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The immune system intergrate cells mainly present in lymphoid organs and tissues that react to modifications provided by the environment. They include cells including adaptive immunity (T and B cells) innate effectors and innate like effectors as well as soluble factors like cytokines and antibodies. This system acts differently in the different organs and tissues and upon environmental stress. Cancer induces also a modification of the homeostasis of the tissues. Immunology is a rapidly evolving science with important recent and not fully completed actors and functions.Various novel therapies rely on the immune system and have demonstrated their high effciency during the very last years. The first most recent waves of immunotherapies rely on the mechanisms of cosignaling but also genitically engeneered T cells prone to kill tumor targets as well as technological development using bispecific antibodies recognizing both tumor and an activating receptor on immune cells.The next steps will embrace various important mechanisms involved in the immune responses including cytokines, blockade of the inhibitory pathways in the tumor micro environment, innate and innate-like cells and vaccines.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Toutes les cellules libèrent plusieurs types de vésicules extracellulaires (VEs) qui transportent protéines, lipides et acides nucléiques. Ces vésicules de petite taille se retrouvent dans tous les fluides biologiques tel que le sang et la lymphe et interagissent avec les cellules environnantes. Le système lymphatique constitue une voie de prédilection pour la mobilisation des accepteurs de cholestérol à partir de la paroi artérielle. Nous avons démontré dans un modèle murin qu’une dysfonction lymphatique précède la formation de la plaque d’athérome et que cette dysfonction touche a priori la capacité de contraction des vaisseaux collecteurs. À la base de toutes ces observations, nous avons émis l’hypothèse que les VEs contribuent à la dysfonction lymphatique liée à l’athérosclérose. Pour répondre à ceci, nous avons mis en place un projet translationnel composé de deux groupes de sujets sains, sans maladie cardiovasculaire, qui se distinguent par la présence d’antécédents familiaux d’accidents cardiovasculaires prématurés chez un parent du premier degré. Nous avons quantifié plusieurs sous-types d’intérêt de VEs en circulation à partir du plasma exempt de plaquettes, par cytométrie en flux ultraspécialisés dans la détection de petites particules (> 100 nm) combiné à d’autres techniques complémentaires standardisées. Ensuite, nous avons évalué la fonction lymphatique grâce à l’imagerie par proche infrarouge après injection du vert indocyanine (ICG). Nos résultats préliminaires sont prometteurs quant aux rôles des VEs et de la dysfonction lymphatique dans le développement de l’athérosclérose et corroborent avec nos observations faites chez la souris. Les sujets avec antécédents familiaux de maladie cardiovasculaire (MCV) présentent des signes de dysfonction lymphatique avant même l’apparition de plaques d’athérome subcliniques. La réponse mécano-sensible de leurs vaisseaux collecteurs paraît défectueuse et est observable de concert avec un profil de VEs qui présument une atteinte lymphatique. Ces résultats restent à être confirmer avec le recrutement de sujets additionnels et l'évaluation de la corrélation avec le score de risque polygénique de développer une MCV, dans l’objectif ultime de faire des VEs et de la fonction lymphatique de nouveaux biomarqueurs dans l’identification précoce des MCV., All cell types release extracellular vesicles (EVs) that carry different types of cellular cargo, such as proteins, lipids and nucleic acids. These small vesicles are found in all biological fluids including blood and lymph and can interact with neighboring cells. The lymphatic system is a preferred route for the mobilization of cholesterol from the arterial wall. We have demonstrated in a mouse model that lymphatic dysfunction precedes the development of atherosclerosis and that that this dysfunction affects the contraction capacity of the collecting vessels. Based on these observations, we hypothesized that EVs contribute to atherosclerosis-associated lymphatic dysfunction. Therefore, we have initiated a translational study involving two groups of healthy subjects that differ in their risk of cardiovascular disease (CVD). We quantified several subtypes of circulating EVs on platelet-free plasma by ultraspecialized flow cytometry in the detection of small particles (> 100 nm) combined to other state-of-the art complementary techniques. Next, we assessed the lymphatic function using near-infrared imaging and injection of indocyanine green (ICG). Our preliminary results are promising for the role of EVs and lymphatic dysfunction in the development of atherosclerosis and corroborate with our observations made in mice. Individuals at high risk of CVD have signs of lymphatic dysfunction even before the onset of subclinical atherosclerosis. The mechano-sensitive response of their collecting vessels appears to be defective and is observable in concert with a profile of EVs that presume lymphatic damage. These results remain to be confirmed with the recruitment of additional subjects and the assessment of the correlation with the polygenic risk score of developing a CVD, in the hope of making these specific EV subsets and lymphatic function new biomarkers in the early detection of CVD.

