Lymphoid organs: lymph node, spleen and thymus

Lymphoid organs are organised tissues in which lymphocytes are generated, selected, positioned and activated. A useful first-principles distinction is between primary and secondary lymphoid organs. The thymus is a primary lymphoid organ: it provides a specialised environment for T cell development, including cortical and medullary thymic epithelial cells, positive selection and negative selection. The lymph node and spleen are secondary lymphoid organs: they do not generate the initial repertoire but bring rare antigen-specific lymphocytes together with antigen-presenting cells. The spleen filters blood, whereas lymph nodes filter lymph. This division of labour means that blood-borne antigen is sampled in the spleen and tissue-derived antigen, carried by afferent lymph, is sampled in lymph nodes.

Secondary lymphoid organs show several defining features. They filter lymph or blood and sample antigens in those fluids; they allow entry of antigen-loaded dendritic cells and other innate immune cells; and they allow recirculating naive T and B cells that have encountered antigen to extravasate, arrest temporarily, proliferate and differentiate. To achieve this, lymph nodes and spleen are connected during embryogenesis to the lymph and bloodstream and are organised into well-defined areas rich in T or B cells. The connective tissue capsule, the subcapsular sinus and the fibroblastic reticular cell network are not mere scaffolding: they create corridors for cell movement and provide survival and guidance signals. Similar principles apply in chronic inflammation, where plasma cells and lymphocytes increase, lymphangiogenesis is induced and blood vessels acquire high endothelial venule-like properties that favour lymphocyte extravasation.

The thymus should be understood as a selection organ rather than a filtration organ. Its cortex contains immature thymocytes interspersed with cortical thymic epithelial cells; its medulla contains more mature thymocytes, medullary thymic epithelial cells and dendritic cells. The thymus has no afferent lymphatics, so it does not sample tissue lymph in the way a lymph node does; instead, blood-borne progenitors enter and selected T cells leave. Thymic epithelial cells present self-antigen, and medullary thymic epithelial cells express a wide range of tissue-restricted antigens. The organ involutes after puberty, but residual thymic tissue continues to support T cell output. These features explain why thymectomy in adulthood is usually tolerated better than thymectomy in infancy.

Lymph node development illustrates the dialogue between lymphoid tissue inducer cells and stromal organiser cells. Some summaries give embryonic day 14.5 for the first identification of lymph node anlagen in mice; current developmental accounts place the first identifiable anlagen earlier. During secondary lymphoid organ development, lymphoid tissue inducer cells interact with stromal lymphoid tissue organiser cells through lymphotoxin α1β2 signalling to the LTβ receptor. This signalling programme instructs stromal cells to become follicular dendritic cells and high endothelial venules, while chemokines such as CCL19 and CCL21 organise T cell zones. The same molecular toolkit can be reused in chronic inflammation, producing tertiary lymphoid organs in sites such as the lung, thyroid and intestine. The clinical importance of this framework is that lymphoid organs are not fixed anatomical boxes; they are inducible, plastic tissues whose architecture reflects the antigens and inflammatory signals they encounter. ^[3]

A lymph node is a kidney-shaped organ with a convex surface pierced by afferent lymphatic vessels and a concave hilum through which efferent vessels and blood vessels pass. Afferent lymph enters the subcapsular sinus, a space beneath the capsule that contains macrophages and dendritic cells. From there, antigen and antigen-presenting cells move into the cortex. The cortex is organised into follicles, which are B cell-rich structures. A primary follicle is a dense aggregate of naive B cells, follicular dendritic cells and a network of reticular fibres. After antigenic stimulation, a secondary follicle develops: a central germinal centre containing proliferating B cells, tingible body macrophages and follicular dendritic cells, surrounded by a mantle zone of naive B cells. The germinal centre is the site of somatic hypermutation, class switching and affinity selection. Follicular dendritic cells hold antigen-antibody complexes on complement receptors and Fc receptors, allowing B cells to test their receptors against displayed antigen.

