Lymphatic system

Lymphatic system consists of blind-ended lymphatic capillaries, lymphatic vessels, lymph nodes, lymphatic tissues, and red bone marrow. ∼1-4 L of lymph is formed in a day, most of it derived from the gastrointestinal tract, especially after a fat-containing meal (Alexander et al., 2010). The liver is another large producer of lymph. Although physiologically very important, lymph flow rates are very low compared to blood perfusion. Lymph nodes accommodate white blood cells and filter foreign bodies from the lymph fluid. T- and B-cells interact with dendritic cells in distinct regions, facilitating adaptive immunity. Collecting lymphatic vessels have valves which ensure that lymph flows unidirectionally. Lymph is collected to large lymphatic trunks, including thoracic duct and right lymphatic duct, that lead the lymph into subclavian veins.

Lymphatic capillaries consist of overlapping endothelial cells, and lack pericytes and smooth muscle cells. Basement membrane is incomplete or lacking. Lymph capillaries can still stay open and expand with the help of anchoring filaments, fibrillar structures that connect the abluminal surface of endothelial cells to the extracellular matrix. Endothelial junctions in lymphatic capillaries serve as a microvalve which allows the interstitial fluid and small particles (≤25 nm) to flow into the lumen, but reduces the leakage from lumen back into the interstitium. Larger particles are transported into lymph by pinocytosis.

Collecting lymphatic vessels are surrounded by smooth muscle cells, pumping lymph against pressure gradient, with contraction rate of 1-15 cycles/min. Intraluminal valves, located 2-3 mm apart, ensure unidirectional lymphatics movement in lymphatic vessels towards the lymph nodes and further into large lymphatic trunks. Lymphangion is the contractile unit, consisting of the lymphatic muscular segment bounded by two valves. Lymphatic pumping is increased by cholecystokinin (CCK), glucagon, endothelin, substance P, serotonin, dopamine, histamine, and ATP; pumping is reduced by vasopressin, vasoactive intestinal peptide (VIP), acetylcholine, and ROS (Alexander et al., 2010).

In lymph node, lymph is filtered through phagocytes and lymphocytes into hilum, and then drained into efferent lymphatic vessel. Lymph nodes in the lumbar and intestinal trunk drain into cisterna chyli, from where lymph is transported into the ∼40 cm long thoracic duct. Lymph is returned into venous circulation at the junction of the internal jugular and subclavian veins.

Lymphangiogenesis is regulated by VEGF-C and VEGF-D, and indirectly by NO. MMP-9 participates in lymphatic regeneration. Inflammation and obesity induces lymphangiogenesis. Existing lymphatic networks can be expanded, venous structures can be reprogrammed, or lymphatic progenitor cells are recruited. TGF-β inhibits lymphangiogenesis (Alexander et al., 2010) Leukotriene B4 (LTB4) is involved in development of lymphoedema.

White blood cells, which have migrated from blood into interstitial space, can return to the circulation via lymphatic vessels and lymph nodes. Lymphatic endothelial cells express chemokines and adhesion molecules, and can direct the leukocytes into lymphatics or into interstitial space.

The spleen is a reticuloendothelial lymphoid organ specialized in filtering blood and producing components of complement and specific antibodies. About 25% of white blood cells and 30% of platelets in the body are located or stored in the spleen.

Chronic venous disease (CVeD) is very common, especially in the lower limbs. Valvular incompetence leads to reflux, venous hypertension, increased capillary pressure, and further to accumulation of fluid within interstitial space (oedema). Lymphatic drainage fails in the advanced stages of the disease. Increased vessel permeability leads also to extravasation of white blood cells and plasma proteins into the tissue.

Cancer cells can travel via lymphatic system to distant sites. Tumour growth can obstruct lymph flow, causing lymph reflux and lymphatic-venous shunting, which may promote metastasis formation. Tumours may release lymphangiogenic factors. Lymphatic vessels and lymph nodes can be visualized with PET after injecting [18F]AIF-NEB into the tissue; the radioligand complexes with endogenous albumin in the interstitial fluid (Wang et al., 2015). Local injection allows the detection of sentinel lymph nodes (SLNs). In early-stage cancer SLN biopsy reduces the need for lymph node dissection which may cause lymphoedema, nerve injury, and other complications. Contrast-enhanced CT and MRI have been used to lymph node staging in cancer patients; enlarged lymph nodes are considered suspicious, and size thresholds have been defined in RECIST criteria (Eisenhauer et al., 2009). 99mTc labelled radiocolloids have been used for lymphoscintigraphy and SLN identification during operation with hand-held γ-probe. Particle sizes between 100 and 200 nm provide efficient lymphatic drainage from the site of interstitial injection, with satisfactory retention in the SLNs (Pereira Arias-Bouda et al., 2020). Variation in the lymph flow speed and pattern may cause false results in SLN mapping.