Les lymphangiomes kystiques sont des malformations congénitales portant sur le système lymphatique. Ce sont des lésions bénignes dysembryoplasiques rares prédominant nettement au niveau de la région de la tête et du cou plus particulièrement dans le triangle cervical postérieur. Ils surviennent généralement durant l'enfance et sont exceptionnels chez l’adulte. Nous rapportons une observation clinique d’un lymphangiome kystique du cou chez un sujet de 22 ans.

The considerable metabolic activity of the central nervous system (CNS) requires an efficient system of tissue drainage and detoxification. The CNS is however devoid of lymphatic vessels, a vasculature ensuring interstitial fluid drainage and immune survey in other organs. A unique system of drainage has recently been identified between the cerebrospinal fluid (CSF), brain interstitial fluids and meningeal lymphatic vessels. This system is coupling a cerebral "glymphatic" flow with a meningeal lymphatic vasculature. The "glymphatic" system includes perivascular spaces and astrocytes, and drains interstitial fluids, from and towards the CSF. Meningeal lymphatic vessels are functionally linked to the cerebral "glymphatic" efflux by clearing intracerebral macromolecules and antigens towards the peripheral lymphatic system. The "glymphatic"-"meningeal lymphatics" system is potentially offering new therapeutic targets to improve cerebral drainage and immune survey in human CNS diseases.

International audience; L’activité métabolique considérable du système nerveux central (SNC) requiert un système efficace de drainage et de détoxification tissulaire. Le SNC est pourtant dépourvu de vaisseaux lymphatiques qui assurent le drainage des fluides interstitiels et la surveillance immunitaire dans la plupart des tissus. Un système circulatoire original a été récemment découvert entre le liquide céphalo-rachidien (LCR), le parenchyme cérébral et les vaisseaux lymphatiques des méninges. Le système « glymphatique » implique les espaces périvasculaires et les astrocytes qui drainent les fluides interstitiels depuis et vers le LCR. Des vaisseaux lymphatiques méningés complètent le système glymphatique cérébral en assurant la clairance des macromolécules et des antigènes vers le réseau lymphatique périphérique. Le couple « glymphatique-lymphatiques méningés » constitue ainsi un ensemble de nouvelles cibles thérapeutiques pour améliorer le drainage cérébral et la surveillance immunitaire dans les maladies du SNC.

Lymphedema results from impaired lymphatic transport with increased limb volume. Lymphedema are divided in primary and secondary forms. Upper-limb lymphedema secondary to breast cancer treatment is the most frequent in France. Primary lymphedema is sporadic, rarely familial or associated with complex malformative or genetic disorders. Diagnosis of lymphedema is mainly clinical and lymphoscintigraphy is useful in primary form to assess precisely the lymphatic function of the two limbs. Erysipelas (cellulitis) is the main complication, but psychological or functional discomfort may occur throughout the course of lymphedema. Lipedema is the main differential diagnosis, defined as an abnormal accumulation of fat from hip to ankle. Lymphedema management is based on complete decongestive physiotherapy (multilayer low-stretch bandage, manual lymph drainage, skin care, exercises). The first phase of treatment leads to a reduction of lymphedema volume and the second phase stabilizes the volume. Multilayer low-stretch bandage and elastic compression is the cornerstone of the complete decongestive physiotherapy. Patient-education programs, including self-management, aim to improve patient autonomy.