The follicle is not isolated from the rest of the node. Afferent lymphatic vessels deliver antigen and antigen-presenting cells to lymph nodes, and efferent vessels serve as routes for cell traffic to downstream lymph nodes. In lymph nodes, dendritic cells accumulate in the subcapsular sinus and transmigrate through the floor of that sinus into the T cell zone, while T cells access the parenchyma through the peripheral medullary sinuses. This means that the follicle sits downstream of antigen entry but upstream of T cell help. Follicular B cells that capture antigen can present peptide on MHC class II to pre-existing or newly arriving T follicular helper cells. That interaction, together with cytokines and co-stimulation, licenses germinal centre reactions. Follicular dendritic cells are themselves instructed by lymphotoxin signals from B cells and stromal cells; without this dialogue, follicular architecture collapses.

The follicle also contains a perifollicular zone that is functionally important, especially in mucosal and splenic tissues. Peripheral lymph nodes, tonsils and intestinal Peyer's patches contained no or few neutrophils, whereas some neutrophils were detected in the perifollicular area of mesenteric lymph nodes. In the spleen, even more neutrophils were detected in the perifollicular area of spleens that had no histological alterations. These neutrophils expressed typical granulocyte molecules such as elastase, myeloperoxidase and the adhesion molecule CD15, and formed projections interacting with outer marginal zone and perifollicular B cells weakly expressing IgD. This does not make the follicle a neutrophil organ, but it shows that the perifollicular niche is immunologically active and not merely a passive border.

A practical way to read a lymph node section is to ask three questions. First, is the follicle primary or secondary? A primary follicle indicates a resting B cell aggregate, whereas a secondary follicle with a germinal centre indicates an active response. Second, is the mantle zone intact? A preserved mantle zone suggests an organised reaction, while its loss can occur in certain lymphomas and in immunodeficiency. Third, is the perifollicular zone expanded? Expansion can reflect antigen load, inflammation or a mucosal influence. These are descriptive principles rather than diagnostic criteria, but they help students connect structure to function. The follicle is therefore both a B cell reservoir and a selection arena: naive B cells enter, antigen is displayed, T cell help is delivered, and selected clones emerge as antibody-secreting plasma cells or memory B cells.

The paracortex is the T cell-dependent zone of the lymph node. It lies between the follicles and the medulla and contains high endothelial venules, fibroblastic reticular cells, interdigitating dendritic cells and recirculating T cells. Naive T cells enter the node from the blood through high endothelial venules, a process dependent on selectins, chemokines and integrins. Once in the paracortex, T cells scan dendritic cells for peptide-MHC complexes. If a cognate antigen is recognised, the T cell arrests, receives co-stimulation, proliferates and differentiates into effector and memory cells. The paracortex is therefore the site where antigen presentation is translated into adaptive T cell responses.

The paracortex is also a transit zone. Afferent lymphatic vessels deliver antigen and antigen-presenting cells to lymph nodes, and efferent vessels serve as routes for cell traffic to downstream lymph nodes. In lymph nodes, dendritic cells accumulate in the subcapsular sinus and transmigrate through the floor of that sinus into the T cell zone, while T cells access the parenchyma through the peripheral medullary sinuses. This arrangement means that dendritic cells carrying tissue-derived antigen move inward towards T cells, while T cells move through the parenchyma in search of their cognate antigen. The high endothelial venules are specialised post-capillary venules with plump endothelial cells; they allow lymphocytes to leave the blood and enter the node. The fibroblastic reticular cell network provides a physical scaffold and guidance tracks, and it also secretes chemokines that keep T cells and dendritic cells in the paracortex. Without this stromal network, the node would lose its compartmental organisation and efficient T cell scanning would be impaired.

Egress from the lymph node is regulated in part by the high concentration of sphingosine-1-phosphate in the lymph and the re-expression of the receptor S1P1 on T cells as they leave the node and enter into the efferent lymph. This is a useful principle: the node is not a dead-end filter but a transit organ. Cells enter through high endothelial venules and afferent lymph, spend hours to days in the parenchyma, and leave through medullary sinuses and efferent lymph. The medulla contains medullary cords, which are rich in plasma cells and macrophages, and medullary sinuses, which are continuous with efferent lymphatics. Medullary macrophages remove particulate antigen, apoptotic cells and debris, while plasma cells secrete antibody into the efferent lymph and blood. The medulla therefore performs two functions: it is a filtration and scavenging zone, and it is an output zone for antibody and for lymphocytes leaving the node.

