Table of contents :

lymphoid system : the lymphoid tissue of the body considered collectively

• lymphoreticular system : the tissues of the lymphoid and reticuloendothelial systems considered together as one system
• lymphatic system / systema lymphoideum / systema lymphaticum : the lymphatic vessels and the lymphoid tissue, considered collectively

• primary or central lymphoid tissues, where lymphocytes differentiate from stem cells
• hematopoietic bone marrow of flat bones => vertebrae, sternum, ribs, iliac wings (in Aves it corresponds to the bursa of Fabricius) from foetal week 20. It represents 4-6% of body weight and contains many cell types, including stroma, bone marrow microvascular endothelial cells (BMEC), adipocytes, osteoblasts and osteoclasts, as well as mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs). The fatty degeneration of red bone marrow (RBM) (25%) into yellow bone marrow (YBM) (75%) is completed around age 21 years.


• thymus is a lymphoepithelial organ with up to 30 g weight (see also follicle of Stannius and diseases of thymus)
• noduli thymici accessorii / accessory thymic nodules : portions of thymus tissue that have been detached from the stalk and left behind in the caudal migration of the gland in embryonic development.
• tractus centralis thymi / central tract of thymus : the medullary core of the thymus; an irregular fibrous bundle carrying the blood vessels and giving attachment to the lobules of the gland.
Organogenesis :

(reproduced with permission from Nature Reviews Immunology (Vol 4, No. 4, pp 278-289 (2004)) copyright Macmillan Magazines Ltd)

(reproduced with permission from Nature Reviews Immunology (Vol 4, No. 4, pp 278-289 (2004)) copyright Macmillan Magazines Ltd)
Genes affecting thymus organogenesis and embryonic patterning :

gene	fetal expression pattern	phenotype of knockout mice/functional analysis
Hoxa3	early : E9.5-E10.5 : third cleft surface ectoderm, third and fourth arch NCCs, third pouch endoderm  late : thymic rudiment until adult	failure of initial thymus and parathyroid organogenesisref1, ref2
Pax1	early : E9.5-E10.5 : all pharyngeal pouch endoderm  late : progressively restricted to a minor population of cells in the adult cortex	thymic hyperplasia and mild thymocyte defects : Pax1/Pax9 double mutants have defective pouch formationref
Pax9	early : E9.5-E10.5 : all pharyngeal pouch endoderm	thymus ectopic and hypoplastic, possible effect on gd-TcR+ T-cell developmentref
Eya1	early : E9.5-E10.5 : all pharyngeal pouch endoderm, cleft ectoderm and NCC mesenchyme  late : N.D.	failure of initial thymus and parathyroid organogenesisref
Foxn1	early : E11.25 : the thymus domain of third pouch (high level of expression); hair follicles and the epidermis frome E14.5  late : all TECs	thymic primordium forms but arrests between E11.5 and E12.5; no colonization of primordium by lymphocytesref1, ref2, ref3, ref4

Cell types :
• thymic epithelial cells (TECs) (CD58 / LFA-3⁺MHC I⁺MHC II⁺) derive from epithelial tissues that originate from the 3^rd pharyngeal pouches and clefts complex during 6^th week of pregnancy, while T-lymphocytes (thymocytes) (there are no B cells !) derive from bone marrow between week 7 and 14 of pregnancy. At the end of pregnancy month 3 each lobe is made up of a central cordon (medullary substance) surrounded by cortical substance : lobes are surrounded by a connectival capsule and capsular septa divides each lobe into lobules
• outer cortical cells are named nurse cells and each may engulf up to 50 thymocytes
• cortical TECs (cTECs) are predominantly K5^-K8⁺K14^-K18⁺ and rarely K5⁺K8⁺K14^-K18⁺MTS20⁺ : a MTS24⁺ subpopulation of cTECs in the latter population are concentrated at the corticomedullary junction (CMJ) and scattered throughout the cortical and subcapsular regions, acting as precursors that generate the former population
• medullary TECs (mTECs) contains a major K5⁺K8^-K14⁺K18^-TR5⁺ subset and a minor K5^-K8⁺K14^-K18⁺ population that is distinguished from the cortical subset by globular morphology and Ulex europaeus agglutinin lectin binding properties.
• some mTECs undergo calcification and necrosis and form the inner part of Hassall's bodies or corpuscles / concentric corpuscles / Leber's corpuscles / thymus corpuscles (spherical or ovoid bodies found in the medulla of the thymus, composed of concentric arrays of epithelial cells which contain keratohyalin and bundles of cytoplasmic filaments)


Hassall's corpuscles instruct dendritic cells to induce CD4⁺CD25⁺ regulatory T cells in human thymus^ref
cTECs and mTECs share a common origin in bipotent precursors, providing definitive evidence that they have a single rather than dual germ layer origin during embryogenesis^ref. This progenitor still persists after birth. To probe the function of postnatal progenitors, a conditional mutant allele of Foxn1 was reverted to wild-type function in single epithelial cells in vivo. This led to the formation of small thymic lobules containing both cortical and medullary areas that supported normal thymopoiesis^ref.
• Hammar's myoid cells : striated muscle cells found in the thymus of nonmammalian vertebrates, especially reptiles and birds, and rarely in mammals
• thymocytes