Lymphatic system contains white blood cells in large numbers. Mannose receptor (CD206) is expressed on the surface of macrophages, playing a role in both innate and adaptive immune systems. Mannose receptor has been targeted by mannose-conjugated albumin, dextran, and liposomes labelled with 68Ga and 64Cu; these tracers may be useful in detecting macrophages, and have been used to localize for example lymph nodes (Choi et al, 2011; Locke et al, 2012; Eo et al, 2015; Kang et al, 2015; Lee et al., 2017). [99mTc]tilmanocept is a mannocylated dextran with FDA approval for lymphatic mapping, and has better tissue kinetics than non-specific radiocolloids. Li et al (2016) developed 18F-labeled mannan, and found high uptake in macrophage-rich organs in healthy rats.

Rapidly proliferating cells, including those in lymphoid organs, rely less on de novo synthesis of DNA building blocks and more on salvage pathway for DNA synthesis where deoxyribonucleosides are converted to nucleotides by deoxyribonucleoside kinases. 1-(2'-deoxy-2'-[18F]fluoroarabinofuranosyl)cytosine ([18F]FAC) has been found to be suitable radioligand for activity of the deoxyribonucleotide salvage pathway, and for imaging lymphoid organs and immune activation (Radu et al., 2008; Brewer et al., 2010).

Mononuclear phagocyte system

Mononuclear phagocyte system (MPS), previously called reticuloendothelial system (RES), is part of the immune system, consisting of phagocytic macrophages and monocytes of myeloid lineage, located in reticular connective tissue. MPS consists of macrophages in the red pulp of the spleen, Kupffer's cells in the liver, osteoclasts in bone and bone marrow, monocytes in the blood and bone marrow, sinus histiocytes in lymph nodes, alveolar macrophages in the lungs, Langerhans cells in the skin macrophages in adipose tissue and peritoneal cavity, intraglomerular mesangial cells in the kidneys, and microglia in the central nervous system. MPS makes and destructs leukocytes, erythrocytes, and plasma proteins.

SPECT imaging of MPS (or reticuloendothelial system) is based on intravenous injection of 99mTc-labelled colloids, which are phagocytosed by macrophages of the MPS. Normally about 90% of the colloid accumulates in the liver, and ∼5% in the spleen and another 5% in the bone marrow (Desai & Thakur, 1985). In acute and chronic hepatic inflammation, colloid phagocytosis in the liver is reduced, even to ∼30-35% (Krishnamurthy & Krishnamurthy, 2009). For PET imaging, nanocrystalline cellulose has been labelled with 89Zr and 64Cu (Sarparanta et al., 2020). Multimodal PET/MR imaging of lymphatic drainage is possible with nanoparticles such as [89Zr]ferumoxytol (Thorek et al., 2014).

Gallium and aluminium ions readily form colloids in aqueous solutions without chelators.

Clever-1

Clever-1 (common lymphatic endothelial and vascular endothelial receptor-1, also known as Stabilin-1 and FEEL-1) is a scavenger receptor, expressed on lymphatic endothelial cells, sinusoidal endothelial cells, and immunosuppressive monocytes and macrophages (Hollmén et al., 2020). Clever-1 binds a wide range of ligands, from lipoproteins to carbohydrates, and is involved in receptor-mediated endocytosis, intracellular sorting, and recycling. Clever-1 is expressed both on the afferent and efferent lymphatics, mediating the migration of incoming lymphocytes into the draining lymph nodes and their exit from the lymph nodes. Clever-1 is involved in inflammation, fibrosis, and cancer.

Monoclonal antibody bexmarilimab binds Clever-1, and may be used in macrophage-guided immunotherapy of cancer (Hollmén et al., 2022). [89Zr]DFO-bexmarilimab has been studied in rabbit model of renal fibrosis (UUO model), where its has shown increased uptake in the fibrotic kidney, supporting its use for clinical PET studies to, for example, stratify patients for bexmarilimab treatment, evaluate the efficacy of treatment, or monitor disease progression (Moisio et al., 2023).


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Literature

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Bikfalvi A: A Brief History of Blood and Lymphatic Vessels. Springer, 2018. ISBN 978-3-319-74376-9. doi: 10.1007/978-3-319-74376-9.

Gloviczki P (ed.): Handbook of Venous and Lymphatic Disorders, 4th ed., CRC Press, 2017. ISBN 978-1-4987-2440-1.

Lee B-B, Rockson SG, Bergan J (eds.): Lymphedema - A Concise Compendium of Theory and Practice, 2nd ed., Springer, 2018. ISBN 978-3-319-52423-8. doi: 10.1007/978-3-319-52423-8.

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Pan W-R: Atlas of Lymphatic Anatomy in the Head, Neck, Chest and Limbs. Springer, 2017. doi: 10.1007/978-981-10-3749-8.

Ramirez C (ed.): The Lymphatic System - Components, Functions and Diseases. Nova Science Publishers, 2016. ISBN 978-1-63484-690-5.

Randolph GJ, Ivanov S, Zinselmeyer BH, Scallan JP. The lymphatic system: integral roles in immunity. Annu Rev Immunol. 2017; 35: 31-52. doi: 10.1146/annurev-immunol041015-055354.



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Updated at: 2023-01-31
Created at: 2016-05-15
Written by: Vesa Oikonen