocytes that engulf foreign The spleen The spleen (Fig 3) is enclosed in a dense, particles and cell debris, effectively filtering The spleen and lymph nodes are two major fibro-elastic capsule that protrudes into and removing them from circulation. secondary lymphoid organs that play key the organ as trabeculae; these trabeculae In the spleen’s destruction of old and roles in: constitute the organ’s framework. Blood senescent red blood cells, they are digested l Filtering out and destroying unwanted enters the spleen from the splenic artery by phagocytic macrophages in the red pathogens; and leaves via the splenic vein, both of pulp. The haemoglobin is then split apart

JENNIFER N.R. SMITH JENNIFER l Maintaining the population of mature which are at the hilum; the splenic vein into haem and globin. The globin is broken

Nursing Times [online] November 2020 / Vol 116 Issue 11 46 www.nursingtimes.net Copyright EMAP Publishing 2020 This article is not for distribution except for journal club use Clinical Practice Systems of life down into its constituent amino acids, Fig 3. Cross-section of the spleen which can be utilised in the synthesis of a new . Haem consists of an iron atom surrounded four non-iron (pyrrole) rings. The iron is removed and transported to be stored as ferritin, then reused to make new haemoglobin in the red bone marrow; Capsule of macrophages convert the pyrrole rings into Trabeculae the spleen the green pigment biliverdin and then into the yellow pigment bilirubin. Both are Trabeculae Red pulp transported to the liver bound to plasma and albumin. Bilirubin, the more toxic pigment, is conjugated in the liver to form a less toxic White pulp compound, which is excreted in bile. Hilum with Malpighian The red pulp partly serves to store a large corpuscles reserve of the body’s platelets – up to a third Splenic Lymphatic of the total supply. In some animals vein – particularly athletic mammals such as nodules horses, greyhounds and foxes – the spleen is Splenic artery also an important reservoir of blood, which is released into circulation during times of stress to improve aerobic performance. In , however, the spleen contributes only a small percentage of blood cells into active circulation under physiological stress; the total stored blood volume is A moderate may be man- phagocytose foreign material such as bac- believed to be only 200-250ml (Bakovic et al, aged conservatively, but an extensively teria on contact, and populations of B- and 2005). The capsule of the spleen may con- burst or ruptured spleen may be treated by T-cells. Lymph nodes are crucial to most anti- tract following haemorrhage, releasing this complete and prompt removal (splenec- body-mediated immune responses: when the reserve into circulation in the body. tomy). However, current data supports phagocytic macrophages trap pathogenic The spleen also plays a minor role in successful non-operative management of material, that material is presented to the haematopoiesis: usually occuring in foe- many traumatic splenic injuries, with the lymphocytes so antibodies can be generated. tuses of up to five months’ gestation, intention of reducing the need for com- Each lymph node is supplied by one or erythrocytes, along with the bone marrow, plete removal (Armstrong et al, 2019). more afferent lymphatic vessels, which are produced by the spleen. Patients being treated for certain malig- deliver crude, unmodified lymph directly nant diseases may also require a partial or from neighbouring tissues. A healthy, fully Clinical significance total and, although other functioning node removes the majority of As the spleen is the largest collection of structures such as the bone marrow and pathogens from the lymph before the fluid lymphoid tissue in the body, infections liver can take over some of the functions leaves via one or more efferent lymphatic that cause white proliferation that are usually carried out by the spleen, vessels. In addition to its lymphatic supply, and antigenic stimulation may cause ger- such patients may be at increased risk of each lymph node is supplied with blood minal centres in the organ to expand, . With an overwhelming post- via a small artery; the artery delivers a resulting in its enlargement (spleno- splenectomy infection, there is also an variety of leucocytes, which populate the megaly). This happens in many diseases – increased risk of sepsis, which is associated inner regions of the node. for example, malaria, cirrhosis and leu- with significant morbidity and mortality. When infection is present, the lymph kaemia. The spleen is not usually palpable, Infection is usually with encapsulated path- nodes become increasingly metabolically but an enlarged spleen is palpable during ogens, including Streptococcus pneumoniae, active and their oxygen requirements deep inspiration. Enlargement may also be Haemophilus influenzae and Neisseria menin- increase. A small vein carries deoxygen- caused by any obstruction in blood flow, gitidis. Clinical guidelines to help reduce the ated blood away from each node and for example in the hepatic portal vein. risk of infection advocate education about returns it to the major veins. In times of infection prevention, vaccination and anti- infection, this venous blood may carry a Removal biotic prophylaxis (Arnott et al, 2018). variety of chemical messengers () The anatomical position of the spleen that are produced by the resident leuco- coincides with the left tenth rib. Given its Lymph nodes cytes in the nodes. These cytokines act as proximity to the abdominal wall, it is one Lymph nodes vary in size and shape, but are general warning signals, alerting the body of the most commonly injured organs in typically bean-shaped structures found clus- to the potential threat and activating a blunt abdominal trauma. The spleen is a tered at specific locations throughout the variety of specific immune reactions. fragile organ and, due to its highly vascu- body. Although their size varies, each node larised nature, any injury causing rupture has a characteristic internal structure (Fig 4). Structure will rapidly lead to severe intraperitoneal The central portions of the lymph node The structure of a lymph node is not unlike haemorrhage; death may result due to are essential to its function; here, there are that of the spleen. Each lymph node is massive blood loss and shock. large numbers of fixed macrophages, which divided into several regions:

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“Swollen lymph nodes and Fig 4. Internal structure of a lymph node a fever are sure signs that Fibrous Subcapsular the body is mounting an sinus effective immune response capsule Aerent against an offending lymphatic vessels pathogen” Eerent lymphatic l Fibrous capsule – this forms a protective vessels outer sheath and has trabeculae that extend periodically into the node, Trabecula Hilum subdividing it into small compartments; Medullary l Outer cortex (nodular cortex) – just inside sinus the capsular margin, this consists of Medullary numerous follicles that are rich in B-cells. cord When pathogens are present, these follicles expand to reveal prominent Cortex germinal centres containing actively dividing, -secreting B-cells; Follicle Germinal centre in l  Inner cortex (paracortex) – this is just follicle below the outer cortex and is particularly rich in T-cells, which also continually circulate throughout most other regions of the node; increase in body temperature serves to slow asplenia/hyposplenism reduces the risk of l Medulla – the central inner portion of down bacterial replication, allowing the infections with encapsulated organisms. Clinical Infectious Diseases; 67: 4, 557-561. the node that contains large numbers infection to be dealt with more efficiently Baković D et al (2005) Effect of human splenic of fixed phagocytic macrophages. by the . Swollen lymph contraction on variation in circulating blood cell counts. Clinical and Experimental Pharmacology These continually monitor the lymph nodes and a fever are both sure signs that and Physiology; 32: 11, 944-951. for potentially pathogenic foreign the body is mounting an effective immune Bilder G (2016) Human Biological Aggin: From material (a process known as immuno- response against the offending pathogen; Macromolecules to Organ Systems. Wiley. Garnitschnig L et al (2020) Postprandial dynamics surveillance), which they phagocytose this will be discussed in more detail in part of splenic volume in healthy volunteers. on contact. 3 of this series. Physiological Reports; 8: 2, e14319. Gujar S et al (2017) A cadaveric study of human spleen and its clinical significance. National Journal Clinical significance Other lymphatic components of Clinical Anatomy; 6: 1, 35-41. During infection, antibody-producing Other types of lymphatic tissue also exist. Małkiewicz A, Dziedzic M (2012) Bone marrow reconversion: imaging of physiological changes in B-cells begin to proliferate in the germinal Mucosa-associated lymphoid tissue bone marrow. Polish Journal of Radiology; 77: 4, centres, causing the affected lymph nodes (MALT) is positioned to protect the respir- 45-50. to enlarge and become palpable and tender. atory and gastrointestinal tracts from Pivkin IV et al (2016) Biomechanics of red blood cells in human spleen and consequences for Some of the cytokines released are pyro- by microbes. The following are physiology and disease. Proceedings of the genic (meaning they cause fever) and act made up of MALT: National Academy of Sciences of the United States directly on the thermoregulatory centre in l Gut-associated lymphoid tissue; of America; 113: 28, 7804-7809. Severa M et al (2019) Thymosins in multiple the hypothalamus to increase body tem- l -associated lymphoid tissue; sclerosis and its experimental models: moving perature. As the majority of human patho- l The palatine, lingual and pharyngeal from basic to clinical application. Multiple Sclerosis and Related Disorders; 27: 52-60. gens divide optimally at around 37°C, this . Sherer Y et al (1999) The dual relationship The tonsils are aggregates of lymphatic between thymectomy and : the tissue strategically located to prevent for- kaleidoscope of autoimmune disease. In: Paul S Nursing Times (ed) Autoimmune Reactions. Contemporary eign material and pathogens from entering Immunology. Totowa, NJ: Humana Press. Self-assessment the body. The palatine tonsils are in the Stewart IB, McKenzie DC (2002) The human online , the in the oral spleen during physiological stress. Sports Medicine; 32: 6, 361-369. cavity and the pharyngeal tonsils (ade-

Test your knowledge with Nursing noids) are at the back of the nasal cavity; as CLINICAL Times Self-assessment after reading a result of this, the tonsils themselves are at SERIES Lymphatic system series this article. If you score 80% or more, high risk of infection and Part 1: Structure, function and oedema Oct you will receive a personalised (tonsillitis). This will also be discussed fur- Part 2: Lymphatic organs Nov certificate that you can download and ther in part 3. NT Part 3: Immunity Dec store in your NT Portfolio as CPD or Part 4: Allergies, anaphylaxis and revalidation evidence. References Armstrong RA et al (2019) Successful non-operative anaphylactic shock Jan 2021 management of haemodynamically unstable Part 5: Vaccinations and To take the test, go to: traumatic splenic injuries: 4-year case series in a UK Feb major trauma centre. European Journal of Trauma Part 6: Immunotherapies Mar nursingtimes.net/NTSALymphatics and Emergency Surgery; 45: 5, 933-938.

JENNIFER N.R. SMITH JENNIFER Arnott A et al (2018) A registry for patients with

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