Thymic crosstalk between epithelial cells and thymocytes occurs both in the cortex and in the medulla thanks to thymic hormones :
• thymulin / serum thymic factor / facteur thymique serique (FTS) is a nonapeptide that needs a Zn²⁺ to express its immunoregulatory properties. IL-1b also induces the synthesis of metallothioneins by TECs, which are thought to be involved in the transfer of Zn²⁺ to thymulin and so in the secretion of Zn²⁺-thymulin (also PRL and IGF are stimulating factors). The administration of an Lys-Arg to elderly individuals and cancer patients can increase the synthesis and/or release of thymulin to normal levels and also increases the number of peripheral T-cell subsets.
• thymic humoral factor (THF) is a polypeptide of 3.2 kDa. It promotes IL-2 production in intact and thymus-deprived mice and augments lymphocyte proliferation in vitro and in vivo. The octapeptide THF-g₂ has the amino acid sequence Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu : it plays a stimulatory role on human myeloid and erythroid hematopoietic progenitor cells, reconstituting the defective CMI in patients with various types of neoplasms and secondary immune deficiencies as a result of chemo and/or radiotherapy. CD10 has been shown to hydrolyze THF-g₂ with high efficiency.
• thymocyte growth peptide (TGP) is a formylpteroyl-Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn. Native TGP contains Zn²⁺, which counteracts degradation of the molecule and is required for full biological activity.
• thymopoietin (Tpo) is a protein of 49 amino acids. 3 variants having largely identical sequences have been described (e.g. thymopoietin-3 (TP-3) / splenin has been isolated from bovine spleen). Thymopoietin specifically interacts with the neuronal N receptors and can regulate the a-bungarotoxin binding sites. Thymopoietin induces the phenotypic differentiation of T precursor cells in vitro while inhibiting phenotypic differentiation of B-cells.
• thymopoietin 32-36 or thymopentin (TP-5) is Arg-Lys-Asp-Val-Tyr, corresponding to amino acids 32-36 of thymopoietin. It appears to represent the active site of thymopoietin in that it has all the biological activities of the native hormone. Some analogs of TP-5, for example TP-3 (Arg-Lys-Asp), and TP-4 (Arg-Lys-Asp-Val) exhibit significant immuno stimulating potencies in vitro and in vivo exceeding those of thymopentin. Thymopentin is able to increase IL-2 and IL-2R production. TP-5 enhances bone marrow NK cells, probably by permitting the maturation of their precursors, and also NK activities in PBMCs of patients having received the drug 3 times per week for 1 month (50 mg sc). TP-5 has been found also to be useful in the treatment of a subgroup of patients with Sezary syndrome. Thymopentin also induces ACTH-like immunoreactivity release by human lymphocytes.
• thymosins
• a-thymosins family
• prothymosin-a is expressed in human kidney, liver, spleen, normal lymphocytes (predominantly T-cells), HTLV-infected T-cells, and myeloma cells. It enhances allo- and auto-Ag-induced human T-cell proliferation and MHC II antigen expression in APCs. It has been shown to potentiate or fully restore the deficient cytotoxic effector function of peripheral mononuclear cells in patients with advanced malignancies. Thymosin-a₁ is a protein of 28 amino acids (3.1 kDa) which is derived from the NTDs of prothymosin-a. A variant lacking 4 carboxyterminal amino acids [des-(25-28)-thymosin-a₁] and another variant possessing 7 additional carboxyterminal amino acids [thymosin-a₁₁] have been isolated from calf thymus fractions. Thymosin-a₁₁, in doses of < 300 ng per mouse, protects susceptible inbred murine strains against opportunistic infections with Candida albicans and shows approximately the same potency as thymosin-a₁. Thymosin-a₁ can induce in vitro differentiation of human thymocytes to T_h1 cells. It also induces terminal differentiation of functionally immature cord blood lymphocytes and has been shown to induce the production of IL-2, high affinity IL-2Rs, and BCGFs by PBMCs. T_h and T_c populations are targets of thymosin activity. In nude mice thymosin-a₁ appears to exert its effect at an early stage of T-cell differentiation and induces a T-cell subpopulation capable of producing IL-3 (but not yet IL-2). Thymosin-a₁ and thymosin-b₄ have been shown to increase the efficiency of Ag presentation by macrophages. Thymosin-a₁ has been found also to be an endogenous modulator of a-thrombin activity. Thymosin-a₁ has been suggested to play a role as an autocrine growth modulator for the human breast cancer cell line MCF-7 in culture. Thymosin-a₁ has been shown to down-regulate the growth of human non-small cell lung cancer (NSCLC) cells in vitro and in vivo.
• prothymosin a₁₄
• parathymosin-a, a peptide isolated from rat thymus, contains approximately 101 amino acids. It shows 43% structural identity with thymosin-a₁ and prothymosin-a in the first 30 aminoterminal amino acids. Parathymosin-a appears to modulate the action of prothymosin-a in protecting sensitive strains of mice against opportunistic infection with Candida albicans and has been shown to block the in vivo immunoenhancing effects of prothymosin-a.
• b-thymosins family
• thymosin-b₄ family
• thymosin-b₄ (paralog genes on X chromosome (escapes X inactivation and encodes an actin sequestering protein) and Y chromosome) is a protein of 43 amino acids with an acetyl-Ser aminoterminus isolated originally from calf thymus. It is produced also by some cell lines, including myoblasts and fibroblasts and also appears to be produced by some human medullary thyroid carcinomas. Thymosin-b₄ has been shown to be induced during differentiation of bone marrow cells induced by GM-CSF. Human thymosin-b₄ has been found to be identical with the human interferon-inducible gene 6-26 and Fx, a protein involved in actin polymerization : it sequesters G-actin monomers and inhibits actin polymerization. Thymosin-b₄ induces the expression of TdT in thymocytes in vivo and in vitro and thus appears to act on lymphoid stem cells, probably controlling the early stages of the maturation process of thymus-dependent lymphocytes. Thymosin-b₄ has been found also to be an activator of CaM-dependent enzymes in the hypothalamus. It also improves and normalizes suppressor cell activities in diabetic patients. Thymosin-b₄ can undergo enzymatic cleavage in vitro and in vivo and yields a tetrapeptide that functions as a negative regulator of hematopoiesis . Thymosin-b₄ by itself has been shown to act as an inhibitor for normal human CD34⁺ hematopoietic progenitor cells, decreasing the growth of both granulo-macrophagic and erythroid progenitors. A fusion protein constructed from TNF with human thymosin-b₄ has been shown to have significant antitumor effects in experimental tumor-bearing animals after systemic injection : the fusion protein had a significantly higher t_1/2 in serum than the original TNF and caused regressions of tumors at concentrations at which TNF was inactive.
• neuroblastoma-derived thymosin
• thymosin-b₄-like
• thymosin-like 1
• thymosin-like 2
• thymosin-like 3
• thymosin-like 4
• thymosin-like 5
• thymosin-like 6
• thymosin-like 7
• thymosin-b₈ contains 39 amino acid residues, of which 31 are identical with the corresponding amino acid residues in thymosin-b₄. The NH₂ terminus of thymosin-b₈ is acetyl-Ala, compared with acetyl-Ser in thymosin-b₄.
• thymosin-b₉ (41 amino acids) is identical with thymosin-b₈ except for the presence of an additional dipeptide, -Ala-Lys-OH, at the carboxy terminus. 32 of its 41 amino acids are identical with those of thymosin-b₄.
• thymosin-b₁₀ is composed of 43 amino acid residues and shows 75% sequence homology with thymosin-b₄. A comparison of human and rat thymosin-b₁₀ cDNA sequences reveal 100% identity for the deduced amino acid sequence and 95% nucleotide identity for the coding region. Thymosin-b₁₀ has been found to be expressed abundantly in embryonic/fetal human brain but absent in adult tissues and probably plays an important role in early neuroembryogenesis and neural maturation. Thymosin-b₁₀ mRNA appears to be expressed specifically in highly metastatic human melanoma cells lines and may be progression marker for human cutaneous melanoma. Thymosin-b₁₀ has been shown also to function as an actin monomer sequestering protein (see: Fx).
• thymosin-b₁₁ isolated from rainbow trout (Oncorhynchus mykiss (a.k.a. Salmo gairdneri)) spleen contains 41 amino acids and is 78% homologous to thymosin-b₄. Thymosin therapy has been reported to promote disease remission and cessation of HBV replication in patients with chronic viral infection. The protein shows a high degree of sequence homology with thymosin-b₁₂.
• thymosin-b₁₂ has been isolated from perch liver and rainbow trout (Oncorhynchus mykiss (a.k.a. Salmo gairdneri)) spleen. The protein is 43 amino acids in length and sequence analysis reveals that it is 79% homologous to thymosin-b₄ and that it shows 84% sequence homology with thymosin-b₁₁.
• thymosin-b₁₅ has been found to be upregulated in the highly motile and metastatic Dunning rat prostatic carcinoma cell lines. Experiments with antisense thymosin-b₁₅ RNA demonstrate that thymosin-b₁₅ positively regulates cell motility, which has been demonstrated to correlate with the metastatic phenotype. Levels of thymosin-b₁₅ levels are elevated also in human prostate adenocarcinoma cells and correlate positively with the Gleason tumor grade.
... & cytokines :
• IL-6
• IL-7
• GM-CSF
... and cytokines (IL-1b), respectively.
CXCL12 is produced by cortical stromal cells and induces thymocyte migration via CXCR4^ref.
cTECs create the hematothymic barrier (a.k.a. blood-thymus barrier), which breaks only near the corticomedullary junction (CMJ), where T-lymphocytes enter bloodstream.
The thymus exports 2% of total thymocytes each day : this number decresaes of 3% per year during the first 3 decades of life.
The thymus has the greatest relative size in newborn and the greatest absolute size at puberty : after puberty the thymic parenchyma undergoes atrophy (cortical thymocytes are replaced by adipous tissue), leading to a slow decline in immune function up to 50, where no function is detectable. It also involutes during pregnancy for reasons that are not yet clear. 2 cytokines of the IL-6 family, LIF and OsM, can cause thymic atrophy with loss of cortical thymocytes : the latter can transform the lymph node into a primary lymphoid organ whose ability to support T cell development and to seed peripheral compartments is similar to that of a normal thymus ! Thymocyte selection is active during fetal and neonatal period, but the levels of glucocorticoids circulating in the fetus are low because some level of protection from maternal glucocorticoids is provided by the placenta that contains high levels of the GC-catabolizing enzyme 11b-HSD type 2. The necessity of them for positive selection of thymocytes has led to the hypothesis that there may be local production of glucocorticoids in the thymus during development : cultured TECs do produce pregnenolone and deoxycorticosterone, and this production can be increased by ACTH. Thymic posttranslational GR knock-outs by RNAi indicate necessity of glucocorticoids in thymocyte development and differentiation, but in time-controlled systemic knock-outs no difference in CD4⁺CD8⁺ thymocytes is found. GR knockout mice have been described that die at E19 : however up to E18 these animals have apparently normal thymocyte populations and T cell development, suggesting that GR in this case is not necessary for the entire process of T cell development and differentiation. The thymus is richly innervated : acute stress results in a rapid loss of cortical thymocytes thought to be at least partly due to the effect of glucocorticoids and endogenous opioids.
• secondary or peripheral lymphoid tissues or organs (SLO), where lymphocytes take part in immune responses.
It is widely accepted that the trafficking of intravascular leukocytes is controlled by a sequence of at least 3 molecularly distinct adhesion and signalling event^{ref1, ref2, ref3}. These adhesion cascades are initiated by a tethering step that allows leukocytes to bind loosely to endothelial cells (step 1a). The marginated cells are then pushed forwards by the blood stream resulting in slow rolling along the vessel (step 1b). Subsequently, rolling cells encounter chemotactic stimuli on the endothelium that engage specific leukocyte receptors (step 2). Chemoattractant binding, in turn, induces intracellular signals triggering activation-dependent adhesion steps that allow leukocytes to stick firmly (step 3) and to emigrate through the vessel wall (step 4). Intravital microscopy analyses have defined the adhesion cascades that mediate T- and B-cell homing to LNs^{ref1, ref2, ref3, ref4}. Early electron-microscopy studies indicated that homing lymphocytes migrate into and across individual high endothelial cells before entering either the basolateral interendothelial junction or the subendothelial space^ref. However, others observed that diapedesis occurs through interendothelial junctions^ref. There is also uncertainty about the adhesion-molecule requirements for lymphocyte migration through endothelial monolayers without a chemotactic gradient^ref. However, in intravital microscopy experiments, T cells rarely emigrate into surgically exposed LNs even though they roll and arrest at a high frequency, and numerous T cells emigrate into undisturbed LNs of the same animal^{ref1, ref2}. This indicates that a crucial fctor is lost during surgical tissue preparation that is required for lymphocytes to undergo diapedesis. As blood flow is always intact, fluid shear flow is probably not sufficient for lymphocyte diapedesis in HEVs. Another interesting issue is whether, and to what extent, transendothelial migration occurs in an abluminal-to-luminal direction^ref : reverse migration across HEVs is probably not unique for pigs, even though its frequency varies between species. The phenotype and immunological function of cells migrating in reverse and the traffic signals that control this unorthodox behaviour are unknown.
In each organs the boundary between T-cell zones (TCZ) and B-cell zones (BCZ) is defined by the following chemokine --- receptor interactions :
• CCL19 & CCL21 --- CDw197 / CCR7 (allows migration of B-cell up to the T/B boundary; instead in brain CCL21 produced by injured neurons binds to CD183 / CXCR3 on microglial cells)
• CXCL13 --- CD195 / CXCR5 (limits B-cell migration up to the T/B boundary but not into T-cell zone)
• lymphatic circulatory apparatus
• lymphatic capillaries (unconstant Ø, up to 30÷60 mm) : present in those organs which have connective tissue. Absent in CNS, PNS, placenta, umbilical cord, cornea and cartilage. In liver, kidney, lungs, heart, pancreas and many endocrine glands the lymphatic network is much smaller than the blood vessels network. They form plexus around arteries. No basal lamina, pores, fenestrae, pericytes. Open junctions between endothelial cells.
• lymphatic plexus : an interconnecting network of lymph vessels, i.e., the lymphocapillary vessels, collecting vessels, and trunks, which provides drainage of lymph in a one-way flow.
• plexus jugularis / jugular plexus : a plexus of lymphatic vessels along the internal jugular vein
• plexus lymphaticus axillaris / axillary lymphatic plexus : a plexus of lymph vessels and nodes in the fossa axillaris.
• Sappey's subareolar plexus : a lymphatic plexus situated beneath the areola of the nipple.
• plexus aorticus : a network of lymphatic vessels about the aorta.
• plexus coeliacus / celiac plexus / plexus celiacus : a plexus composed of lymphatic vessels, the superior mesenteric lymph nodes, and the celiac lymph nodes behind the stomach, duodenum, and pancreas.
• plexus hypogastricus : a plexus of lymphatic vessels in the hypogastric region.
• plexus iliacus externus : a lymphatic plexus situated about the external iliac vessels.
• plexus inguinalis / inguinal plexus : a lymphatic plexus situated near the end of the long saphenous vein and along the femoral artery and vein in the iliopectineal fossa
• plexus sacralis medius : fine network of lymphatic vessels in the hollow of the sacrum.
• plexus lumbalis / lumbar plexus : a lymphatic plexus in the lumbar region.
• Panizza's plexuses : 2 plexuses of the lymph vessels in the lateral fossae of the frenum of the prepuce.
• Quénu's hemorrhoidal plexus : a lymphatic plexus found in the perianal skin.
• precollectors : thick basal lamina and rarely smooth muscle cells. Uneffective valves. Along their way are located interrupting lymph nodes, with variable distribution.
• lymphatic collectors : along their way are regularly located lymph node stations (more than one large lymph node), sometimes grouped into lymph centres. Many effective semilunar valvula lymphaticum / lymphatic valve (any of the usually doubled cusps in the collecting lymphatic vessels, serving to ensure flow in only one direction). 2 antiparallel helicoidal layers of smooth muscle cells (except that near valves). No elastic tissue, anchoring to tissue.
• superficial (above fascia comune, in subcutaneous tissue, independently by blood vessels). Effector and sensitive innervations.
• deep (below common fascia, satellite to blood vessels)
According to their location regarding to lymph node, they are named :
• afferent or prelymph-nodal collectors
• efferent or postlymph-nodal collectors
• trunci lymphatici / lymphatic trunks : the lymphatic vessels (right or left lumbar, intestinal, right or left bronchomediastinal, right or left subclavian, and right or left jugular trunks) that drain lymph from various regions of the body into the right lymphatic or thoracic duct.
• trunci intestinales / intestinal trunks : short lymphatic vessels which leave the gastrointestinal tract and participate in formation of the thoracic duct
• truncus jugularis / jugular trunk : either of the 2 vessels, right and left, draining the deep cervical lymph nodes: on the right side, into the right lymphatic duct or subclavian vein, and on the left side, into the thoracic duct or subclavian vein.
• truncus subclavius / subclavian trunk : either of 2 lymphatic vessels, right and left, draining the axillary lymph nodes; that on the right into the right lymphatic duct or subclavian vein, that on the left into the thoracic duct or the subclavian vein.
• truncus bronchomediastinalis / bronchomediastinal trunk : either of the 2 lymphatic vessels, right and left, draining the pulmonary, bronchopulmonary, tracheobronchial, tracheal, and parasternal lymph nodes: that on the right side into the right lymphatic duct or subclavian vein, and that on the left into the thoracic duct or the subclavian vein.
• truncus lumbalis or lumbaris / lumbar trunk : either of the 2 lymphatic vessels, right and left, draining lymph upward from the lumbar lymph nodes and helping form the thoracic duct
• principal lymphatic ducts / ductus lymphatici : the main lymph channels into which the converging lymph vessels drain, which in turn empty into the blood stream. Effective valves. Effector and sensitive innervations.
• ductus lymphaticus dexter / right lymphatic duct : a vessel draining the lymph from the upper right side of the body, typically formed by the right jugular, subclavian, and bronchomediastinal lymphatic trunks, any one of which may, however, end separately in the right brachiocephalic vein; when all 3 lymphatic vessels unite, a right lymphatic duct (called also ductus thoracicus dexter / right thoracic duct) is formed, which empties directly into the junction of the internal jugular and subclavian veins.
• ductus thoracicus / thoracic duct : the largest lymph channel in the body, which collects lymph from the portions of the body below the diaphragm and from the left side of the body above the diaphragm; it begins in the abdomen (pars abdominalis) at the junction of the intestinal, lumbar, and descending intercostal trunks (which consists of a plexus or the cistern of Pecquet / cisterna chyli / ampulla chyli / chylocyst / Pecquet / receptaculum chyli / receptaculum Pecqueti : a dilated portion of the thoracic duct at its origin in the lumbar region; it receives several lymph-collecting vessels, including the intestinal, lumbar, and descending intercostal trunks) at about the level of L2 vertebra, enters the thorax through the aortic hiatus of the diaphragm (pars thoracica), ascends to cross the posterior mediastinum, and enters the neck (pars cervicalis), where it forms a downward arch (arcus ductus thoracici) across the subclavian artery, and ends at the junction of the left subclavian and internal jugular veins.
• lymph nodes (LN) / nodus lymphaticus / lymphoglandula / lymphonodus / nodus lymphoideus function as an immunologic filter for lymph, varying from 1 to 25 mm in diameter (see also diseases of lymph nodes)