Lymph node architecture is maintained by stromal cells and by continuous lymphocyte traffic. When inflammation becomes chronic, plasma cells and lymphocytes gradually increase in number, lymphangiogenesis is induced, and blood vessels acquire characteristics of high endothelial venules specialised in allowing extravasation of lymphocytes. In some conditions, the chronic infiltrate organises into structured lesions with distinct T and B cell-rich aggregates; these are called ectopic lymphoid tissue, lymphoid tissue neogenesis or tertiary lymphoid organs. The paracortex and medulla are therefore best seen as adaptable compartments: they can expand, reorganise and acquire new vascular features in response to persistent antigen. A useful clinical corollary is that lymphadenopathy can reflect follicular hyperplasia, paracortical expansion or medullary plasmacytosis, depending on which compartment is driving the response. The pattern of expansion, rather than size alone, helps explain why different immune stimuli produce different histological appearances.

Lymphatic drainage follows a general rule: lymph travels from tissues through initial lymphatics to regional lymph nodes, then through efferent vessels to downstream nodes and eventually to central collecting ducts. Along the way, nodes act as filters and as immunological sampling stations. The exact route depends on the organ and on anatomical boundaries such as the dentate line, the mesenteric border and the hepatic ligaments. In the abdomen, the stomach provides a clear teaching example. Lymph from the proximal portion of the stomach drains into the superior gastric nodes surrounding the left gastric artery, while lymph from the distal portion of the lesser curvature drains into the suprapyloric nodes. Lymph from the body and fundus drains along the left gastroepiploic and short gastric arteries to the pancreaticosplenic lymph nodes, and lymph along the right gastroepiploic vessels drains into the subpyloric nodes. All lymph from the stomach eventually passes to the coeliac nodes located around the root of the coeliac artery.

The duodenum shows how anterior and posterior lymphatic groups can differ. The anterior group drains into the pancreaticoduodenal nodes located along the superior and inferior pancreaticoduodenal arteries and into pyloric nodes located along the gastroduodenal artery; the posterior group connects posteriorly to the head of the pancreas and drains into the superior mesenteric nodes; the efferent vessels from the duodenum drain into the coeliac nodes. The jejunum and ileum have lymphatic plexuses in their walls that drain into mesenteric nodes, with numerous nodes along the arteries adjacent to the intestine and in the proximal part of the superior mesenteric artery, draining to the superior mesenteric nodes. The terminal ileum drains into ileocolic nodes along the branches of the ileocolic artery. The colon follows a sequential relay: lymph flows to epicolic nodes on the colon, then paracolic nodes along the mesenteric border, then intermediate mesocolic nodes along the colic arteries, and then to superior or inferior mesenteric nodes.

The rectum and anus illustrate boundary-dependent drainage. Lymph from the upper rectum ascends along the superior rectal vessels and passes to the inferior mesenteric nodes; lymph from the lower rectum and anus above the dentate line drains into the internal iliac nodes; lymphatics from the anus below the dentate line drain into the superficial inguinal nodes and then to the external iliac nodes. The regional lymph nodes for anal cancer are the mesorectal, inguinal, superior rectal (haemorrhoidal), external iliac, and internal iliac (hypogastric) nodes. The liver has superficial and deep pathways: superficial networks under the capsule drain to diaphragmatic, phrenic and hepatic hilar nodes, while deep networks along hepatic veins drain to nodes around the inferior vena cava above the diaphragm and deep networks following portal veins drain to hepatic hilar nodes and then to hepatoduodenal ligament nodes. Pancreatic drainage differs between head and body: the head and neck drain through pancreaticoduodenal and pyloric nodes to coeliac, hepatic and superior mesenteric nodes, whereas the body and tail follow the splenic vessels to the coeliac node. For perihilar cholangiocarcinoma, AJCC staging treats nodes in the hepatoduodenal ligament as regional and posterior pancreaticoduodenal nodes as non-regional.