The lymphatic system of the pelvis collects the lymph of the genital and urinary organs and of the digestive tract. It is formed by lymphatic nodes and vessels situated inside the conjunctive tissue, near the organs (visceral lymphatic nodes) but especially along the external, internal and common iliac vessels (iliac lymphatic nodes). These nodes receive afferent vessels issued from the different pelvic organs. From the iliac lymphnodes arise efferent vessels running towards lymphatic collectors, situated above them, and which end in the lymphatic lombar duct. The lymphatic pathways represent the preferential way of scattering of cancerous cells. Therefore, the knowledge of the anatomy, of the situation and of the draining of the nodes is of the utmost importance in the evaluation of a cancer of a pelvic organ.

The pleural lymphatic system has a great absorption capacity. Its most known function is fluid resorption. The pleura which cover the lungs (visceral pleura), the mediastinum, diaphragm and thoracic wall (parietal pleura) are formed by a mesothelial cell layer (mesothelium). This permeable layer is in direct contact with the vascular endothelium. The mesothelium is based over a connective tissue (interstitium) containing the blood and lymphatic vessels. The primary lymphatic vessels drain interstitium but are also in direct contact with pleural space by the stoma or openings, situated in the lower parts of parietal pleura, i.e: diaphragm, over lower ribs and mediastinum but not existing in the adjacent visceral pleura. In addition, a part of interstitial pulmonary fluid entered in the pleural cavity by passing the visceral pleura would be absorbed by these openings. The resorption process is active and directly related to the function of smooth muscles of lymphatic vessels. Besides resorption, we must emphasize that this "pumping" activity is permanent and the origin of negative pressure (the pleural void) in pleural cavity, a unique property. The other resorbed elements are molecules, bacterial and cellular debris, cells, red blood and cancer cells.

The lymphatic vascular system is widely developed among vertebrates. Lymphatic vessels provide the interstitial fluid (20% of the body weight) drainage through interstitial prelymphatic channels, capillaries, precollectors and collectors flowing into the venous blood. Endothelial cells of capillaries are overlapped and fixed to interstitial collagen and elastic fibres by anchoring filaments facilitating the fluid transfer. Precollectors and collectors have valves controlling the lymph flux direction. In addition to external mechanisms, the lymphangions of collectors have contracting muscle cells driving the flow. Lymphatic endothelial cells are routinely identified by the expression of podoplanin, LYVE-1 and VEGFR3. In the embryo, prelymphatic endothelial cells emerge from the cardinal veins and migrate into the mesenchyma forming embryonic lymphatic sacs. Prox1, Sox18 and COUP-TFII play a major role in the endothelial speciation, VEGFC as VEGFD combined to VEGFR3 in cell migration and proliferation and FoxC2 in valves development. In cancer or inflammation, various factors secreted by cancer cells and/or inflammatory cells induce a neolymphangiogenesis. Recently it has been shown that cells from the bone marrow could be potential precursors for lymphatic endothelial cells.

Whereas lymphatics in pulmonary non-tumoral diseases have been less studied than blood microcirculation, they clearly play a significant role. This review is a short update on lymphatics in various non-tumoral pulmonary diseases, from asthma to interstitial pneumonitis, excluding lymphangioleiomyomatosis. A lymphatic remodelling has been evidenced in asthma as well as in acute or chronic (UIP as NSIP) interstitial lung diseases. Such a remodelling can be explained as a side effect of local changes in fluidics but could also be an active player in the fibrosing process. Moreover the association of juxta-alveloar lymphatics and granulomas provides new insights in the emergence of these lesions in pulmonary sarcoidosis.