(reproduced with permission from Nature Reviews Immunology (Vol 3, No. 11, pp 867-878 (2003)) copyright Macmillan Magazines Ltd)
• histology
• trabeculae nodi lymphatici or lymphoidei / trabeculae of lymph node : strands of dense connective tissue radiating out from the capsule through the interior of the node
• cortex : many architectural elements (cords, channels, corridors and the fibroblastic reticular cell (FRC) conduits) facilitate cell interactions. The fine structure of the LN cortex is complex and variable^{ref1, ref2, ref3, ref4}, but nevertheless, common structural features have been identified^{ref1, ref2} :
• T cell zone (paracortex : T/B ratio 3:1) : on the base of electron-microscopy strudies, it has been proposed that the paracortex is arranged in paracortical cords that originate between or below the B-cell follicles and extend towards the medulla where they merge into medullary cords^ref. It is the site where circulating lymphocytes enter the LNs^ref and where T-cell interact with DCs^ref. The cords are bordered by lymph-filled cortical sinuses and permeated by reticular fibres. At the centre of each paracortical cord is an HEV that is surrounded by concentric layers of pericytes known as fibroblastic reticular cells (FRCs). A narrow space between the basement of the HEV and the pericytes is known as the perivenular channel. It has been propose that this channel receives an ultrafiltrate of lymph from the FRC conduit. Networks of FRCs that are often arranged in spiral layers around the HEVs enclose 10-15 mm wide corridors along which lymphoytes are thought to migrate^ref1.
• B-cell zone (more superficial) that consists of ...
• primary follicles : they contain B cells and FDCs. Under unknown stimuli, Ag-specific B-cells migrate to the paracortex, where they are activated by T_h cells (the latter are activated by interdigitated DCs). Once activated, both T_h cells and B-cells migrate back to the primary lymphatic follicle, where FDCs continue stimulation.

