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Home , Adaptive immune system, Immune system, Lymph node, Red pulp, Tubal tonsil, White pulp

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Clinical Practice Keywords / // Systems of This article has been Lymphatic system double-blind peer reviewed In this article... ● The role of the lymphatic system in providing immune responses ● How different lymphocytes respond to pathogenic micro- and ● The role of the in providing immunity

The lymphatic system 3: its role in the

Key points Authors Yamni Nigam is professor in biomedical science; John Knight is associate The lymphatic professor in biomedical science; both at the College of and Health Sciences, system plays an Swansea University. important role in the immune system Abstract The lymphatic system plays an important role in providing immune responses to harmful micro-organisms and toxins that enter the body. This article, the third in a It produces a range six-part series on the system, discusses its main functions in providing immunity. of cells that detect and kill invading Citation Nigam Y, Knight J (2020) The lymphatic system 3: its role in the immune pathogenic system. Nursing Times [online]; 116: 12, 45-49. micro-organisms and toxins otential (micro- Immune cells of the can deal organisms capable of causing lymphatic system with many ) are ubiquitous in the The immune system includes a vast range pathogens, but Penvironment and can enter the of distributed defence cells: these are the others need a more body via the (through direct contact, leucocytes (white cells). The more- specialised response particularly if the is injured basic innate immune leucocytes are the from lymphocytes through cuts, grazes or burns), the respira- first responders, responsible for imme- tory system (through inhalation), the gut diate and non-specific engagement with a Circulating (through ingestion) and the genito- ; they include phagocytes (cells transports some of urinary tract (through sex or the insertion capable of engulfing and absorbing bac- these cells around of invasive devices such as catheters). teria and other small cells and particles) the body to Although each of these sites is protected such as and dendritic cells, encounter pathogens by unique barriers and defences, some which encounter and indiscriminately ‘eat’ and toxins pathogens can breach these preliminary unwanted microbes or infected cells. defences and enter the body. If innate cells cannot deal with the path- Various ‘checkpoints’ The immune system comprises a range ogen, more-specialised cells known as in the lymphatic of cells – some basic and innate, others lymphocytes need to be ‘introduced’ to a system can raise a extremely specialised – to detect and pathogen to recognise it as a threat, before response when remove pathogens from the body. The lym- they can launch an attack on it. lymph containing phatic system works alongside the pathogens passes immune system to destroy unwanted Macrophages through them pathogens either locally and directly, or by These large-cell phagocytes are derived alerting the whole body to the from (large phagocytic white and helping to mount a wider systemic blood cells); they can be fixed in tissues or . mobile in the blood. Macrophages are The first two articles in this series dis- capable of reeling in microbes with their cussed the role of lymph in supporting the cytoplasmic extensions (pseudopods) and cardiovascular system, and examined the engulfing them; they are tough cells that organs and tissues that make up the lym- survive well and can perform this function phatic system. This article focuses on the many times over. Macrophages are also immune function of the lymphatic system. able to trap antigens (small

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found on the surface of all cells) and pre- Fig 1. Major immune components of the lymphatic system sent them to other leucocytes of the immune system. Healthy cells in the body contain self- antigens, which act as important flags to prevent the immune system from attacking the body’s own cells. Phagocytes recognise pathogens and the toxins they may pro- duce as foreign bodies by the presence of their different (non-self ) antigens; they engulf and sequester (capture/trap) these foreign pathogens, which are then rapidly killed by intracellular digestion. Lymphocytes -associated Lymphocytes are sentinel cells of adaptive lymphoid immunity; they make up 20-30% of circu- lating leucocytes and include B-lympho- Spleen cytes and T-lymphocytes. marrow harbours about 12% of the body’s lympho- cytes, whereas the spleen and lymph nodes Intestine contain approximately 55% of resident Peyer’s patches lymphocytes; the remainder are found in other lymphatic organs and tissues. Free lymphocytes in the blood amount to only about 2% of the population Inguinal lymph (Pabst, 2018). node