Drainage is not fixed after surgery or radiotherapy. In a re-operative sentinel lymph node biopsy series for ipsilateral breast tumour recurrence, lymphatic drainage was visualised in 80% of the AX group and 95% of the non-AX group. Preoperative lymphoscintigraphy identified at least one sentinel lymph node, defined as a re-SLN, in 121 (89%) of the 136 patients. In the non-AX group, lymphatic drainage was visualised in 96% of patients without radiotherapy and 93% of those with radiotherapy. Re-SLNs were visualised at the ipsilateral axilla in 98% of patients without radiotherapy and in 64% of those with radiotherapy. Aberrant drainage was significantly more frequent in patients with radiotherapy (60%) than in those without radiotherapy (19%). More than half (52%) of patients with radiotherapy showed aberrant drainage to the contralateral axilla, whereas only 2% of those without radiotherapy did. In the AX group, aberrant drainage to the contralateral axilla was observed in nearly two-thirds (64%) of patients with radiotherapy but in 5% of those without radiotherapy. The visualisation rate was markedly low (71%) in patients in whom 20 or more lymph nodes had been removed in prior surgery. Lymphatic drainage was visualised at the ipsilateral axilla in 87% of patients in the non-AX group and in 52% in the AX group. Aberrant drainage was visualised significantly more frequently in the AX group (75%) than in the non-AX group (33%). Lymphatic drainage was visualised at the internal mammary chain in 16% of the non-AX group and 55% of the AX group. These observations reinforce a general principle: lymphatic channels follow anatomy, but obstruction, dissection and irradiation can reroute flow. ^[4]

The spleen is the largest secondary lymphoid organ and the main filter for blood-borne antigen. It has a white pulp and a red pulp. White pulp is the lymphoid compartment: it consists of periarteriolar lymphoid sheaths rich in T cells, follicles rich in B cells, and a marginal zone that surrounds the follicles and interfaces with the red pulp. The marginal zone contains marginal zone B cells, macrophages and dendritic cells. It samples blood-borne antigen and is important for responses to encapsulated bacteria and for T-independent antibody production. The red pulp is the filtration compartment: it contains splenic cords, splenic sinuses lined by sinusoidal endothelial cells, macrophages and plasma cells. Red pulp macrophages remove aged erythrocytes, antibody-coated cells and particulate antigen. Blood enters the spleen through the splenic artery, passes through central arterioles and then through the marginal zone and red pulp before leaving via splenic veins.

The marginal zone is not only a B cell reservoir. Neutrophils may generate an innate layer of antimicrobial immunoglobulin defence by undergoing marginal zone B-helper reprogramming in the spleen. In homeostatic conditions, peripheral lymph nodes, tonsils and intestinal Peyer's patches contained no or few neutrophils, whereas some neutrophils were detected in the perifollicular area of mesenteric lymph nodes; even more neutrophils were detected in the perifollicular area of spleens that had no histological alterations. Splenic neutrophils expressed typical granulocyte molecules such as elastase, myeloperoxidase and CD15, and formed projections interacting with outer marginal zone and perifollicular B cells weakly expressing IgD. Consistent with a homeostatic role, perifollicular neutrophils were also detected in spleens from healthy rhesus macaques and mice; simian neutrophils expressed elastase and were positioned between marginal zone B cells and red pulp sinusoidal endothelial cells, whereas mouse neutrophils expressed Ly6G and surrounded a marginal zone area containing B cells weakly positive for IgD and macrophages strongly positive for MOMA-1.

The cellular composition of lymphoid organs differs markedly. Neutrophils amounted to 10%, 2%, 0.5% and 0.3% of total cells in spleens, mesenteric lymph nodes, peripheral lymph nodes and tonsils, respectively. In spleen and mesenteric lymph nodes, marginal zone B cells co-expressing IgD and the memory molecule CD27 were more abundant than in other lymphoid tissues and strongly expressed the complement receptor CD21. Enzyme-linked immunosorbent assay demonstrated induction of IgM secretion by marginal zone B cells exposed to splenic but not circulating neutrophils, which were therefore defined as B-helper and conventional neutrophils, respectively. This illustrates a broader principle: the spleen is not merely a graveyard for red cells; it is an immunological organ in which innate cells can shape B cell responses.