‡
• secondary follicles
• germinal centre (GC) / Flemming centre / secondary nodule : the area in the center of a lymph nodule containing aggregations of actively proliferating Ag-activated B-cell blasts that have migrated into the follicle lymph nodes; it appears as a spherical mass surrounded by a capsule of elongated cells that is partially invested by a crescentic cap of small lymphocytes.
• B cell clones which express mIg molecules with high affinity for the Ag presented by FDCs are selected for (positive selection) and continue to proliferate. B cell clones which fail to recognize antigen or express low affinity mIg molecules die by apoptosis and are phagocytosed. This accounts for affinity maturation, also via somatic hypermutation (SHM).
• B cell clones which survive this process under class switch recombination (CSR)
• differentiation into memory or plasma cells before leaving the GC. Also rare T_h cells are present.
• segregation of B cells to the dark and light zones of GCs, in which they carry out SHM and antigen-driven selection, respectively, depends on chemokines :
• centroblasts undergoing SHM express high levels of CXCR4 and localize to the dark zone, which is consistent with higher expression of its ligand CXCL12 in the dark zone compared with the light zone
• by contrast, expression of CXCR5 and its ligand CXCL13 / BLC are concentrated in the light zone and contribute to recruitment of centrocytes to this zone^ref.
3-4 antigen-specific B cells colonize a follicle to establish a GC and become rapidly dividing GC centroblasts that give rise to dark zones. Centroblasts produce non-proliferating centrocytes that are thought to migrate to the light zone of the GC, which is rich in antigen-trapping FDCs and CD4⁺ T cells. It has been proposed that centrocytes are selected in the light zone on the basis of their ability to bind cognate antigen. However, there have been no studies of GC dynamics or the migratory behaviour of GC cells in vivo. The direct visualization of B cells in lymph node germinal centres by 2-photon laser-scanning microscopy in mice. Nearly all antigen-specific B cells participating in a GC reaction were motile and physically restricted to the GC but migrated bi-directionally between dark and light zones. Notably, follicular B cells were frequent visitors to the GC compartment, suggesting that all B cells scan antigen trapped in GCs. Consistent with this observation, high-affinity antigen-specific B cells can be recruited to an ongoing GC reaction. The open structure of GC enhances competition and ensures that rare high-affinity B cells can participate in antibody responses^ref.
• follicular mantle zone (naive mature CD5⁺ IgM⁺IgD⁺ B cells displaced by an expanding germinal centre). They are often mixed with marginal zone B-cells (CD5^-IgM⁺IgD^-) equivalent to those of spleen marginal zone
• medulla (mainly a B-cell zone) is a labyrinth of lymph draining sinuses that are separated by medullary cords, which contain many plasma cells, and some macrophages and memory T cells. The function of the medulla is still poorly understood : activated B cells committed to becoming plasma cells migrate to the medulla where they develop into Ab-producing plasma cells. Some memory B cells remain in the lymph node while others leave by efferent lymphatic vessel and reach target organ(s).
• the only efferent lymphatic vessel that exit from the ...
• hilus : a discrete region where the capsule is penetrated by efferent lymph and blood vessels
• the microvascular anatomy and haemodynamics have been characterized in mouse inguinal LNs^ref :
• blind-ending afferent lymph vessels collect and channel interstitial fluid, enter capsular septa and open into the marginal or subcapsular sinus (a bowl-shaped lymph sinuses separating the capsule that covers the LN from the cortical parenchyma of a lymph node), from which lymph flows into the cortical or intermediate sinuses (lymph sinuses in the cortex of a lymph node, which arise from the marginal sinuses). From here, the lymph is drained towards the hilus through the fibroblastic reticular cell (FRC) conduit and, through trabecular sinuses, across the LN parenchyma towards medullary sinuses (lymph sinuses in the medulla of a lymph node, which divide the lymphoid tissue into a number of medullary cords). The intranodal lymph channels are enclosed by fibroblastic reticular cells (FRCs)^ref, mannose receptor-expressing sinus-lining endothelial cells^{ref1, ref2} and, expecially in the subcapsular sinus, macrophages and CD11b⁺ DCs^ref, which sample the lymph and remove microorganisms and debris that are in it. These cells also transport and/or process antigenic material for presentation to B and T cells. The T-cell rich paracortical cord (light blue) is shown adjacent to a B-cell follicle (pink) and demarcated by lymph-filled sinuses (green). The paracortical cord is penetrated by reticular fibres consisting of type 1 and type 3 collagen that are contained within the sleeves of the FRCs forming a conduit. At the centre of each cord is a high endothelial venule (HEV) that is surrounded by concentric layers of FRCs. The FRC conduit drains lymph into the perivascular channel. Afferent lymph is the main route by which antigens reach LNs. 2 mechanisms of antigen delivery cnn be distinguished^ref :
• antigenic material becomes lymph borne and is taken up by DCs in a LN : this requires that the LNs are continuously stocked with immature DCs that can uptake and process antigens. CD11b⁺ (myeloid) DCs are concentrated in the superficial paracortex, well positioned to capture lymph-borne proteins from the subcapsular sinus^ref. The progeny of Langerhans cells as well as CD8a^hi (lymphoid) DCs and plasmacytoid DCs are distributed throughout the T-cell area in LNs^{ref1, ref2, ref3}. The route(s) by which LNs are supplied with these resident subsets are probably diverse. Langerhans cells give rise to CD8a^low or CD8a⁺ DCs in LNs, indicating this population enters the LNs through the lymph. Plasmacytoid DCs express L-selectin, and it has been porposed that they migrate to LNs through HEVs^{ref1, ref2}. Antibody specific for L-selectin blocks the marked increased of both CD8a⁺ and CD8a^- DCs in LNs of virus-infected mice, but conclusive proof for L-selectin-dependent DC homing through HEVs awaits careful homing experiments.
• antigen is acquired by DCs in peripheral tissues and the DCs can then carry the processed antigen to draining LNs^ref
Free antigen and/or antigen-loaded DCs are transported to the LNs from distal tissues through afferent lymph vessels. Lymph-borne molecules do not have free acces to the lymphocyte compartment. Only small molecules with a molecular radius < 4 nm can reach the T-cell area through the FRC conduit. FRCs wrap around collagen fibres, forming channels that project from the subcapsular sinus into the T-clell area. So, the FRC imposed size barrier to lymph-borne molecules might not be absolute, but select macromolecules, such as antibodies, can gainaccess to the nodal parenchyma by mechanisms that remain to be identified. LNs must also function as sites of innate recognition of lymph-borne pathogens : microorganisms that breach the body's surface barriers can use the lymphatics to reach the systemic circulation and to disseminate : good examples are Yersinia pestis^ref (LNs infected by less virulent Yersinia strains recruit numerous inflammatory cells. So, it has been speculated that the success of Y.pestis might be due to its ability to block the recruitment of phagocytes to the LNs), HIV-1^ref, Mycobacterium spp, Bacillus anthracis^ref, ... Initial evidence that the FRC conduit can influence leukocyte recruitment came from experiments in plt/plt mice, in which defective T-cell homing was restored by intracutaneous injection of CCL21 or CCL19, but not CXCL12^{ref1, ref2}. The exogenously applied chemokines were rapidly transported to HEVs and presented to rolling T cells in the lumen of the vessel. Chemokine transcytosis in abluminal-to-luminal direction was first described in dermal venules where it involved the caveoli network^ref. Similarly, chemokines transverse HEVs in intracellular vesicles rather than across intercellular junctions^ref, but these transport vesicles are still incompletely characterized. So far, the list of chemokines that were shown to be transported from a non-endothelial source to LN HEVs include :
• homeostatic chemokines
• CCL19^ref
• CCL21
• CXCL12
• inflammatory chemokines^{ref1, ref2}
• CCL2 from inflamed skin^ref gets released into the lymph, transported to draining LNs, and translocated to the luminal surface of HEVs where it activates CCR2 on rolling monocytes, triggering integrin-mediated arrest^ref
• CXCL9 interaction with CXCR3 has been defined as a second mechanism for monocyte recruitment to LNs that drain inflamed tissues^ref, but it is not known whether CXCL9 is produced by the inflamed HEVs or by other intra- (or extra-) nodal cells from where the chemokine might have been translocated.
The ability to modulate multi-step adhesion cascades in HEVs remotely by secreting chemokines into the lymph enables peripheral tissues to control the composition and function of leukocytes in draining LNs. It is conceivable that this mechanism opens a gate to LNs not only for monocytes, which might then give rise to macrophages and/or DCs, but also for other circulating leukocytes, such as granulocytes, which express L-selectin and LFA1 and several receptors for inflammatory chemokinesref. However, recent work indicates that there are are also counter-regulatory mechanisms :
• the lymphatic endothelium expresses the non-signalling serpentine receptor D6 / chemokine binding protein 2 (CBBP), which binds the majority of pro-inflammatory b-chemokine family members, including CCL2^ref. After ligation, D6 triggers internalization and degradation of its cargo and might therefore control the leakage of chemokines into the lymph^ref
• HEVs express a similar non-signaling chemokine receptor - the Duffy antigen-related receptor for chemokines (DARC)^ref, which might also function in the transport, presentation and turnover of chemokines. It binds pro-inflammatory chemokines such as CXCL1, CXCL5, CXCL8 / IL-8, CCL2, CCL5 and CCL7, but not lymphoid chemokines such as CCL21, CCL19, CXCL12 and CXCL13 that are normally expressed in HEV^ref
• venous blood flows through high endothelial venule (HEV) along a venular tree, the trunk of which is formed by a large collecting venule in the medulla. This venule drains into a large vein at the hilus. Adhesive interactions between leukoctes and endothelial cells are absent in LN arterioles and capilaries, but they occur frequently in venules : recent work indicates that the medulla-associated segments of the venular tree express unique adhesion molecules that are distinct from those expressed by HEVs^ref. Some T and B memory lymphocytes reach LNs from peripheral tissues through the afferent lymph vessels^ref, but all T and B naive lymphocytes enter these organs in high endothelial venules (HEVs)^{ref1, ref2}. This route of lymphocyte traffic is highly efficient^{ref1, ref2}. A single inguinal mouse LN recruits 2% of the recirculating pool per day^ref. During inflammation, lymphocyte accumulation in draining LNs is markedly increased^{ref1, ref2, ref3, ref4}, whereas their exit into the efferent lymphatics is transiently blocked^ref, rapidly increasing lymphocyte numbers in the draining LNs, which might enhance the probability for antigen encounter by the rare T cells that express a relevant TcR. Lymphocyte homing remains inconsequential unless lymphocytes are presented with antigen by DCs^ref : if they fail to recognize specific antigen within a few hours, they return to the circulation through efferent lymph vessels and the thoracic duct^ref. Homed lymphocytes in pig LNs leave through HEVs rather than through efferent lymphatics^ref. Electron-microscopy studies of rat LNs found that 92% of lymphocytes in HEVs migrated towards the nodal parenchyma, whereas the remainder were oriented towards the lumen^ref. We have little knowledge about what determine show long lymphocytes stay in the LNs. A few adhesion molecules have been identifed on intranodal lymphatics. These include the pan-endothelial-cell marker CD31 / PECAM1a - the mannose receptor, which interacts with p90-110^{L-selectin / CD62L / MEL-14 / LAM-1 / LECAM-1 / Leu-8ref} - and common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER1), an adhesion molecule with as-yet-unknown ligand specificity that is also expressed by HEVs^{ref1, ref2}. Classic experiments in sheep have shown that transient antigen challenge precipitates a transient (6-18 hours) reduction in lymphocyte egress into efferent lymph vessels despite a several-fold increase in lymphocyte recruitment through HEVs^ref. The decrease in lymphocyte output is most marked with viral and bacterial challenges and is lower or absent in response to noninfectious stimuli. Over several days after challenge, cell output in efferent lymph rises markedly, reaching a peak at day 3 to 4. Although the signals that regulate the magnitude of lymphocyte entry and egress in LNs are still unknown, a hint has come from studies of FTY720 : whatever the precise mechanism(s), together these observations raise the possibility that S1P and its receptors (particularly EDG1 / S1P₁ and EDG6 / S1P₄) are involved in regulating the overall lymphocyte content in LNs.