For many years, the intraocular lymphatic system and particularly the drainage of the aqueous humor by this system have been considered non-existant. Our study is the first to demonstrate, in a dynamic in vivo fashion, the existence of lymphatic drainage in the mouse eye. This has become possible with lymphoscintigraphy with nano-molecules of rhenium sulphide, marked by technetium-99m and injected into the anterior chamber of the mouse eye. Readings were taken using an experimental gamma camera specially built for the small animal. The hypothesis of a "uveolymphatic" drainage pathway within the ciliary body, contributing to aqueous outflow, has recently been highlighted by new improvements in microbiology (discovery of lymphatic endothelial-specific markers) and imaging. This new pathway may lead to many prospects: the development of techniques for visualization and quantification of this in vivo lymphatic flow may help to increase our understanding of the physiopathology and perhaps treatment of chronic glaucoma as well as neoplastic conditions.

The eminent Greek anatomist professor Miltiades Papamiltiades contributed considerably to the study of lymphatic system and to the development of a new staining technique in exfoliative cytology. Born Greek and French in spirit, his work written in French language and scattered in articles, communications and notes contributed to the propagation of French medical thought and to the Hellenic-French friendship.

Diagnosis of superficial vascular anomalies, previously called "angiomas", is basically clinical. Ultrasound and duplex Doppler imaging is a simple and helpful tool to confirm the clinical diagnosis and/or to suggest further required imaging modalities. The purpose of this work is to demonstrate the usefulness of duplex Doppler and ultrasound for exploring vessel and soft tissue components of vascular anomalies.

Cutaneous cystic lymphatic malformations consist of dilatations of various sizes, developed from the lymphatic system. Various clinical presentations exist, which are more or less complex and severe. MRI is the best examination to determine the extent of deep lesions. Therapeutic decisions usually follow multidisciplinary consultations. In localized superficial forms, whether surgical excision or abstention is required. In macrocystic forms, sclerotherapy is the first-line treatment.

Our knowledge of the anatomy of the lymphatic system may have changed little, if at all, since the first descriptions of this system in the 17th and 18th centuries, but the identification of specific markers of lymphatic endothelial cells and of some of the genes involved in the occurrence of lymphoedema in humans has revolutionized our understanding. This article provides an overview of current fundamental knowledge relating to lymphoedema based on both the historical anatomy description and the most recent data about lymphangiogenesis.

Compression therapy for venous and lymphatic edema of the lower limbs raises a major challenge concerning the optimal pressure ensuring both efficacy and patient compliance. We present a mathematical model of tissue fluid transfers which is aimed at determining the lowest pressure required to prevent edema.The model is based on a set of equations, derived from published experimental data, which describe the fluid and solute transfers between blood, interstitium and lymphatics, and the mechanical properties of interstitial compartment. It enables us to compute the changes in tissue volume, at the ankle level, resulting from increases of capillary pressure in case of venous insufficiency, and from an impairment of lymph drainage; as well as the effect of various external pressures upon this volume.An increase of capillary pressure to 40 and 50 mmHg results in an ankle edema which is completely prevented by an external pressure of 10 mmHg. This result is in keeping with the observation by Partsch that vesperal leg swelling is reduced by low compression stockings. The dose effect reported in this study is also found by simulation. The complete blockade of lymphatic return leads to an edema, the prevention of which requires a counterpressure of at least 30 mmHg. When an increase of venous pressure to 60 mmHg, and a reduction by 2/3 of lymphatic drainage are combined, simulating chronic venous insufficiency, the resulting edema is prevented by a 25 mmHg counterpressure.These first results of simulation are in reasonable agreement with clinical experience. As nearly every combination of disturbances may be simulated, the computer model could help to understand and treat edemas, as long as their cause can be identified.

Lymph node (LN) involvement is one of the most significant prognostic factors of patients with rectal cancer. However, the distribution of rectal LN is not well known. The rectal LN are mainly located around the rectal arteries. In the mesorectum, the LN are mainly located posteriorly. The number of LN by patient varies considerably. Many reasons can explain this variability. Acquired factors such as infection, inflammation or metastatic involvement facilitate the detection of LN. In contrast, preoperative radiotherapy reduces the number and size of lymph nodes. The procedure of resection affects the number of LN harvested. Extensive lymphadenectomies increase the number of LN harvested. The technique used by pathologist has equally a major influence. The fat clearing method allows detection of a greater number of LN than manual dissection particularly for small LN. Toxicity of these solutions and a time-consuming process explain that fat clearing method is rarely used in clinical practice. Detection of rectal lymph nodes is difficult and tedious but is necessary for an accurate staging of patients with rectal cancer.