The perifollicular zone contains B-helper neutrophils that form DNA-containing NET-like projections in close contact with B cells expressing IgD. Compared with red pulp B-helper neutrophils, outer marginal zone and perifollicular B-helper neutrophils had more abundant projections and often interacted with B cells expressing activation-induced cytidine deaminase, a hallmark of ongoing immunoglobulin gene diversification in germinal centre and some extrafollicular B cells. By expressing inhibitors of proteases, reactive oxygen species and TNF, such as progranulin and SLPI, B-helper neutrophils may clear antigen and deliver B-helper signals without causing inflammatory tissue damage. These cells occupied lymphoid sites characterised by continuous antigenic filtration, including presence of bacterial 16S RNA; although largely blocked by mesenteric lymph nodes, some mucosal antigens undergo systemic translocation to influence immune cells, and spleens and mesenteric lymph nodes contained perifollicular lipopolysaccharide in addition to B-helper neutrophils, but lipopolysaccharide was only detectable after post-natal mucosal colonisation by bacteria.

Red pulp function depends on the open circulation and on sinusoidal endothelial cells. Splenic sinuses are lined by elongated endothelial cells with stress fibres and interendothelial slits. Red cells must deform to pass through these slits; aged or rigid cells are retained and phagocytosed by red pulp macrophages. Plasma cells in the red pulp secrete antibody into the blood. Thus, the spleen links innate filtration with adaptive antibody production. In summary, lymph nodes, spleen and thymus are complementary: the thymus selects T cells, lymph nodes sample lymph and organise B and T cell responses, and the spleen samples blood while maintaining red cell quality control.

The marginal zone is the strip of lymphoid tissue that sits between the white pulp follicle and the red pulp, at the interface where blood leaves the arterial circulation and enters the slow, open sinuses of the spleen. Position matters here: the marginal zone is positioned at the interface between the circulation and the immune system. Blood-borne antigen arrives continuously, so the cells stationed in this strip must be able to respond quickly and without waiting for a germinal centre to form. Marginal zone B cells are in a state of active readiness that enables them to mount prompt immunoglobulin responses to blood-borne antigens through a pathway that does not require a T cell-dependent germinal centre reaction. In humans, marginal zone B cells have a circulating counterpart, contain mutated immunoglobulin genes and express surface IgM and IgD together with the memory molecule CD27. This distinguishes them from hypermutated IgM memory B cells, which arise from a canonical germinal centre reaction and express surface IgM and CD27 but not IgD. The practical consequence is that a marginal zone response can be rapid and largely T-independent, but it is still refined: the cells carry mutated immunoglobulin genes, so diversification has occurred.

Neutrophils are part of this niche. They home to the marginal zone in response to blood-borne bacteria. Neutrophils colonised peri-marginal zone areas after post-natal mucosal colonisation by microbes and enhanced their B-helper function upon receiving reprogramming signals from splenic sinusoidal endothelial cells, including interleukin 10. These reprogrammed splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating marginal zone B cells through a mechanism involving the cytokines BAFF, APRIL and IL-21. In the presence of these B-helper neutrophils, marginal zone B cells accumulated more mutations in the VH3-23 gene, which is often utilised by marginal zone B cells. Neutrophils therefore do more than phagocytose: they can stimulate marginal zone B cells to undergo somatic hypermutation in addition to class switch recombination and plasma cell differentiation.

The timing of this colonisation is instructive. Splenic colonisation by B-helper neutrophils started during fetal life but strongly increased as early as two days after birth, a time coinciding with mucosal colonisation by bacteria. Perifollicular areas contained lipopolysaccharide in adult spleens and mesenteric lymph nodes but not in fetal spleens and peripheral lymph nodes. The niche is therefore built and then furnished: the stromal scaffold is present before birth, but the B-helper population expands only once the mucosa is colonised. This explains why the splenic marginal zone is best understood as a mucosal-interface organ inside the bloodstream.

The zone is plastic and can be damaged. In the presence of inflammation caused by sepsis, HIV infection, hyper-IgD syndrome or systemic lupus erythematosus, B-helper neutrophils became disorganised and infiltrated lymphoid follicles, possibly to present antigen to T cells. Inflammation was associated with loss of marginal zone tissue and of the B-helper subset with predominant marginal zone B-helper activity. This is a recurring theme in lymphoid organs: the same cells that provide homeostatic help can, under inflammatory pressure, leave their post and contribute to follicular infiltrates.