• an unresolved issue is that intraperitoneal injection of a protein antigen can elicit T-cell responses in distant LNs that do not receive lymph from the injection site^ref. How does such antigen enter LNs, how is it processed and presented?
• locations
• nodi lymphoidei parietales / parietal lymph nodes : lymph nodes that receive lymph from the walls of a body cavity
• nodi lymphoidei viscerales / visceral lymph nodes : lymph nodes that receive lymph from the viscera in a body cavity; cf. nodi lymphoidei parietales.
• head and neck lymph nodes (a.k.a. cranial, oral, and nasal-associated lymphoid tissue (CONALT))
• nodi lymphoidei occipitales / occipital lymph nodes : several small nodes near the occipital insertion of the semispinalis capitis muscle.
• superficial lymph nodes (1÷6)
• deep lymph nodes (1÷3)
• nodi lymphoidei mastoidei / mastoid lymph nodes / nodi lymphatici retroauriculares / retroauricular lymph nodes / posterior auricolar lymph nodes (1÷4) : lymph nodes, 2 or 3 on each side, that are superficial to the mastoid attachment of the sternocleidomastoid muscle and deep to the posterior auricular muscle; they drain the nasal fossae and paranasal sinuses, hard and soft palate, middle ear, and nasopharynx and oropharynx.
• nodi lymphoidei parotidei / parotid lymph nodes
• nodi lymphoidei parotidei superficiales / superficial parotid lymph nodes : lymph nodes lying in the subcutaneous tissue of the parotid gland directly in front of the tragus.
• anterior auricolar lymph nodes
• inferior auricolar lymph nodes
• nodi lymphoidei parotidei profundi / deep parotid lymph nodes : lymph nodes on the lateral wall of the pharynx lying deep to or embedded in the deep substance of the parotid gland, through which lymph drains from the external acoustic meatus, auditory tube, tympanum, soft palate, and posterior nasal cavity.
• extraglandular lymph nodes
• nodi lymphoidei parotidei profundi infraauriculares / infra-auricular deep parotid lymph nodes : deep parotid lymph nodes situated below the ear.
• nodi lymphoidei parotidei profundi intraglandulares / intraglandular deep parotid lymph nodes : deep parotid lymph nodes situated within the substance of the parotid gland. (4÷10)
• nodi lymphoidei parotidei profundi preauriculares / preauricular deep parotid lymph nodes : deep parotid lymph nodes situated in front of the ear.
• nodi lymphoidei faciales / facial lymph nodes : lymph nodes situated along the course of the facial artery and vein, which receive afferent vessels draining the eyelids, conjunctiva, nose, cheeks, lips, and gums, and send efferent vessels to the submandibular nodes.
• nodus lymphoideus malaris / malar lymph node : one of a variable number of facial lymph nodes situated in the region of the zygomatic minor muscle.
• nodus lymphoideus mandibularis / mandibular lymph node : one of a variable number of facial lymph nodes situated near the angle of the mandible, into which lymph from some of the superficial tissues of the head and neck is drained.
• nodus lymphoideus buccinatorius / buccinator lymph node / buccal lymph node and nodus lymphaticus buccalis : one of a variable number of facial lymph nodes lying on a line between the angle of the mandible and the mouth, receiving the afferent vessels draining the temporal and infratemporal fossae and nasopharynx; their efferent vessels drain into the superior deep cervical nodes
• nodus lymphoideus nasolabialis / nasolabial lymph node : one of a variable number of facial lymph nodes situated near the junction of the superior labial and facial arteries, which drains the upper lip and external nose into the submandibular node.
• nodi lymphoidei submandibulares / submandibular lymph nodes : the 3 to 6 nodes alongside the submandibular gland, through which lymph drains from the adjacent skin and mucous membrane (deep : 5÷8)
• nodi lymphoidei submentales / submental lymph nodes : nodes under the chain into which the lymph from some of the superficial tissues of the head and neck is drained (superficial : 2÷8)
• nodi lymphoidei retropharyngeales / retropharyngeal lymph nodes : deep lateral cervical lymph nodes, one median and two lateral groups, situated behind the upper part of the pharynx, especially concerned with drainage of the nasal fossae, paranasal sinuses, hard and soft palates, middle ear, nasopharynx, and oropharynx. (deep: 2÷4)
• node of Rouvière : the most superior of the lateral group of the retropharyngeal lymph nodes, located at the base of the skull
• nodi lymphoidei linguales : deep cervical lymph nodes receiving afferent vessels from the tongue.
• nodi lymphoidei cervicales laterales profundi / deep lateral cervical lymph nodes : a chain of lymph nodes situated in the posterior cervical triangle; the chain is subdivided into smaller chains of lymph nodes, including a
• superior group
• lateral
• anterior
• nodus lymphoideus jugulodigastricus / jugulodigastric lymph node / hauptganglion of Küttner / Küttner's ganglion : one of the deep lateral cervical lymph nodes lying on the internal jugular vein at the level of the greater cornu of the hyoid bone, i.e., just below the posterior belly of the digastric muscle
• inferior group
• lateral
• anterior
• nodus lymphoideus juguloomohyoideus / jugulo-omohyoid lymph node : one of the deep lateral cervical lymph nodes lying on the internal jugular vein just above the tendon of the omohyoid muscle.
• nodi lymphoidei cervicales laterales superficiales / superficial lateral cervical lymph nodes (4÷5) : lymph nodes situated along the external jugular vein that send efferent vessels to the deep lateral cervical lymph nodes.
• nodi lymphoidei cervicales laterales profundi / cervical lateral lymph nodes
• nodi lymphoidei cervicales laterales profundi inferiores / inferior deep cervical lateral lymph nodes / substernocleidomastoideal deep cervical lymph nodes (15÷30) : a group of lymph nodes adjacent to the carotid sheath, partly deep to the sternocleidomastoid muscle and extending into the subclavian triangle. They receive lymph from the back of the scalp and neck, the tongue, the superficial pectoral region, and part of the arm and drain into the jugular trunk.
• nodi lymphatici jugulares laterales / lateral jugular lymph nodes : deep lateral cervical lymph nodes situated lateral to the internal jugular vein that empty into the jugular trunk.
• nodi lymphoidei accessorii / accessory nodes : a chain of lymph nodes of the inferior deep lateral cervical group that follow the spinal accessory nerve and receive lymph from the occipital, postauricular, and suprascapular nodes and from the scalp, neck, and shoulder.
• nodi lymphoidei supraclaviculares / supraclavicular lymph nodes : the deep lateral cervical lymph nodes situated inferior to the omohyoid muscle, extending into the omoclavicular portion of the posterior triangle of the neck.
• nodi lymphoidei cervicales laterales profundi superiores / superior deep cervical cervical lymph nodes / supraclavicular deep cervical lymph nodes : a group of lymph nodes adjacent to the carotid sheath deep to the sternocleidomastoid muscle; they receive lymph from a number of structures of the head and neck and drain into the inferior deep cervical nodes or the jugular trunk.
• nodi lymphoidei cervicales anteriores / anterior cervical lymph nodes : a group of lymph nodes ventral to the larynx and trachea, consisting of superficial vessels on the anterior jugular vein (nodi lymphoidei cervicales anteriores superficiales) and deep vessels (nodi lymphoidei cervicales anteriores profundi) on the middle cricothyroid ligament as well as ventral to the trachea.
• nodi lymphoidei cervicales anteriores superficiales / superficial anterior cervical lymph nodes : lymph nodes along the external jugular vein as it emerges from the parotid gland, being superficial to the sternocleidomastoid muscle; they receive afferent vessels from the auricle and parotid region.
• nodi lymphoidei cervicales anteriores profundi / deep anterior cervical lymph nodes : a group of numerous large lymph nodes that form a chain along the internal jugular vein, extending from the base of the skull to the root of the neck, situated near the pharynx, esophagus, and trachea; they receive lymph from both superficial and deep structures.
• nodi lymphoidei infrahyoidei / infrahyoid lymph nodes : lymph nodes lying beneath the deep cervical fascia anterior to the thyrohyoid membrane that receive lymph from the anterior cervical nodes and epiglottic region and drain into the deep cervical nodes.
• nodi lymphoidei prelaryngeales / nodi lymphoidei prelaryngei / prelaryngeal lymph nodes : deep anterior cervical lymph nodes situated in front of the larynx that help drain the thyroid gland.
• nodi lymphoidei pretracheales / pretracheal lymph nodes : deep anterior cervical lymph nodes situated in front of the trachea near the inferior thyroid veins that helps drain the thyroid gland.
• nodi lymphoidei paratracheales / paratracheal lymph nodes : lymph nodes on either side of the esophagus, extending upward into the neck, which receive lymph from the esophagus, trachea, and tracheobronchial lymph nodes. (5÷11)
• nodi lymphoidei thyroidei / thyroid lymph nodes : deep anterior cervical lymph nodes situated around the thyroid gland.
• Delphian node : a lymph node encased in the fascia in the midline, just anterior to the thyroid isthmus, so called because it is exposed first at surgery and, if diseased, is indicative of disease in the thyroid gland, but not of a specific disease process.
• upper limb lymph nodes
• nodi lymphoidei profundi membri superioris / deep lymph nodes of upper limb : the lymph nodes situated internal to the deep fascia of the upper limb, most of which are grouped in the axilla; they accompany the radial, ulnar, interosseous, and brachial arteries and end in the brachial axillary lymph nodes.
• axillary lymph centre / nodi lymphoidei axillares / axillary lymph nodes : the 20 to 30 lymph nodes of the axilla, which receive lymph from all the lymph vessels of the upper limb, most of those of the breast, and the cutaneous vessels from the trunk above the level of the umbilicus (10÷60)
• brachial or lateral group / nodi lymphoidei brachiales / brachial lymph nodes / lateral axillary lymph nodes : 4 to 6 axillary lymph nodes lying medial to, and behind, the axillary vein, which drain most of the upper limb (4÷7)
• thoracic, pectoral or anterior group / nodi lymphoidei axillares pectorales / pectoral axillary lymph nodes / nodi lymphoidei axillares anteriores / anterior axillary lymph nodes : 4 or 5 axillary lymph nodes along the inferior border of the pectoralis minor muscle near the lateral thoracic artery; they receive lymph from the skin and muscles of the anterior and lateral thoracic walls and mammary gland and drain into the central and apical nodes (3÷6)
• subscapular or posterior group / nodi lymphoidei axillares subscapulares / subscapular axillary lymph nodes / nodi lymphoidei axillares posteriores / posterior axillary lymph nodes : 6 or 7 axillary lymph nodes along the inferior margins of the posterior axillary wall along the course of the subscapular artery; they receive lymph from the skin and superficial muscles of the posterior part of the neck and the posterior thoracic wall and drain into the apical and central nodes (2÷6)
• central group / nodi lymphoidei axillares centrales / central lymph nodes : 3 or 4 axillary lymph nodes embedded in adipose tissue near the base of the axilla; they receive lymph from the lateral, pectoral, and subscapular nodes and drain into the apical nodes (2÷10)
• subclavicular or apical group / nodi lymphoidei axillares apicales / apical lymph nodes : 6 to 12 axillary lymph nodes partly posterior to the superior part of the pectoralis minor muscle and partly in the apex of the axilla, receiving afferent vessels that accompany the cephalic vein and draining all other axillary nodes; their efferent vessels unite to form the subclavian trunk. (2÷9)