B-lymphocytes B-lymphocyte cells (B-cells) are formed and mature in the bone marrow. Once released, they develop the ability to deter- mine which antigens they should react to factories – while a small proportion are other more-specialised lymphocytes to kill (immunocompetence) and which are retained as memory B-cells, able to quickly them. This ‘coating’ of foreign cells by harmless (self-tolerance). Mature B-cells mass produce the same again if molecules is known as opsonisa- colonise secondary lymphoid organs such that particular is encountered in tion and makes the pathogen more attrac- as lymph nodes or the spleen and: future. Plasma cells are capable of pro- tive to circulating phagocytes. l Are responsible for ducing around 2,000 antibodies per Finally, when bound to their corre- (which acts via the humors – fluids second (Alberts et al, 2015). They are usu- sponding antigens, antibodies can activate such as blood or lymph); ally detectable in the humor (plasma) after a system of potent plasma of the l Combat pathogens by producing and 4-7 days and float freely in blood and . This group of 20 or so dispatching antibodies. lymph, binding to foreign antigens on the , once activated, forms a Collectively called immunoglobulins surface of the pathogen or to the that conglomerate – termed a membrane attack (Ig), antibodies are among the most abun- triggered their formation. complex (MAC) – which attacks and rup- dant protein components in the blood and tures pathogens’ membranes leading to cell an important part of the immune system The role of antibodies. Although they cannot and death. The complement system (Alberts et al, 2015). As a naïve B-cell directly destroy antigens or kill pathogens can be activated by antigen-antibody com- becomes fully mature, it can display thou- themselves, the action of antibodies can: plexes or recognition of . sands of membrane-bound antibodies on l Help to inhibit micro-organisms; its surface, and each B-cell has its own l Highlight them for detection and T-lymphocytes unique set of these ready to identify and attack by other immune cells. Pathogens are not always found in fluids; bind to a particular antigen. If a random First, as antibodies bind to the foreign many become intracellular (invade the encounter with a potentially pathogenic pathogens, they neutralise them by physi- cells) where antibodies cannot reach. For- foreign antigen results in binding and trig- cally blocking binding sites on the path- tunately, another branch of adaptive gering of any of these membrane anti- ogen so it cannot attach to tissue cells and immunity can provide more direct cell-to- bodies, it activates the B-cell. cause disease. cell combat. This is cell-mediated immu- The B-cell rapidly clones itself, forming Second, antibodies cause nity and is facilitated by the T-lympho- masses of B-cells, all with the same of pathogens as they can bind to more than cytes (T-cells), which are produced in the instructions for producing the antibody one antigen simultaneously. Agglutinated bone marrow and mature in the thymus designed to fight that particular antigen. pathogens clump and cannot move around gland (see part 2). The majority of these cloned cells become as easily, so it is easier for macrophages to There are a few different types of

JENNIFER N.R. SMITH JENNIFER B-plasma cells – large antibody-producing detect and phagocytose them, and for T-cells, but the two main ones are:

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Fig 2. Immune reactions inside a discussed the importance of tissue drainage and the transport of lymph back into the to ensure Helper T-cell homoeostasis. While lymph is circulating contacting Activated helper around the body, it passes through various displayed antigen T-cell interacts with ‘checkpoint’ sites of the lymphatic system; B-cell and releases these sites include lymph nodes, the , which spleen and various types of mucosa-asso- activate the B-cell ciated lymphoid tissue (MALT) (Fig 1). The lymph nodes, in particular, play a major role in trapping foreign material. Displayed antigen Immunity at the lymph nodes Approximately 600-700 lymph nodes are displaying antigen situated in clusters around the body in Cytokines lymphatic vessels; they range from about stimulate 1-2mm to 2cm in size and are often pal- B-cell to pable in the , armpit and . proliferate These tightly packed balls of lymphoid Antigen cells and protein primarily act to: l Monitor lymph arriving at each node B-cell combining for pathogens that may have entered with antigen Activated B-cell the system; l Attempt to eliminate them before they can cause any damage to the body. l Helper T-cells; acting as the major endogenous pyrogen to The lymph nodes play host to a series of l Cytotoxic T-cells. promote during infection, as well as complex cellular interactions that typically They are able to locate compromised helping B-cells to rapidly undergo prolifer- lead to of residing cells, the lym- body cells (those that have been hijacked ation and clonal expansion. phocytes and macrophages; depending on by pathogens or become cancerous). How- Helper T-cells also play a crucial role in what they detect at the lymph node, they ever, T-cells can only do this if they are helping B-cells to become fully activated to can activate locally in the node or activate ‘told’ to do so by other cells: during phago- produce antibodies. They do this by immunity systemically outside the node. cytosis, phagocytes ingest and break up ‘checking’ that the antigen presented by The structure of lymph nodes is dis- pathogens into numerous tiny molecules. B-cells is one the body needs to react to and cussed in part 2. T-cells are mainly gath- Some of these molecules are moved onto destroy. In fact, helper T-cells play the most ered in the paracortex, whereas B-cells grooved proteins, termed major histocom- vital role in the provision of immunity. cluster primarily in the follicles of the patibility complexes (MHCs), on the sur- outer . Lymph (carrying invader face of the and displayed there. Dendritic cells. These cells are effective APCs antigens, either free or bound to dendritic Cells that can do this are known as antigen- that migrate from the bone marrow into cells) enters nodes via an afferent lym- presenting cells (APCs). peripheral tissues. They are a pivotal link phatic vessel. Macrophages lining the lym- T-cells are unable to recognise whole between the and phatic sinuses of the lymph node may antigens, but they can recognise parts of the . So-called transfer free antigens to T- and B-cells, them when they are displayed on an APC. because their surface membrane looks sim- which are equipped with receptors that are Just as naïve B-cells carry antibodies on ilar to the tree-like of neurones, each capable of recognising specific for- their surface for one specific antigen, naïve dendritic cells are key in activating T-cells eign antigens. helper T-cells have receptors that will only by presenting microbial antigens to them. Antigens usually reach the lymph node bind to one specific combination of MHC Their wispy extensions and surface pattern carried by APCs, which home into the par- and antigen. If these cells meet an APC dis- recognition receptors recognise common acortical region and stimulate antigen- playing the correct MHC-antigen match, features of many microbial pathogens, specific T-cells (Fig 2). If a responsive T-cell the helper T-cells will bind to it. Once making them efficient antigen catchers. encounters a specific antigen on the bound, the helper T-cell is activated and, Dendritic cells bind to and phagocytose antigen-presenting , it with the help of chemical messengers pathogens and, once activated and dis- becomes activated to now proliferate and (cytokines), quickly clones itself to produce playing phagocytosed antigens, migrate differentiate into effector T-cells, resulting many more helper T-cells and cytokines. from tissue into lymphatic vessels. in enlargement of this T-cell zone. Acti- Some of these cytokines now activate vated T-cells leave the lymph node via the cytotoxic T-cells, which can kill marked, The role of lymph and lymph nodes efferent . rogue cells by releasing potent enzymes As potential sites of infection are infil- Stimulation of B-cells in the primary that puncture the target , trated by a dense network of lymphatic follicles of the lymph node results in the resulting in cell death. Cytokines are impor- (see part 1), it is also inevitable development of secondary follicles with tant molecules in the immune system – in that pathogens and/or their antigens will the formation of germinal centres. particular, 1 plays a significant end up circulating in the lymphatic Antigen-activated B-cells migrate to the