Malignant transformation of this compartment produces marginal zone lymphoma, an indolent B-cell lymphoma arising from marginal zone B cells within lymphoid follicles, accounting for approximately 5 per cent to 15 per cent of non-Hodgkin lymphomas^[1]. The condition is characterised by diagnostic challenges and diverse treatment options^[1]. Clinically, the take-home is that marginal zone biology links innate sensors, stromal cells, B cells and antibody output; disturbance at any of these levels can produce immunodeficiency, autoimmunity or lymphoma.

Removing or losing splenic function removes the body's main blood-facing B cell organ. The reasoning from first principles is straightforward. Encapsulated bacteria resist phagocytosis unless they are coated with antibody and complement. The marginal zone exists precisely to provide that rapid antibody coat: it is a B cell area specialised in T-independent immunoglobulin responses to circulating antigen. With the spleen absent or functionally silent, blood-borne organisms pass through the circulation with less antibody coating, less complement deposition and less clearance by red pulp macrophages. The result is a susceptibility to fulminant bloodstream infection, which can progress from fever to shock within hours.

The organisms that matter most are the encapsulated ones: Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b; Gram-negative organisms such as Capnocytophaga after animal bites are also of concern. Babesia causes babesiosis, which is a distinct protozoal infection from malaria, and both are of concern in asplenic patients. These are ordinary clinical associations rather than figures from a trial, so they are stated in general terms. The same logic explains why the risk is life-long rather than transient: the anatomical niche is not replaced by another organ, and hepatic clearance cannot fully substitute for splenic marginal zone antibody production.

Asplenia may be anatomical or functional. Anatomical causes include surgical splenectomy for trauma, immune thrombocytopenia, hereditary spherocytosis, staging or tumour clearance, and gastric or pancreatic surgery in which the splenic hilum is sacrificed. Functional causes include sickle cell disease with repeated infarction, coeliac disease, splenic irradiation, and haematological infiltration. Congenital asplenia is rare but important because it may present in infancy with overwhelming sepsis. In all of these, the peripheral blood film may show Howell-Jolly bodies, target cells and Pappenheimer bodies, and ultrasound or radionuclide imaging may confirm absent or shrunken splenic tissue.

Management principles are preventive. Patients are educated about the risk of fever and about the need to seek urgent assessment rather than wait. Vaccination is directed against the encapsulated organisms, with pneumococcal, meningococcal and Haemophilus influenzae type b coverage, and timing around elective splenectomy is planned so that responses are generated before the organ is removed. Antibiotic prophylaxis, usually a penicillin, is used particularly in the early years after splenectomy and in children, and some patients continue it long term. Prompt empirical antibiotics for any febrile illness are the mainstay of survival, and patients are advised to carry a record of their asplenic status. Malaria advice and precautions against animal bites are part of the same conversation.

Two further points deserve emphasis. First, the risk is not confined to bacteria: protozoal infection, notably babesiosis, can be severe in asplenic patients, and travel advice must reflect this. Second, the spleen has other roles beyond defence, including removal of aged red cells and platelets and a reservoir function, so asplenic patients may show thrombocytosis and atypical red cell morphology. These are generally benign consequences, but they can confuse interpretation of blood counts in a patient who is unwell. The unifying clinical message is that asplenia is a state of impaired blood-borne immune surveillance, and the clinician's task is to anticipate the organisms that exploit it.

The thymus arises from the endoderm of the third pharyngeal pouch, with contributions from the corresponding cleft ectoderm and from neural crest-derived mesenchyme. The two primordia migrate caudally and medially into the superior mediastinum, where they fuse and are colonised by blood-borne lymphoid progenitors. Epithelial development depends on the transcription factor Foxn1; without it, the thymic epithelium fails to differentiate and T cell development is severely impaired. This is why thymic aplasia presents with profound T cell deficiency and susceptibility to viral and fungal infection, in contrast to asplenia, which affects antibody responses to encapsulated bacteria.

The mature organ is divided into lobules by septa, each with an outer cortex and an inner medulla. The cortex contains cortical thymic epithelial cells and dense populations of immature thymocytes. Here, thymocytes test their T cell receptors against self-peptide presented on MHC molecules; those that fail to recognise self-MHC at all die by neglect, and those that recognise it too strongly may be deleted. Surviving cells move to the medulla, where medullary thymic epithelial cells express a wide range of tissue-restricted antigens under the control of AIRE, allowing deletion of strongly self-reactive clones. The medulla also contains Hassall's corpuscles, dendritic cells and developing regulatory T cells. The output is a repertoire that can recognise foreign peptide in the context of self-MHC while tolerating self.