• nodi lymphoidei superficiales membri superioris / superficial lymph nodes of upper limb : the lymph nodes of the upper limb that are superficially placed; all except those in the hand and on the back of the forearm converge toward and accompany the superficial veins
• nodi lymphoidei cubitales / cubital lymph nodes / epitrochlear lymph nodes : 1 or 2 superficially placed lymph nodes situated above the medial epicondyle, medial to the basilic vein, the efferent vessels of which accompany the basilic vein and join the deep lymph vessels
• nodi lymphoidei supratrochleares / supratrochlear lymph nodes : 1 or 2 lymph nodes superficial to the deep fascia proximal to the medial epicondyle and medial to the basilic vein and draining into the deep lymph vessels.
• chest lymph nodes
• parietal lymph nodes
• nodi lymphoidei parasternales / parasternal lymph nodes (6÷10) : nodes located along the course of the internal thoracic artery, which drain the mammary gland, abdominal wall, and diaphragm.
• nodi lymphoidei intercostales / intercostal lymph nodes : lymph nodes in the back of the thorax, along the intercostal vessels (2÷3 per intercostal space)
• anterior diaphragmatic lymph nodes
• subscapular lymph nodes : the 5 to 7 lymph nodes extending along the subscapular veins at the lower border of the axilla, which drain the skin and muscles of the dorsal posterior shoulder region and lower part of the back of the neck.
• nodi lymphoidei deltopectorales / deltopectoral lymph nodes / nodi lymphoidei infraclaviculares / infraclavicular nodes : 1 or 2 lymph nodes in the groove between the pectoralis major and deltoid muscles, just inferior to the clavicle, which drain into the apical lymph nodes
• nodi lymphoidei interpectorales / interpectoral lymph nodes : small inconstant lymph nodes that may occur between the mammary gland and apical lymph nodes.
• nodi lymphoidei paramammarii / paramammary lymph nodes : lymph nodes on the lateral mammary gland that drain into the axillary lymph nodes.
• visceral lymph nodes
• anterior mediastinic lymph nodes
• right or prevascular anterior mediastinic lymph nodes
• left or preaorticocarotideal anterior mediastinic lymph nodes
• transverse chain anterior mediastinic lymph nodes
• diaphragmatic anterior mediastinic lymph nodes
• nodus lymphoideus ligamenti arteriosi / lymph node of ligamentum arteriosum : the lowest anterior mediastinal lymph node situated anterior to the ligamentum arteriosum.
• posterior mediastinic lymph nodes (8÷12)
• nodi lymphoidei juxtaoesophageales / juxtaesophageal lymph nodes : posterior mediastinal lymph nodes situated on both sides of the esophagus.
• bronchial lymph nodes
• nodi lymphoidei tracheobronchiales / inferior tracheobronchial lymph nodes
• nodi lymphoidei tracheobronchiales inferiores / inferior tracheobronchial lymph nodes : nodes in the angle of the bifurcation of the trachea, receiving lymph from adjacent structures.
• nodi lymphoidei tracheobronchiales superiores / superior tracheobronchial lymph nodes : nodes between the trachea and the bronchus on either side, receiving lymph from adjacent structures (5÷7)
• tracheal road fork lymph nodes (9÷12)
• nodi lymphoidei bronchopulmonales / bronchopulmonary lymph nodes / hilar lymph nodes and nodi lymphatici hilares : lymph nodes embedded in the root of the lung, mainly at the hilum that drain into the tracheobronchial lymph nodes
• nodi lymphoidei intrapulmonales / intrapulmonary lymph nodes / nodi lymphoidei pulmonales / pulmonary lymph nodes : nodes located along the larger bronchi within the lung substance, through which lymph from the lung drains
• nodus lymphoideus arcus venae azygos / lymph node of arch of azygos vein : a lymph node sometimes present on the azygos vein at the point where it arches over the root of the lung.
• nodi lymphoidei prepericardiaci / nodi lymphoidei prepericardiales / prepericardial lymph nodes : lymph nodes situated between the pericardium and sternum.
• nodi lymphoidei pericardiaci laterales / nodi lymphoidei pericardiales laterales / lateral pericardial lymph nodes : lymph nodes accompanying the pericardiacophrenic artery.
• nodi lymphoidei prevertebrales / prevertebral lymph nodes : lymph nodes situated in back of the thoracic aorta.
• nodi lymphoidei phrenici superiores / superior phrenic lymph nodes : several nodes on the thoracic surface of the diaphragm, receiving lymph from the intercostal spaces, pericardium, diaphragm, and liver; called also diaphragmatic lymph nodes.
• abdominal lymph nodes
• nodi lymphoidei abdominis parietales / parietal abdominal lymph nodes : the lymph nodes that drain the abdominal walls, comprising the
• left lymph nodes
• intermediate lymph nodes
• lumbar, aortic or lumboaortic lymph nodes (20÷30 ?) : numerous large lymph nodes extending from the aortic bifurcation to the aortic hiatus of the diaphragm, as 3 parallel chains: left, intermediate, and right
• nodi lymphoidei lumbales dextri / right lumbar lymph nodes / nodi lymphatici lumbares dextri : the chain of lumbar lymph nodes situated partly in front of the vena cava and partly behind it on the psoas major muscle
• nodi lymphoidei cavales laterales / lateral caval lymph nodes : a group of lymph nodes of the right lumbar group that are on the right side of the inferior vena cava.
• nodi lymphoidei precavales / precaval lymph nodes : a group of lymph nodes of the right lumbar group that is in front of the inferior vena cava.
• nodi lymphoidei retrocavales / retrocaval lymph nodes / postcaval lymph nodes / nodi lymphoidei postcavales : a group of lymph nodes of the right lumbar group situated behind the inferior vena cava
• nodi lymphoidei lumbales intermedii / intermediate lumbar lymph nodes / nodi lymphatici lumbares intermedii / paraaortic lymph nodes : the chain of lumbar lymph nodes that lie in the median plane, between the left and right lumbar lymph nodes
• nodi lymphoidei lumbales sinistri / left lumbar lymph nodes / nodi lymphatici lumbares sinistri : the chain of lumbar lymph nodes situated at the side of the abdominal aorta on the psoas major muscle, comprising 3 groups:
• nodi lymphoidei mesenterici / mesenteric lymph nodes (MLN) : nodes that lie at the root of the mesentery, receiving lymph from parts of the small intestine, cecum, appendix, and large intestine (130÷150)
• nodi lymphoidei mesenterici inferiores / inferior mesenteric lymph nodes : nodes situated along the inferior mesenteric vessels and receiving lymph from the adjacent region; they comprise two groups: the sigmoid and superior rectal lymph nodes.
• nodi lymphoidei sigmoidei / sigmoid lymph nodes : a group of lymph nodes of the inferior mesenteric group, situated along the sigmoid arteries.
• nodi lymphoidei mesenterici juxtaintestinales / juxtaintestinal mesenteric lymph nodes : the mesenteric lymph nodes situated close to the wall of the intestine between the branches of the jejunal and ileal arteries; they drain into the superior mesenteric lymph node.
• nodi lymphoidei mesenterici superiores / superior mesenteric lymph nodes : mesenteric lymph nodes situated along the superior mesenteric artery and draining various other groups of nodes in the region.
• nodi lymphoidei mesenterici superiores centrales / central superior mesenteric lymph nodes : the middle group of superior mesenteric nodes, situated along the ileal and jejunal branches of the superior mesenteric artery.
• nodi lymphoidei mesocolici / mesocolic lymph nodes : lymph nodes situated in the mesocolon; they drain through the superior mesenteric lymph node (20÷30)
• nodi lymphoidei colici dextri/medii/sinistri / colic lymph nodes : a subgroup of the mesocolic lymph nodes, situated along the right, middle, and left colic arteries.
• nodi lymphoidei paracolici / paracolic lymph nodes : a subgroup of the mesocolic lymph nodes, situated along the medial borders of the ascending and descending colon and along the mesenteric borders of the transverse and sigmoid colon.
• paracardial lymph nodes : a group of small lymph nodes forming a chain or ring (annulus lymphaticus cardiae), around the cardiac opening of the stomach.
• nodi lymphoidei gastrici dextri/sinistri / right/left gastric lymph nodes : a few nodes along the right and left gastric arteries that receive lymph from the stomach, spleen, duodenum, liver, and pancreas.
• nodi lymphoidei hepatici / hepatic lymph nodes : a variable number of lymph nodes situated along the proper and common hepatic arteries and the bile ducts that receive lymph from the stomach, spleen, duodenum, liver, and pancreas (3÷6)
• nodus lymphoideus foraminalis / foraminal lymph node / node of anterior border of epiploic foramen / node of epiploic foramen : a hepatic lymph node situated along the upper part of the common bile duct
• nodus lymphoideus cysticus / cystic lymph node / node of neck of gallbladder : a hepatic lymph node situated in the curve of the neck of the gallbladder at the junction of the cystic and common hepatic ducts
• pancreaticolienal lymph nodes (8÷10)
• right and left lateral aortic
• nodi lymphoidei retroaortici / retroaortic lymph nodes / postaortic lymph nodes / nodi lymphoidei postaortici : a group of lymph nodes of the left lumbar group, situated behind the aorta and formed by peripheral nodes of the right and left lateral aortic lymph nodes (4÷5)
• nodi lymphoidei preaortici / preaortic lymph nodes : a group of lymph nodes of the left lumbar group that is in front of the aorta and drains the abdominal part of the alimentary canal and its derivatives.
• terminal colic lymph nodes : lymph nodes associated with the main trunks of the superior and inferior mesenteric arteries, being continuous with the corresponding preaortic lymph nodes.
• epicolic lymph nodes : minute lymph nodes situated on the wall of the bowel and sometimes in the epiploic appendices.
• nodi lymphoidei phrenici inferiores / inferior phrenic lymph nodes : parietal lymph nodes accompanying the inferior vessels of the diaphragm.
• nodi lymphoidei epigastrici inferiores / inferior epigastric lymph nodes : lymph nodes along the deep epigastric vessels, receiving lymph from the lower abdominal wall.
• nodi lymphoidei abdominis viscerales / visceral abdominal lymph nodes : the numerous lymph nodes that drain the abdominal viscera
• nodi lymphoidei aortici laterales / lateral aortic lymph nodes : 2 chains (right and left) of the left lumbar group that are on the left side of the aorta and drain the suprarenal glands, kidneys, ureters, testes, ovaries, pelvic viscera (except the intestines), and posterior abdominal wall.
• nodi lymphoidei pylorici / pyloric lymph nodes : lymph nodes found anterior to the head of the pancreas, receiving lymph from the pyloric part of the stomach. They are subdivided into 3 groups:
• nodus lymphoideus suprapyloricus / suprapyloric lymph node : a pyloric lymph node located superior to the duodenum on the right gastric artery.
• nodi lymphoidei subpylorici / subpyloric lymph nodes : pyloric lymph nodes located inferior to the pylorus.
• nodi lymphoidei retropylorici / retropyloric lymph nodes : pyloric lymph nodes situated posterior to the pylorus.
• nodi lymphoidei pancreatici / pancreatic lymph nodes : nodes found along the pancreatic arteries that drain lymph from the pancreas to the pancreaticosplenic lymph nodes.
• nodi lymphoidei pancreatici inferiores / inferior pancreatic lymph nodes : lymph nodes associated with the inferior pancreatic artery.
• nodi lymphoidei pancreatici superiores / superior pancreatic lymph nodes : lymph nodes associated with the superior pancreatic artery.
• nodi lymphoidei pancreaticoduodenales / pancreaticoduodenal lymph nodes
• nodi lymphoidei pancreaticoduodenales inferiores / inferior pancreaticoduodenal lymph nodes : lymph nodes situated along the inferior pancreaticoduodenal artery.
• nodi lymphoidei pancreaticoduodenales superiores / superior pancreaticoduodenal lymph nodes : lymph nodes situated along the superior pancreaticoduodenal artery.
• nodi lymphoidei coeliaci / celiac lymph nodes : a few nodes along the celiac trunk, which receive lymph from the stomach, spleen, duodenum, liver, and pancreas.
• nodi lymphoidei splenici / splenic lymph nodes : lymph nodes in the capsule and larger trabeculae of the spleen that drain into adjacent lymph nodes; called also nodi lymphoidei lienales
• nodi lymphoidei gastroomentales dextri/sinistri / right/left gastroomental lymph nodes / nodi lymphatici gastroepiploici dextri/sinistri / right/left gastroepiploic lymph nodes : lymph nodes situated in the greater omentum along the pyloric half of the greater curvature of the stomach in association with the right and left gastroepiploic arteries
• nodi lymphoidei appendiculares / appendicular lymph nodes : lymph nodes situated along the appendicular artery and in the mesoappendix that drain into the ileocolic lymph nodes.
• nodi lymphoidei precaecales / prececal lymph nodes : lymph nodes situated in front of the cecum that drain into the anterior ileocolic lymph nodes.
• nodi lymphoidei retrocaecales / retrocecal lymph nodes : lymph nodes situated in back of the cecum that drain into the posterior ileocecal lymph nodes.
• nodi lymphoidei rectales superiores / superior rectal lymph nodes : a group of lymph nodes of the inferior mesenteric group, situated along the superior rectal artery.
• pelvic lymph nodes
• circumflex iliac lymph nodes : lymph nodes situated along the deep iliac circumflex vessels.
• nodi lymphoidei pelvis parietales / parietal pelvic lymph nodes : the lymph nodes that drain the wall of the pelvis
• nodi lymphoidei iliaci externi / external iliac lymph nodes : the 8 to 10 nodes along the external iliac vessels; they receive afferent vessels from the inguinal lymph nodes, deep part of the abdominal wall below the umbilicus, and some pelvic viscera and send efferent vessels to the common iliac lymph nodes.(6÷10)
• nodi lymphoidei iliaci externi intermedii / intermediate external iliac lymph nodes : the external iliac lymph nodes situated between the external iliac vessels.
• nodi lymphoidei iliaci externi laterales / lateral external iliac lymph nodes : the external iliac lymph nodes situated on the lateral aspect of the external iliac vessels.
• nodi lymphoidei iliaci externi mediales / medial external iliac lymph nodes : the external iliac lymph nodes situated on the medial aspect of the external iliac vessels.
• nodi lymphoidei interiliaci / interiliac lymph nodes : the external iliac lymph nodes situated between the external and internal iliac vessels and the obturator artery.
• nodi lymphoidei obturatorii / obturator lymph nodes : the external iliac lymph nodes situated in the obturator canal.
• nodi lymphoidei iliaci interni / internal iliac lymph nodes : nodes grouped around the origins of the branches of the internal iliac vessels; they receive afferent vessels from the pelvic viscera, perineum, and buttocks and send efferent vessels to the common iliac lymph nodes (10÷12)
• nodi lymphoidei gluteales inferiores / inferior gluteal lymph nodes : the internal iliac lymph nodes situated along the inferior gluteal artery.
• nodi lymphoidei gluteales superiores / superior gluteal lymph nodes : the internal iliac lymph nodes situated along the superior gluteal artery.