The pleural space, derived from the intraembryonic coelom, is limited by a serous membrane including the mesothelium formed by cells possessing not only the characteristic features of epithelial cells but also the potential of secretory cells (cytokines and growth factor). Blood supply to visceral pleurae differs depending on the species while the lymphatic circulation is directly connected to the pleural space via pores in the parietal pleura. Pleural physiology and movement of pleural fluid are directly related to the particular structures of the pleura.

This paper report a CME course about lymphedema of upper and lower limbs. The anatomy and physiology of lymphatic system, the different forms of lymphatic insufficiency and the clinical characters of the lymphatic edema, primary and secondary lymphedemas, complications of lymphedema, treatment and prevention are discussed.

The authors report the case of a young woman with right lower limb edema who also presented one steatorrhea. Her clinical history is typical for one primary lymphedema and the lymphoscintigraphic investigation of the lower limbs confirms the diagnosis. The scan showed the absence of the right iliac and lomboaortic lymph nodes but also that the thoracic duct was normally present. One C14-triolein breath test is pathological and proves the malabsorption of the fats. The authors discuss the interest of the scintigraphic techniques in such case and review the problem of the association between lower limb lymphedemas and fatty malabsorption.

Diseases of the lymphatic system in children include a group of exceptional conditions difficult to manage. The anatomy of lymphatic system is complex in the lung. Variable from one subject to another, its complex physiology plays an important role in air-blood exchanges occurring in the lung. In the pulmonary interstitium and in the pleura, the lymphatic system acts like an overflow valve capable of regulating variations in interstitial fluid. The presence or development of dysplasic lymphatics causes leakage, dilatation, and reflux of the lymph through incontinent valves leading to chylothorax and/or fluid overload in the pulmonary interstitium. Symptomatic care is usually proposed, based on a fat-free diet supplemented with light-chain triglycerides and liposoluble vitamins. Other therapeutic options can be proposed. Medical options include cytotoxic agents, somatostatin, and interferon-alpha. Surgery may also be useful, but an assessment of therapeutic efficacy is very difficult due to partial effects and the small number of cases studied.

Lymphoscintigraphic investigations represent techniques of nuclear medicine very contributive for the management and treatment of the limb edemas, either primary or secundary. Their principle is presented and methodologies proposed in the literature are reviewed. Their diagnostic contributions are detailed. The sensitivities and specificities of several protocols of investigation are reported. Some limitations of these examinations are analyzed and discussed. Clinical indications for their use are proposed and their interest with regard to the various treatments that can be applied to these limb edemas is discussed.

The paper presents a study of the evolutional morphogenetic stages of the lymphatic and conjunctive neck structures formation. The authors make particular appreciations concerning the pattern of organization and also, the functional connections of lymphatic and conjunctive elements at intravisceral, perivisceral and perivascular level. Our study proves that these structures form the barriers but also, the spread pathways of the tumoral and inflammatory process which, after an endocavitary development, diffuse either on the adjacent organs or to the main cervical lymph nodes. We emphasized the importance of these anatomical structures in the neck oncological surgery.