After puberty the thymus involutes, with adipose and fibrous tissue replacing much of the cortex, but it does not disappear. Residual thymic tissue continues to support naive T cell output, and the organ can regenerate after stress such as chemotherapy or infection. This is why thymectomy in an adult is usually tolerated, whereas in infancy it removes a capacity that is harder to replace. The finding of a small thymus on imaging in an adult is therefore normal, not pathological, and should not prompt investigation in the absence of other features.

Thymoma is a neoplasm of thymic epithelial cells. It is typically a well-circumscribed, lobulated anterior mediastinal mass, and it is distinguished from thymic hyperplasia, lymphoma and germ cell tumours. Many thymomas are asymptomatic and are found incidentally; others cause local effects such as cough, chest discomfort or superior vena cava obstruction. The most important association is myasthenia gravis, caused by autoantibodies against the acetylcholine receptor or related proteins. Other associations include pure red cell aplasia and hypogammaglobulinaemia, and the combination of thymoma with immunodeficiency is important to recognise because it changes infection risk. Thymic carcinoma is a separate, more aggressive epithelial malignancy and should not be confused with thymoma.

Management rests on resection where feasible, with staging based on invasion of surrounding structures and on histological classification. The key principle is that the tumour is judged by its epithelial component, while the lymphocyte-rich background is reactive. This makes small biopsies hard to interpret and explains why complete excision with careful sampling is the preferred approach. Invasion of the capsule and adjacent structures predicts recurrence, and postoperative radiotherapy or systemic therapy is considered in more advanced disease. Thymoma is also an illustration of a broader rule: tumours of a primary lymphoid organ disturb selection, and the resulting autoimmunity may be the first clinical clue.

Several confusions recur when students and clinicians look at lymphoid tissue. The first is to treat the marginal zone as a passive border. It is an active B cell area specialised for T-independent responses to circulating antigen, and it is populated by reprogrammed B-helper neutrophils that deliver BAFF, APRIL and IL-21 signals. A second pitfall is to assume that neutrophils in a lymphoid organ mean infection: peri-marginal zone neutrophils are found in normal, histologically unaltered spleens, and their organisation is lost in inflammation rather than gained.

A third pitfall concerns organised lymphoid aggregates in chronic inflammation. Not every dense infiltrate is a tertiary lymphoid organ. According to pathologists, the term tertiary lymphoid organ can only be used when all the following criteria are fulfilled: the organised infiltrate contains anatomically distinct yet adjacent T and B cell compartments; the T cell area contains an extensive network of fibroblastic reticular cells; high endothelial venules that are PNAd-positive or MECA-79-positive are present in the T cell area; there is evidence of B cell class switching and germinal centre reactions in the B cell follicles; activation-induced cytidine deaminase enzyme is present; and follicular dendritic cells are present. Often not all criteria are fulfilled, but the organised structure can still function as a tertiary lymphoid organ. That caveat matters: a partially organised infiltrate may be biologically relevant without meeting every morphological criterion.

A fourth pitfall is to forget the physical limits of conduits. Conduits extend from the subcapsular sinus through the cortex and are micrometre-scale in diameter. The pores within their collagen core are about 4 to 5 nanometres, and this core limits access to molecules larger than 70 kDa. Small antigens can reach the T cell zone quickly through these channels, but large antigens and particulate material must be carried by cells. Reasoning about which antigens reach which compartment without this constraint leads to false predictions about how a lymph node handles a virus, a bacterium or a vaccine. ^[2]

A fifth pitfall is to treat an absent or small thymus on adult imaging as disease, when involution is expected; and conversely to assume that a mediastinal mass is benign because the patient feels well. A sixth is to assume that lymphatic drainage is fixed. After axillary surgery and radiotherapy, drainage may be rerouted, and in a re-operative sentinel node series lymphatic drainage was visualised in 80 per cent of the axillary dissection group and 95 per cent of the non-dissection group. Restaging a recurrence on the assumption that the original drainage pattern still holds can miss disease entirely. ^[4]