• nodi lymphoidei sacrales / sacral lymph nodes : the internal iliac lymph nodes situated along the lateral and median sacral vessels; they receive lymph from the rectum and posterior pelvic wall.
• nodi lymphoidei iliaci communes / common iliac lymph nodes : the 4 to 6 lymph nodes grouped at the sides and dorsal to the common iliac vessels; they receive afferent vessels from the lateral and internal iliac lymph nodes and send efferent vessels to the lateral aortic lymph nodes (8÷10)
• nodi lymphoidei iliaci communes intermedii / intermediate common iliac lymph nodes : the common iliac lymph nodes situated between the common iliac vessels.
• nodi lymphoidei iliaci communes laterales / lateral common iliac lymph nodes : the common iliac lymph nodes situated on the lateral aspect of the common iliac vessels.
• nodi lymphoidei iliaci communes mediales / medial common iliac lymph nodes : the common iliac lymph nodes situated on the medial aspect of the common iliac vessels.
• nodi lymphoidei iliaci communes promontorii / promontory common iliac lymph nodes : the common iliac lymph nodes situated in front of the sacral promontory.
• nodi lymphoidei iliaci communes subaortici / subaortic common iliac lymph nodes : the common iliac lymph nodes situated below the bifurcation of the aorta
• nodi lymphoidei pelvis viscerales / visceral pelvic lymph nodes : the lymph nodes that drain the pelvic viscera
• nodi lymphoidei parauterini / parauterine lymph nodes : lymph nodes situated around the uterus, consisting of superficial (beneath the peritoneum) and deep (in the substance of the uterine wall) nodes: they drain into the lumbar, external and internal iliac, sacral, and superficial inguinal lymph nodes.
• nodi lymphoidei paravaginales / paravaginal lymph nodes : lymph nodes situated around the vagina; they drain into the external and internal iliac, common iliac, and superficial inguinal lymph nodes.
• nodi lymphoidei paravesicales / paravesicular lymph nodes : lymph nodes situated around the urinary bladder; they drain into the external and internal iliac lymph nodes and, in association with some lymph nodes from the prostate, into the sacral and common iliac lymph nodes.
• nodi lymphoidei vesicales laterales / lateral vesicular lymph nodes : the paravesicular lymph nodes situated in relation to the lateral umbilical ligament.
• nodi lymphoidei prevesicales / prevesicular lymph nodes : the paravesicular lymph nodes situated in front of the urinary bladder.
• nodi lymphoidei retrovesicales / retrovesicular lymph nodes / postvesicular lymph nodes / nodi lymphoidei postvesicales : the paravesicular lymph nodes situated in back of the urinary bladder
• nodi lymphoidei pararectales / pararectal lymph nodes / anorectal lymph nodes / nodi lymphoidei anorectales : lymph nodes situated around the rectum, embedded in its muscular coat; they drain into the inferior mesenteric, sacral, internal iliac, common iliac, and superficial inguinal nodes
• nodus lymphoideus lacunaris intermedius / intermediate lacunar lymph node : a lymph node situated between the external iliac vessels at the lacuna vasorum
• nodus lymphoideus lacunaris lateralis / lateral lacunar lymph node : a lymph node situated on the lateral aspect of the external iliac vessels at the lacuna vasorum.
• nodus lymphoideus lacunaris medialis / medial lacunar lymph node : a lymph node situated on the medial aspect of the external iliac vessels at the lacuna vasorum.
• lower limb lymph nodes
• nodus lymphoideus tibialis anterior / anterior tibial lymph node : a lymph node situated along the anterior tibial artery.
• nodus lymphoideus tibialis posterior / posterior tibial lymph node : a lymph node situated along the posterior tibial artery.
• small peronier lymph nodes
• nodus lymphoideus fibularis / fibular lymph node / peroneal lymph node : a lymph node situated along the peroneal artery
• nodi lymphoidei poplitei / popliteal lymph nodes : lymph nodes embedded in the fat of the popliteal fossa; their efferent vessels accompany the femoral vessels to the deep inguinal lymph nodes.(4÷6)
• nodi lymphoidei poplitei profundi / deep popliteal lymph nodes : the popliteal lymph nodes situated at the sides of the popliteal vessels.
• nodi lymphoidei poplitei superficiales / superficial popliteal lymph nodes : the popliteal lymph nodes situated at the termination of the small saphenous vein.
• inguinal lymph centre / inguinal lymph nodes
• nodi lymphoidei inguinales superficiales / superficial inguinal lymph nodes : lymph nodes situated in the subcutaneous tissue inferior to the inguinal ligament on either side of the proximal part of the greater saphenous vein; they drain the skin of the lower abdominal wall, penis, scrotum or labia majora, perineum, and buttocks (15÷20)
• nodi lymphoidei inguinales superficiales inferiores / inferior superficial inguinal lymph nodes : the lower superficial inguinal lymph nodes situated below the opening of the saphenous vein.
• inferomedial
• inferolateral
• nodi lymphoidei inguinales superficiales superolaterales / superolateral superficial inguinal lymph nodes : the upper superficial inguinal nodes situated on the lateral side of the opening of the saphenous vein.
• nodi lymphoidei inguinales superficiales superomediales / superomedial superficial inguinal lymph nodes : the upper superficial inguinal lymph nodes situated on the medial side of the opening of the saphenous vein.
• nodi lymphoidei inguinales profundi / deep inguinal lymph nodes : nodes deep to the fascia lata along the femoral vein; they receive lymph from the deep structures of the lower limb and from the penis or clitoris, and superficial inguinal lymph nodes and drain into the external iliac lymph nodes (1÷8)
• Cloquet's node / node of Cloquet : the highest of the deep inguinal lymph nodes
• spleen (see also diseases of spleen) : 80-300 g (highest between age 25-35 years); from foetal week 12 up to foetal week 38 and in some diseases it sustains hemopoiesis. 14-40% of individuals has small accessory spleens in epiploon retrocavity. In addition to capturing Ags from the blood that passes through the spleen, migratory macrophages and DCs bring Ags to the spleen via splenic artery(there are no lymph vessels in parenchyma !), triggering immune responses. Capsular septa are short and don't divide spleen into lobes => no contractility. It contains 40 ml of blood and 33% of the platelets produced by bone marrow, and clears 20 ml of erythrocytes a day. See also splenic vein. From the examinations performed on 38 individuals it was possible to determine a mean value of 11.1 cm for the craniocaudal extent of the spleen, 11.8 cm for the anatomical length of the spleen, 10.4 cm for the width of the spleen, and 4.2 cm for the thickness of the spleen^ref.
• trabeculae splenicae / trabeculae of spleen / trabeculae lienis : fibrous bands that pass into the spleen from the tunica fibrosa and form the supporting framework of the organ
• trabecular veins : vessels coursing in splenic trabeculae, formed by tributary pulp veins.
• facies colica splenis or lienis : the surface of the spleen in contact with the colon
• facies gastrica splenis or lienis : the surface of the spleen in contact with the stomach
It can be functionally divided into :
• red pulp (RP) : capillaries can open into ...
• tissue (free blood cells form Billroth cords, representing a blood reserve: open circle (90%))
• directly into sinus of spleen / splenic sinus / sinus splenicus / sinus lienalis (a dilated venous sinus not lined by ordinary endothelial cells) (closed circle (10%)).
Macrophages surrounding ellipsoid or sheathed arteries or arterioles (arterial branches having spindle-shaped thickenings in their walls and forming the penicilli of the spleen) form the Schweigger-Seidel sheaths, which remove old/defective/opsonized blood cells (hemocatheresis : platelets and RBCs (erythrocatheresis)).
• marginal zone (MZ) sinus : memory function; at least a major number of human splenic CD27⁺ MZ B cells are migratory. Phenotypic data suggest a recirculation pathway between the spleen and mucosal tissues in humans^ref
• white pulp (WP) is structurally similar to a lymph node, although the spleen receives antigen directly from the blood and not through afferent lymphatics. It consists of  :
• marginal zone (MZ). It is made up of primary and secondary lymphoid follicles (see above for lymph nodes), containing
• marginal zone B cells (MZB). The origin of marginal-zone B cells is debated, and probably includes post-GC memory B cells and naive B cells involved in T-cell-independent immune responses.
• long-lived memory B cells
• T-dependent Ags
• marginal zone metallophilic macrophages (MMM)
• marginal zone macrophages (MZM) : the MARCO-MZB interaction is a mechanism for the retention of MZBs in the MZ by MZMs
• resting CD4^-8^-11b / Mac-1⁺205 / DEC205^- DCs
• resting CD4⁺8^-11b / Mac-1⁺205 / DEC205^- DCs
Depletion of MZM can be experimentally induced by administration of clodronate encapsulated in liposomes.
The marginal zone is a B-cell-rich zone located between B-cell follicles and the T-cell area in the spleen (a similar region is present in Peyer’s patches, but usually not in lymph nodes)
• periarteriolar lymphoid sheath (PALS) / noduli lymphoidei splenici / splenic lymphoid nodules / noduli lymphoidei lienales / folliculi lymphatici splenici / folliculi lymphatici lienales : aggregations of lymphatic tissue that ensheath the arteries in the spleen. Together with the artery itself it is named Malpighi lienal nodule / malpighian bodies or corpuscles of spleen), in which you can distinguish ...
• B cell zones (BCZ) : B cells appear at pregnancy month 3, while first plasma cells appear at pregnancy month 5÷6.
• newly formed (NF) or transitional (TR) B cells
• follicular (FO) B cells
• T cell zones (TCZ) : T cells appear at pregnancy month 4. Here initial T and B cell activation occurs. T-cell areas contain :
• both resting and activated CD4^-8⁺11b / Mac-1^-205 / DEC205⁺ DCs
• activated CD4^-8^- DCs migrated from marginal zone.
• activated CD4⁺ DCs migrated from marginal zone.
• NK cells represent 5÷15% of all spleen lymphocytes
Similar to the lymph node, the spleen has a conduit system consisting of a tubular network containing collagen fibres that are surrounded by reticular fibroblast. The white pulp is known to restrict cellular movement to lymphocytes and DCs, but the conduit also limits the entry of large molecules. Locally produced chemokines are also found in the conduit area : CCL21 in the T-cell area and CXCL13 / BLC in the B-cell area. Theories explaining how the blood in the spleen gets from the arteries to the venous sinuses :
• open or slow circulation theory holds that the capillaries open directly into the pulp reticulum, and that the blood gradually filters back into the venous sinuses
• closed or fast circulation theory holds that the capillaries empty directly into the venous sinuses
• closed-open circulation theory : the theory that both an open and a closed circulation are present in the spleen; e.g., a closed circulation in a contracted spleen may become an open circulation when the organ is distended
• penicilli arteriae lienalis / penicilli arteriae splenicae : brushlike groups of arterial branches of the lobules of the spleen
• artery of the pulp : a name given the first portion of one of the penicilli arteriae splenicae
• skin-associated lymphoid tissue (SALT) / cutaneous-associated lymphoid tissue (CALT)
• pineal-associated lymphoid tissue (PALT)
• (organized) mucosa-associated lymphoid tissue (MALT) (O-MALT) in lamina propria and submucosal tonaca of epithelia. It contains intraepithelial lymphocytes (IELs : mostly gd T cells) that recircle around blood and different MALTs : such a "common mucosa" theory is used by vaccines targeting mucosal immunity but immune responses at the site of induction is stronger than at distant sites and the urogenital tract seem to function more independently than others. Anyway common mucosal immunity can be efficiently induced in mice following immunization through the skin with vaccine formulations containing 1a,25-(OH)₂-vitamin D₃, chemical agents capable of locally enhancing cAMP levels, or exposure of skin to UVB^Ref. Lymphocyte traffic patterns, regulated by selective expression of adhesion proteins in peripheral or mucosal lymphatic tissues, maintain anatomic segregation of immunological memory by causing Ag-primed cells to return to specific anatomic destinations where they will encounter conditions that further facilitate expression of peripheral or mucosal immunity. Among potentially myriad factors, these conditions include prevalence of specific cytokines, adhesion to- and costimulation by specific stromal cells, and still unknown microenvironmental factors intrinsic to those lymphoid compartments that favor commitment of B cells to specific Ig isotypes or T cells to peripheral or mucosal immunity. MALT plasma cells produce mainly IgA dimers and IgM pentamers. As neither phagocytes nor killer cells nor complement factors are available on the external side of the epithelial barrier, the only biological activity of secretory antibodies is neutralization of the biological activity of the antigen by competitive binding (e.g. prevent absorption of viruses, Bacteria and toxins by blocking their adhesion), enabling them to be flushed away in the stream of secreted fluids and mucous washing over the epithelial membranes. IgA may also facilitate transport of pathogens and toxins out of the body by causing them to be conveyed into bile and other exocrine secretions. Ag-specific IgA has been shown to neutralize viral pathogens during transport across M cells of Peyer's patches, where nondegradative endosomal transport might otherwise deliver a pathogen into the host. Fc receptor-like 4 (FCRL4) / immunoglobulin superfamily receptor translocation-associated 1 (IRTA1) is a novel surface B-cell receptor related to Fc receptors, inhibitory receptor superfamily (IRS), and cell adhesion molecule (CAM) family members selectively and consistently expressed by a B-cell population located underneath and within the tonsil epithelium and dome epithelium of Peyer patches (regarded as the anatomic equivalents of marginal zone of spleen). Similarly, in mucosa-associated lymphoid tissue (MALT) lymphomas IRTA1 was mainly expressed by tumor cells involved in lympho-epithelial lesions. In contrast, no or a low number of IRTA1⁺ cells was usually observed in the marginal zone of mesenteric lymph nodes and spleen. Interestingly, monocytoid B cells in reactive lymph nodes were strongly IRTA1⁺. Tonsil IRTA1⁺ cells expressed the memory B-cell marker CD27 but not mantle cell-, germinal center-, and plasma cell-associated molecules. PCR analysis of single tonsil IRTA1⁺ cells showed they represent a mixed B-cell population carrying mostly mutated, but also unmutated, IgV genes. The immunohistochemical finding in the tonsil epithelial areas of aggregates of IRTA1⁺ B cells closely adjacent to plasma cells surrounding small vessels suggests antigen-triggered in situ proliferation/differentiation of memory IRTA1⁺ cells into plasma cells. Collectively, these results suggest a role of IRTA1 in the immune function of B cells within epithelia^ref.
• gut-associated lymphoid tissue (GALT) :