JENNIFER N.R. SMITH JENNIFER role in initiating the inflammatory process, system. Parts 1 and 2 of this series medullary cords, where they differentiate

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l Dendritic cells arriving at the spleen Table 1. Clinical significance of lymph node swelling with a foreign antigen present it to Swollen area Location Swelling commonly indicative of T-cells in the periarterial lymphatic sheath, which become activated. T-cells / Neck/ ● Upper now activate B-cells in follicles to tonsils become antibody-producing plasma Axial lymph nodes Armpits ● Lower respiratory tract cells, either in the red or . infections Antibodies leave the follicles to travel ●  of / widely through the systemic circulation; ● Mammary plexus Circular clusters around Mastitis l A pathogen such as a enters the the areolae ● Carcinoma of the breast spleen in the blood. Follicular B-cells Gut-associated Throughout the inner ● Gastrointestinal disturbances come into contact with the virus and lymphoid tissues layer (mucosa) of the ● Infections and malignancies present viral antigen to nearby T-cells. (GALT), also known as Both cells co-stimulate and activate Peyer’s patches each other. The B-cells produce Groin ● Infections/malignancies of the antibody against the virus; l  , urinary Macrophages in the spleen can also system and colon pick up the foreign pathogen or antigen, presenting to T-cells which activate B-cells to produce plasma cells into antibody-producing plasma cells and structurally larger version of a lymph node. and antibody. begin production of specific antibodies The that makes up 75% of spleen The spleen often enlarges when blood- (Fig 2). Antibodies produced in the course tissue has a major job of destroying old red borne infections are present, but splenic of a humoral immune response also leave blood cells and breaking down haem, while enlargement () is also associ- the lymph node predominantly via the the white pulp is fundamental to the adap- ated with other ; one example is efferent lymphatic vessel to systemically tive immune response. In the white pulp, failure, which would affect iron fight the infection. the spleen’s anatomical structure supports breakdown in the splenic red pulp. The immune system at a lymph node both B- and T-cell activation. works in synergy to help defeat pathogens; Surrounding the central arteriole Memory B-cells indeed, it has been shown that follicular bringing blood into the white pulp is the Memory B-cells are able to persist in the B-cells can also undergo to periarterial lymphatic sheath (Fig 3), pre- body, maintaining memory for a given acquire antigen to show helper T-cells (Mar- dominantly harbouring macrophages and antigen for decades; they are most abun- tínez-Riaño et al, 2018). Following B-cell T-cells. Around the sheath is the marginal dant in the spleen, making up 45% of the activation, antigens are sequestered and zone, containing more macrophages and total B-cell population in this , but memory B-cells home into the germinal follicles, which are also fed via a blood cap- they also recirculate in the blood (Hauser centres of the lymph node. illary. Follicles contain naïve B-cells. and Höpken, 2015). In the case of an The white pulp can mount an immune antigen first encountered in the spleen, Lymph node swelling response to foreign invaders arriving in the memory B-cells produced during the Following the events described above, some the blood in a number of ways: primary response tend to congregate in noticeable effects may become apparent. As the antibody-producing B-cells begin to Fig 3. Microanatomy of white pulp of the spleen proliferate in the germinal centres and T-cells robustly clone into effector T-cells, White pulp the scaffolding meshwork of the lymph node (fibroblastic network) Marginal relaxes and becomes elastic and flexible to Renal surface Periarterial Primary lymphatic zone follicle support the large number of expanding Germinal sheath cells. The affected lymph nodes begin to centre Splenic Red pulp enlarge and may become palpable and tender. Health professionals use this fact in localising and tracing the origins of infec- tions at the time of diagnosis (Table 1). As Capsule B-cell action subsides and the T-cells leave the lymph node to travel around the body to Splenic fight the infection, the lymph node mesh- work returns to its original size. Gastric surface Vascular Immunity in the spleen sinusoid The spleen plays an important role in Artery Vein mounting a targeted response to invading