Treatment of lymphedema (LE) includes complex decongestive physiotherapy (manual lymphatic drainage, bandaging, exercises, skin care, elastic stockings). Surgical therapy is rarely useful. However, lymphovenous anastomosis (LVA) is the most used surgery in LE. We have assessed LVA in lower limb LE.Thirteen patients (5 women, 8 men) with primary (n=10) or secondary LE (n=3) were included. Primary LE started at a mean âge (+/- SD) of 28.9 +/- 14.5 years. LE was located in left lower limb (n=7), right (n=4) or both (n=2). LVA was performed 7.1 +/- 4.9 years after the onset of LE by the same surgeon. Two to five lymphatic vessels were used for LVA. Assessment of LVA was based upon objective criteria (volumetry, erysipelas) and subjective criteria (global discomfort, heaviness, cutaneous tenderness, difficulties for doing significant effort or walking more than 1 km). Global assessement of LVA was collected for each patient.Before LVA, excess of volume (+/- SD) of LE was 1906 +/- 1277 ml or 28.5 +/- 18% in comparison with the controlateral limb. After LVA, excess of volume (+/- SD) remained stable with 1863 +/- 1468 ml or 24.4 +/- 18.9%. Volumetry was appreciated with a mean (+/- SD) follow-up of 52 +/- 3 months. Frequency of erysipelas was unchanged for the 6 patients with recurrent episodes. Only heaviness and cutaneous tenderness were significantly reduced after LVA. But global discomfort (+/- SD) decreased from 6.7 +/- 2.7 to 5 +/- 3.2 on visual analogic scale (NS). No differences were observed for significant effort or walking more than 1 km. Global assessment of LVA by the patient was very good (n=3), good (n=2), intermediate (n=5) and bad (n=3).LVA failed to improve the volume of lower limb LE and reduce the frequency of erysipelas. LVA improves few subjectives criteria but not global discomfort. Further studies are needed to evaluate LVA and to select patients to obtain best results.

An important study of lips arterial supply was enabled using multiple sources of information: anatomical dissection, cadaver and "in vivo" arteriography and phlebography. Literature was a great help, especially a recent analysis of lips microvascularisation done by H. Sick. The classical figure of labial circular artery was found out to be quite seldom, whereas an important number of anatomical variations where shown. Also there was a total independence between inferior and superior lip venous drainage, for embryological reasons. Finally lymph drainage was studied by anatomical dissection with the use of Gerota mass and the G. Hidden's work. It appeared that cutaneous and mucosal drainage were separate, since the nodes were different. All these information have been useful and confirmed during more than a thousand surgical procedures performed in our maxillo-facial surgery unit of Besançon medical school.

Edema is defined as an excess of interstitial fluids. Its appearance is always linked to a relative functional insufficiency of the lymphatic drainage, but the use of the word lymphedema is restricted to the conditions where the lymphatic insufficiency is the primary pathogenetic factor of edema formation. The lymphatic insufficiency may result from: 1) an incompetence of the lymphatic capillaries, either due to their aplasia (Milroy's disease) or to their destruction (lipodermatosclerosis of chronic venous insufficiency); 2) an insufficiency of the lymphatic collectors related to their hypoplasia (primary lymphedema), or their destruction by trauma, infection or carcinologic treatments; a drug related functional insufficiency of lymphatic collectors is probable, but more data are needed on this topic; 3) pathologic lymphatic nodes (surgical excision, invasion by hematological disorders or cancer) could interfere with their ability to concentrate lymphatic fluids. Local tissue changes in the lymphedematous limbs are important and should be taken into account in the care management of such patients.

Classification of lymphedema is debated, because authors don't agree with the disordered physiology. Kinmonth divided all cases into primary and secondary lymphedema. Three types of primary lymphedema have been recognized: congenital, precox and tarda. Secondary lymphedema develops as a consequence of disruption or obstruction of the lymphatic pathways. Iatrogenic lymphedema are caused by surgery and/or radiation therapy. Post-infectious lymphedema are mainly caused by filariasis in tropical areas, and by cellulitis in occidental areas. Neoplastic disease (breast, prostatic cancer, Kaposi's sarcoma) are a major cause of secondary lymphedema. Less frequent etiologies are rheumatoid lymphedema, pathomimic lymphedema, pretibial myxoedema. Reduced lymphatic drainage is associated with severe chronic venous insufficiency and contributes to the leg swelling and the risk of infection.

Treatment of lymphedema includes essentially complex decongestive physiotherapy. Surgical methods are various but the main problem is to select patients. Genital organs may benefit from excisional procedures. Results of surgery in upper or lower limb lymphedema are variable. Secondary lymphedema is considered as the best indication using microlymphaticovenous anastomosis. Surgery in lymphedema should be considered as an additional tool of treatment.