Cell types :
• intestinal intraepithelial lymphocytes (iIELs) reside between the basolateral faces of intestinal epithelial cells (IECs). Mucosal T-cell subsets :
• TcRab T lymphocytes
• acquired effector/memory ab-TcR⁺ T cells
• CD8ab⁺ and CD8ab-CD8aa acquire gut tropism and a memory phenotype after non-self antigen stimulation by Peyer's patch and mesenteric lymph node (MLN) DCs and have effector/CTL function
• CD4⁺ and CD4+CD8aa⁺ acquire gut tropism and a memory phenotype after non-self antigen stimulation by Peyer's patch and MLN DCs and have effector/help function
• natural memory ab-TcR⁺ T cells : DN and CD8aa⁺ acquire gut tropism and a memory phenotype after self-antigen selection in the thymus and have effector and/or regulatory functions
• gd-TcR⁺ T cells : DN and CD8aa⁺ acquire gut tropism and differentiation during ontogeny and have tissue repair and regulatory functions
The majority of iIELs express the cytotoxic CD8+ phenotype, either as a CD8aa homodimer or a CD8ab heterodimer. NK-like cytotoxicity of iIELs partly depends on CD4^-CD8aa⁺ and CD4^-CD8^- iIELs and TcR^- NK cells. Cell death program of IECs is regulated by self-produced  IL-15 through the activation of intraepithelial NK cells.
• a myeloid-derived mucosal DC in mice populates the entire lamina propria of the small intestine. Lamina propria DCs were found to depend on the chemokine receptor CX₃CR1 to form transepithelial dendrites, which enable the cells to directly sample luminal antigens. CX₃CR1 was also found to control the clearance of entero-invasive pathogens by DCs. Thus, CX₃CR1-dependent processes, which control host interactions of specialized DCs with commensal and pathogenic bacteria, may regulate immunological tolerance and inflammation^ref.
Anatomy :
• salivary glands (expecially parotid glands)
• nasopharyngeal lymphoid system or Waldeyer's ring : Storr pores allows a wide contact surface on tonsillar cryptae. Tonsils / tonsillae (small rounded mass of lymphoid tissue) :
• Santorini-Luschka pharyngeal tonsil / adenoid tonsil / tonsilla adenoidea / tonsilla pharyngea or pharyngealis / third tonsil : the diffuse lymphoid tissue and follicles in the roof and posterior wall of the nasopharynx
• noduli lymphoidei tonsillae pharyngealis / lymphoid nodules of pharyngeal tonsils : small collections of lymphoid tissue associated with the laryngeal tonsils.
• Gerlach's tubal tonsils / tonsilla tubaria / eustachian tonsil / tonsil of torus tubarius : a collection of lymphoid tissue associated with the pharyngeal opening of the auditory tube
• palatine tonsils or amygdalae / tonsilla palatina / faucial tonsil : either of 2 small, almond-shaped masses located between the palatoglossal and palatopharyngeal arches, one on either side of the oropharynx, composed mainly of lymphoid tissue, covered with mucous membrane, and containing various crypts and many lymph follicles
• submerged tonsil : a palatine tonsil that is shrunken and atrophied and is partly or entirely hidden by the palatoglossal arch
• lingual tonsil / tonsilla lingualis : an aggregation of lymph follicles on the floor of the oropharyngeal passageway, at the root of the tongue.
• noduli lymphoidei tonsillae lingualis / lymphoid nodules of lingual tonsil / folliculi linguales / lingual follicles : lymphoid nodules on the root of the tongue, associated with the lingual tonsil
• laryngeal tonsil in tunica propria of upper part of ventriculus laryngis Morgagnii
• inductive sites : the enteric bacterial flora appears to be the major stimulus for the development of the mucosal immune system, as reflected by the death of MALT in adult germfree animals. When germfree animals are given an intestinal flora, their MALT greatly expands along the length of intestine and secretory IgA is produced in quantity. Some bacteria are more effective than others when given to germfree mice in inducing the GC reactions in PPs, stimulating IgA plasma cells in the lamina propria. Intestine develops immunological  tolerance to Ags of enteric bacterial flora, i.e., intestinal lymphocytes do not proliferate when stimulated with Ags of their own intestinal bacteria but do proliferate when stimulated with Ags of intestinal bacteria isolated from other humans.
• noduli lymphoidei aggregati intestini tenuis / aggregated lymphoid nodules of small intestine / ileal Peyer's patches (PP) (IPP) / Peyer's glands or plaques / noduli lymphatici aggregati [peyeri] : oval elevated areas of lymphoid tissue on the mucosa of the small intestine, composed of ...
• many lymphoid follicles closely packed together. The dome epithelium of PP is regarded as the anatomic equivalents of marginal zone of spleen
• follicle-associated epithelium (FAE), containing enterocytes and microfold (M) cells
• noduli lymphoidei solitarii / isolated lymphoid follicles (ILF) / solitary lymphatic or lymphoid nodules / noduli lymphatici solitarii / folliculi lymphatici solitarii / solitary lymphatic or lymphoid follicles : small concentrations of lymphoid tissue scattered throughout the mucosa and submucosa of the small and large intestines
• effector sites (lamina propria)
• noduli lymphoidei aggregati appendicis vermiformis / aggregated lymphoid nodules of vermiform appendix / folliculi lymphatici aggregati processus vermiformis : oval elevated areas of lymphoid tissue occupying the greater part of the submucosa of the appendix vermiformis. It is anatomically equivalent to avian bursa of Fabricius (whose functional equivalent is hematopoietic bone marrow). If the human appendix functions as a primary lymphoid organ, it may occur during the early development, when GC T cell density is low.
• nasal-associated lymphoid tissue (NALT)
• (constitutive) bronchus-associated lymphoid tissue (BALT) is occasionally found in the upper bronchi of some species (mice and humans) and is induced by an antigen-independent developmental pathway^{ref1, ref2} : it contains significant numbers of normal IgD-secreting plasma cells due to activation by OMPs from colonizing Moraxella catarrhalis and Haemophilus influenzae.
• noduli lymphatici bronchiales :  lymph nodules situated in the lining of the bronchi.
• induced BALT (iBALT) : although the presence of BALT in mouse and human lungs is controversial, there are reports that infection or inflammation triggers the organization of lymphoid structures in the lungs of both species^{ref1, ref2, ref3, ref4}. These structures do not fit the classical definition of BALT, as they are not formed independently of antigen^{ref1, (Plesch, B.E.C., van der Brugge-Gamelkoorn, G.J. & van de Ende, M.B. Development of bronchus associated lymphoid tissue (BALT) in the rat, with special reference to T and B cells. Dev. Comp. Immunol. 7, 79–84 (1983). )}. Because inducible BALT (iBALT) appears in the lung only after infection or inflammation, it is generally assumed that iBALT is simply an accumulation of effector cells that were initially primed in conventional lymphoid organs; however, it is also possible that inflammatory responses directly trigger the neo-formation of iBALT, which promotes the recruitment, priming and expansion of antigen-specific lymphocytes in situ. Thus, iBALT may functionally replace conventional lymphoid organs in respiratory immune responses. A fundamental tenet of immunology is that primary adaptive immune responses are initiated in secondary lymphoid organs, such as lymph nodes, Peyer's patches or spleen^{ref1, ref2, ref3}. These lymphoid organs are organized to recruit naive lymphocytes from the blood and to promote their interaction with activated antigen-presenting cells from surrounding tissues^ref. Once lymphocytes have been activated and clonally expanded in centralized lymphoid organs, the resulting effector cells localize to the infected or inflamed tissues and perform their effector functions^ref. For example, B and T cells responding to influenza virus are first detected in the lymph nodes that drain the respiratory tract, and are only later found in the lung^ref. Consistent with an essential role for lymphoid organs in primary immune responses, splenectomized lymphotoxin--null (Lta^-/-) mice^{ref1, ref2} or alymphoplastic (aly/aly, also known as Map3k14^-/-) mice^{ref1, ref2} — which lack spleen, lymph nodes and Peyer's patches — are unable to generate primary immune responses to a variety of pathogens^ref, antigens^ref and allografts^ref. However, Lta^-/- mice infected with respiratory viruses are capable of generating antigen-specific B and T cells^{ref1, ref2}, albeit with delayed kinetics, suggesting that lymphocytes can also be primed in non-lymphoid tissues. Consistent with this idea, the bone marrow seems to function as an alternative site of lymphocyte priming to systemic antigens when lymph nodes are unavailable^{ref1, ref2}. Another tissue that facilitates primary immune responses to respiratory infections is the BALT^ref. Lymphoid structures, complete with B cell follicles, germinal centers, and T cell zones, form in the lung in response to influenza infection^ref. This finding casts new light on respiratory immunity, showing that it is more self-contained than previously thought. These data are consistent with published reports showing that T cells can be primed directly in the lung^ref. Therefore, it is somewhat surprising that iBALT is often overlooked as an inductive site for immune responses to respiratory infections, particularly as GCB cells and iBALT are easily detected in the lungs of normal mice. The most probable explanation for this oversight is that immune responses initiated in iBALT are delayed relative to the immune response in the draining lymph nodes, owing to the time it takes to form iBALT. Therefore, immune responses initiated in iBALT of normal mice are obscured by the rapid and robust responses initiated in conventional lymphoid organs. Notably, other studies have shown that iBALT is particularly prominent after multiple respiratory infections^ref. iBALT induced by one infection will alter the kinetics and location of subsequent immune responses to respiratory antigens. For example, the ability of previous influenza infection to prevent tolerance induction by the intranasal administration of ovalbumin may be the result, in part, of the presence of iBALT^ref. In addition, the formation of iBALT in chronic lung diseases, such as pulmonary tuberculosis (PTB) or COPD, may be a component of the pathology^ref. Although the iBALT that develops after influenza infection resembles constitutive BALT, it is distinct in that it is induced by inflammatory insult. In addition, the size of iBALT varies widely, from small clusters of B cells, T cells and DCs to well-developed follicular areas. Furthermore, unlike constitutive BALT, iBALT is found in perivascular, peribronchial and even interstitial areas in the lower airways of the lung, and does not always occur under a dome epithelium. However, iBALT does contain B-cell follicles centered around networks of FDCs, separated by interfollicular regions containing DCs and T cells. High endothelial venules (HEVs) expressing PNAd are also present in iBALT, allowing for the recruitment of naive T cells^ref. Thus, iBALT shares functional and structural characteristics with classically defined BALT^{ref1, ref2}. However, whereas the development of secondary lymphoid organs — such as lymph nodes and Peyer's patches — and the expression of CXCL13 / BLC and CCL21 in the spleen are typically dependent on LT^{ref1, ref2, ref3}, the formation of iBALT and the expression of CXCL13 and CCL21 in the lung occur independently of LT. Similarly, germinal-center formation in the lung, but not the spleen or NALT, is LT independent. Thus, the development and organization of iBALT is governed by mechanisms that are distinct from those that regulate the development and organization of conventional secondary lymphoid organs. Notably, iBALT is often observed in the lungs of Lta^-/- mice that have not been intentionally infected^ref. A number of possibilities have been proposed to explain this phenomenon. For example, the lack of IgE in Lta^-/- mice may result in respiratory inflammation and lymphocyte accumulation in the lung^ref. In addition, the inability of Lta^-/- mice to express AIRE in the thymus may cause autoimmune inflammation in the lung and other tissues^ref. Alternatively, the constitutive expression of CCL21 in the lungs may result in the enhanced recruitment of lymphocytes owing to the loss of CCL21 in conventional lymphoid organs^ref. Finally, it is possible that respiratory infection with opportunistic pathogens may result in increased lymphocyte accumulation in the lungs of Lta^-/- mice. Lta^-/- mice re-derived by embryo transfer and maintained on antibiotics to prevent infection with Pneumocystis carinii and other respiratory pathogens did not have significant infiltration in the lungs of Lta^-/- mice under the age of 4–5 months. However, as these mice aged, accumulations of lymphocytes in the lungs (particularly B cells) occurred. This may be the result of delayed colonization of the lung by opportunistic pathogens or to other defects in Lta^-/- mice. Importantly, the possibility that the relatively normal respiratory immune responses observed in SLP mice resulted from pre-existing iBALT in Lta^-/- recipient mice was eliminated by confirming results with splenectomized Rorc^-/- mice. As Rorc^-/- mice lack lymph nodes and Peyer's patches^ref, but express LT normally and do not spontaneously develop iBALT, they provided an independent method to evaluate the requirement for spleen, lymph nodes and Peyer's patches in respiratory immune responses. These experiments showed that T- and B-cell responses were generated with near-normal to normal kinetics in splenectomized Rorc^-/ mice, and suggest that any pre-existing lymphoid accumulations in the lungs of Lta^-/- recipient mice did not measurably influence results. Thus, the formation of iBALT occurs as a normal component of the immune response to respiratory infections and may also occur as a consequence of pathological inflammation in the lung. One surprising outcome of these experiments was that iBALT initiated immune responses that were not only protective, but resulted in less morbidity and mortality than immune responses initiated in conventional lymphoid tissues, probably simply a function of the reduced size of the immune response at early times after infection in SLP mice. Although the influenza-specific CD8⁺ T-cell response in SLP mice was about 20% of WT levels on days 9 and 10, this was sufficient to substantially lower the viral load in SLP mice. By day 14, when large numbers of T cells were present in the lungs of SLP mice, virus was already eliminated, which limited additional T-cell activation. Thus, the T-cell response in SLP mice is limited at both early and late time points of infection. Because activated T cells produce large quantities of TNF, a reduced T-cell response in SLP mice should result in less weight loss and morbidity. Therefore, the increased survival and reduced morbidity of SLP mice is probably the result of 'just enough' immunity, which begins to clear virus without the systemic production of pathologic levels of cytokines. Together, these data alter our perception of how respiratory immune responses occur in normal animals, and overturn the immunological dogma that primary immune responses are generated only in constitutively present secondary lymphoid organs. Secondary lymphoid organs, such as spleen and lymph nodes, accelerate and amplify immune responses to antigens or pathogens in peripheral tissues. Yet these lymphoid organs are not absolutely required for immunity and may, under certain circumstances, facilitate the development of overly robust and perhaps damaging immune responses. However, smaller and possibly less pathologic immune responses can be initiated locally within the lung, but only after a delay, during which lymphocytes are recruited and organized at the site of infection. Although peripheral lymphoid organs are not absolutely required for the initiation of immune responses, these data do not contradict the idea that lymphoid tissues facilitate immune responses and provide a significant benefit to the host, particularly in response to highly virulent pathogens. Instead, the lung, and perhaps other non-lymphoid organs, have the ability to organize local immune responses; furthermore, they suggest that the immune response generated in these local sites can be protective, yet functionally different, to those initiated in conventional lymphoid organs. If so, then this argues that vaccines that target immune responses to local tissues rather than to conventional lymphoid organs may provide protection with reduced potential for immune-mediated damage.
• vagina
• noduli lymphatici vaginales : small collections of lymphatic tissue deep to the epithelial surface of the vagina.
• urinary tract
• noduli lymphatici vesicales : collections of lymphatic tissue in the lining of the urinary bladder.
• conjunctiva
• noduli lymphatici conjunctivales : lymph nodules situated in the conjunctiva.
• mammary glands during breast feeding
• tertiary extralymphoid tissue
• mucosal epithelia
• liver sustains hematopoiesis from foetal week 6 up to foetal week 38
• extraembryonic yolk sac (and intraembryonic splanchnopleura ?) sustains hematopoesis from foetal week ? up to foetal week ?

• Ag-specific cells will be brought into contact with Ag
• memory cells will be widely disseminated enabling a widespread response to Ag

Copyright © 2001-2014 Daniele Focosi. All rights reserved | Terms of use | Legal notices
 About this site  | Acknowledgements  |    |    | Current link partners
Abbreviations and acronyms  |  Medical terminology  |  Add a link  | Translate   | Softwares

---