JENNIFER N.R. SMITH JENNIFER pathogens. It is often considered to be a

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Fig 4. Location of mucosal-associated lymphoid tissue One part of GALT, Peyer’s patches, are nodules of lymphoid tissue situated in the distal portion of the . Another, the appendix, situated at the entrance of the , contains Pharyngeal lymphoid tissue that can destroy bacteria to prevent it breaching, or being absorbed by, the intestinal wall. In both GALT and BALT, mucosal is scattered with cells known as M-cells, which can Lingual tonsil trap antigens, small particles or entire micro-organisms and deliver them from the lumen to macrophages and dendritic cells beneath the epithelium. These, in turn, activate B-cells and T-cells lying under the epithelium in the mucosal Tonsils tissue, which proceed to deal with them Adenoids through the humoral and cellular means Lymph nodes previously described.

Conclusion In summary, the lymphatic system forms a major part of the immune system, Bronchus-associated defending the body against infections and lymphoid tissue harmful bacteria or . However, there are circumstances when the immune system becomes overactive and begins to react to substances that are normally harmless. These substances – such as dust or pollen – can cause an allergic reaction. Part 4 of this series on the lymphatic Peyer’s patches system focuses on and the more severe allergic responses, which could lead Di use tissue to or life-threatening anaphy- lactic shock. NT

References Alberts B et al (2015) Molecular Biology of the Cell. Garland Science. Hauser AE, Höpken UE (2015) B-cell localization and the splenic marginal zones, where blood- vessels. It is strategically positioned at migration in health and disease. In: Alt FW et al borne antigens may predominantly col- entry points of particularly sensitive (eds). Molecular Biology of B Cells. Academic Press. Mak TW et al (2014) T-cell development, activation lect. In response to an antigen first encoun- tissue, such as the respiratory and gastro- and effector functions. In: Primer to the Immune tered in a lymph node, some of the memory intestinal tracts, and includes: Response. Academic Cell. B-cells produced remain in the follicle of l Gut-associated lymphoid tissue Martínez-Riaño A et al (2018) Antigen phagocytosis by B cells is required for a potent the lymph node and are ready to react rap- (GALT); humoral response. EMBO Reports; 19: 9, e46016. idly if the antigen is ever conveyed again to l Bronchus-associated lymphoid tissue Pabst R (2018) The bone marrow is not only a the lymph node. However, other memory (BALT); primary lymphoid organ: the critical role for T-lymphocyte migration and housing of long-term l  B-cells may leave the original lymph node The paired palatine (visible at the rear memory plasma cells. European Journal of and enter the blood, circulating among the of the throat), lingual (located at the Immunology; 48: 7, 1096-1100. body’s chain of lymph nodes and main- root of the ) and the naso-

taining peripheral surveillance for the pharyngeal tonsils (adenoids) (Fig 4). CLINICAL antigen (Mak et al, 2014). The tonsils are the largest aggregates of SERIES Lymphatic system lymphatic tissue located in the pharynx; Part 1: Structure, function and oedema Oct Immunity offered by mucosal- together, they form a ring of tissue (Wal- Part 2: Lymphatic organs Nov associated lymphoid tissue deyer’s tonsillar ring) that is ideally situ- Part 3: Immunity Dec The spleen and lymph nodes are not the ated to remove pathogens from the air or Part 4: Allergies, anaphylaxis and only lookout points of the body. Mucosa- before they can enter the or gas- anaphylactic shock Jan 2021 associated lymphoid tissue is a form of dif- trointestinal tract. As a result of stimula- Part 5: and fuse lymphoid tissue, an arrangement of tion by pathogens here, sore throats and Feb lymphoid cells and protein, found in swollen tonsils are often a visible and Part 6: Mar

JENNIFER N.R. SMITH JENNIFER mucous membranes outside the lymphatic painful sign of a viral or other infection.

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