The anatomy in this page is used every time a cancer is staged, an infection is investigated or a mediastinal mass is assessed. For small bowel tumours, the regional lymph nodes for jejunal and ileal malignant tumours based on the AJCC criteria are the mesenteric and superior mesenteric nodes, and the caecal and ileocolic nodes are the regional nodes for the terminal ileum. For biliary tumours, the distinction between regional and non-regional nodes has direct prognostic meaning. In AJCC staging for perihilar cholangiocarcinoma, nodes in the hepatoduodenal ligament are regional, whereas posterior pancreaticoduodenal nodes are non-regional. Radiologists and surgeons therefore need a shared map, because calling a node regional or non-regional changes the stage and the treatment plan.

In haemato-oncology, marginal zone biology underpins diagnosis and management. Marginal zone lymphoma is an indolent B-cell lymphoma arising from marginal zone B cells within lymphoid follicles, accounting for approximately 5 per cent to 15 per cent of non-Hodgkin lymphomas, and it is characterised by diagnostic challenges and diverse treatment options^[1]. Recognising the normal marginal zone, with its IgM and IgD co-expression, CD27 positivity and mutated immunoglobulin genes, is what allows the pathologist to distinguish a reactive expansion from a clonal process.

In immunology and transplantation, the concept of tertiary lymphoid organs has moved from description to clinical relevance. Tertiary lymphoid structures in chronic autoimmunity and chronic transplant rejection have been linked with tissue destruction, and they may be inductive sites for self-reactive T lymphocytes and antibodies. In a model of colitis in mice lacking RORγT, induction of B cell-rich tertiary lymphoid organs was associated with more severe immunopathology, and the disease was prevented by treatment with LTβR immunoglobulin or with intravenous immunoglobulins to saturate Fc receptors on effector cells. The same structures are being explored as vaccine allies: mice pretreated with protein-caged nanoparticle adjuvants in the absence of specific viral antigens were protected against several respiratory viruses, with the protection attributed to prior development of inducible bronchus-associated lymphoid tissue.

Microanatomical detail translates into practice. High endothelial venules are post-capillary venules with cuboidal endothelium and are the sites of entry of naive lymphocytes from the blood into lymph nodes, through interactions between lymphocyte surface molecules and venular ligands. Peripheral node addressin, defined by the MECA-79 antibody, is the functional ligand set for L-selectin on these cells. Binding to peripheral node addressin slows L-selectin-high lymphocytes in their progress through the vessel, allowing chemokine and integrin engagement and eventual migration toward the paracortical or cortical zones. Fibroblastic reticular cells, which express podoplanin but not CD31, produce the conduit scaffold and the T zone chemokines CCL19 and CCL21, and they produce IL-7, which is critical for naive T cell survival. This is why an inflamed node can swell within hours: the same machinery that supports surveillance also supports rapid recruitment.

Therapeutic manipulation of egress is already in use experimentally. Continuous administration of FTY720, a sphingosine-1-phosphate receptor agonist that prevents egress of lymphocytes from lymph nodes, prevented diabetes in non-obese diabetic mice, but only if the mice had already developed pancreatic tertiary lymphoid organs; treatment caused additional accumulation of lymphocytes in those structures, and cessation was followed by rapid islet destruction and diabetes. The lesson is that the lymph node egress mechanism, dependent on the lymph sphingosine-1-phosphate gradient and receptor expression on T cells, also governs lymphocyte traffic through ectopic lymphoid tissue.

Finally, cytokine biology informs bedside interpretation. Interleukin-7 deficient mice lack lymph nodes and Peyer's patches, whereas overexpression of interleukin-7 induces development of additional lymph nodes. Interleukin-7 expression is augmented in the synovial tissue of patients with rheumatoid arthritis, and there is a strong correlation between interleukin-7 expression and lymphotoxin beta expression. In perivascular tertiary lymphoid organs of patients with idiopathic pulmonary hypertension, strong immunoreactivity for interleukin-7 was found close to the reticular fibroblastic network. These observations tie together the themes of this page: stromal cells, cytokines, lymphocytes and anatomy act as one system, and disease emerges when any component is displaced.