Immunology of the Lymphatic System

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Lymphatic endothelial cells in tumor draining lymph node may scavenge tumor antigen and cause antigen specific T cell apoptosis [ 48 ]. Thus the regulation of lymphangiogenesis and T cell responses may be controlled in a more complex way. Thus, interruption of any step of lymphatic trafficking may result in skewed immune responses. Moreover, lymphatics play direct roles in lymph node immune function. Soluble factors and cells draining from the afferent lymph are required to maintain the homeostasis of lymph node architecture.

A known consequence of this is the disruption of lymph node cell compartmentalization and macrophage distribution and survival [ 71 - 73 ]. Thus, lymph borne factors and cells maintain the lymph node microenvironment for initiating adaptive immune responses. Besides attracting DC and T cells via expression of CCL21, lymphatic endothelial cells express chemokine decoy receptor D6, which scavenges inflammatory chemokine CCL2 and CCL5, decreasing their functional level, thus to prevent inappropriate cell adhesion in lymphatic vessels during inflammation [ 76 , 77 ].

Considering that lymphatic endothelial cells express self-antigen and cause self-reactive T cell tolerance, immune regulation by lymphangiogenesis may be involved in each step of the initiation of T cell response. A fine tuned immune function should generate an effective immune response to foreign antigens, but should not overly damage surrounding tissues. Lymphatic endothelial cells play important roles in suppressing T cell responses in inflammation.

With recent technological breakthroughs and our improved understanding of lymphatic functions, the perspective of studying the involvement of lymphatic remodeling during the initiation steps of immune responses and immune regulation seems achievable. Lymphatic vessels serve as the channels sending peripheral antigens and immune cells to the draining lymph nodes to initiate proper immunity. During steady state, lymph nodes maintain peripheral tolerance. Upon activation, lymph nodes quickly initiate protective adaptive immunity to produce antibody, cytotoxic immune cells and memory against the invading foreign antigens.

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Semin Cell Dev Biol. Author manuscript; available in PMC Feb 1. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Semin Cell Dev Biol. See other articles in PMC that cite the published article. Abstract Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes.

Overview Lymphatic vessels have three primary roles in normal human biology. Open in a separate window. Initial lymphatic vessels, collecting lymphatic vessels and the draining lymph node A. Lymphatic transport of antigen and cells to lymph node 2. Antigen presentation in lymph node 3. Lymph node conduit system Multiphoton microscopy and 3D re-construction images of second harmonic generation, to reveal collagen distribution in lymph node.

Lymph node macrophages A. Lymphocyte egress from lymph nodes After travelling through the lymph node, lymph enters efferent lymphatic vessels, flows through the downstream lymph node s and eventually returns to the blood circulation via the subclavian veins. Lymphatic endothelial cells and peripheral tolerance In the past several years, accumulating evidences show that lymphatic endothelial cells express peripheral tissue antigens, suggesting that they directly participate in immune regulation [ 5 , 42 , 43 ]. Lymphangiogenesis and immune regulation The growth of lymphatic vessels, termed as lymphangiogenesis, is frequently observed in inflammatory diseases and cancer progression.

Conclusion Lymphatic vessels serve as the channels sending peripheral antigens and immune cells to the draining lymph nodes to initiate proper immunity. Footnotes Conflict of interest: Liao S, Ruddle NH. Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. Kuka M, Iannacone M. The role of lymph node sinus macrophages in host defense. Ann N Y Acad Sci. Dendritic-cell trafficking to lymph nodes through lymphatic vessels.

Peripheral tolerance induction by lymph node stroma. Advances in experimental medicine and biology. Lymphatic and interstitial flow in the tumour microenvironment: Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE Molecular and cellular biology. Functionally specialized junctions between endothelial cells of lymphatic vessels.

INTRODUCTION

The Journal of experimental medicine. The lymph as a pool of self-antigens. Dendritic cell function in vivo during the steady state: Rapid leukocyte migration by integrin-independent flowing and squeezing. DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. Pflicke H, Sixt M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia.

Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. CCR7 is involved in the migration of neutrophils to lymph nodes. Neutrophils exhibit differential requirements for homing molecules in their lymphatic and blood trafficking into draining lymph nodes. Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes.

Int J Biochem Cell Biol. Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.

Chemokines, sphingosinephosphate, and cell migration in secondary lymphoid organs. Annual review of immunology. Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node.

Anderson AO, Shaw S. Conduit for privileged communications in the lymph node. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex.

A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation. Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes.

Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Sphingosinephosphate and lymphocyte egress from lymphoid organs. Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure. The intestinal wall, particularly that of the ileum, contains three separate lymphatic capillary beds that originate with and drain distinct anatomic spaces: These all independently intersect with, and drain into, contractile lymphatic collecting vessels that originate at the mesenteric border and run antiparallel to the intestinal wall through mesenteric fat until they reach mesenteric lymph nodes In humans, there is a fourth lymphatic capillary bed that is located in the mesenteric fat itself, mostly localized just beneath the serosal epithelial covering of the mesenteric adipose tissue These four lymphatic capillary networks carry many critical antigens to draining lymph nodes, and the villus lacteals also transport dietary fat that is packaged into chylomicrons 8.

Thus, the mesenteric lymph node is subjected to periodic high loads of fat that filter through this space, and the lymph node has had to evolve mechanisms to prevent fatty acid—driven inflammation, for instance 8. It is quite possible that microbial lipids, likely available to the host , are components of chylomicrons and regularly affect the mesenteric lymphatic corridor. This relationship caused us to wonder if significant remodeling of the fat-localized mesenteric collecting vessels occurred. We developed a method to better identify human mesenteric collecting lymphatic vessels, which only weakly stain for many lymphatic markers.

Remarkably, we find that the collecting vessels are interrupted by the development of B cell—rich tertiary lymphoid structures that obstruct the path to the usual draining lymph node Tertiary lymphoid structures are common features in many inflammatory diseases and in cancers , but until we were able to view them in three-dimensional analyses, it was unclear that the structures were connected to existing collecting lymphatic vessels and thus in a position to affect both lymph transport and which cells and molecules arrived to the draining lymph node.

It will be interesting to determine whether this is true in other inflammatory diseases. It is not possible to know what the consequences of such obstruction would be in humans. However, various studies in mice may offer a clue. One illuminating study arose from an analysis of the consequence of Yersinia pseudotuberculosis infection in mice. The explanation for the development of chronic inflammation and impaired immunity is that migratory DCs arising from the lamina propria failed to arrive in the draining lymph node, apparently because collecting vessels became excessively leaky, allowing for a spilling out of immune cells and chylomicrons within lymph into the adjacent fat However, the concept of leaking, or high permeability, of collecting vessels as the basis of disease deserves more attention.

Collecting vessels are known to have a basal level of permeability to proteins like albumin This permeability is sufficient to broadcast antigens to DCs and macrophages that closely associate with the muscular wall of the collecting vessel Indeed, the associated DCs appear to support collecting vessel integrity and lower permeability 80 , suggesting that high permeability might be associated with infection or inflammation-mediated loss or modification of these support DCs.

Although development of tertiary lymphoid structures was not reported in connection with the Y. The structures form within ten days after cessation of DSS administration.

Immunology of the lymphatic system

In this experimental model, as in humans, they are highly enriched in B cells The structures formed in the absence of lymphoid tissue inducer cells, and they functioned to contain bacteria and perhaps bacterial products transported from the DSS-damaged epithelial border However, they were also proinflammatory and drove immune pathology The study did not carry out three-dimensional imaging or look at the preexisting lymphatic network.

A number of research questions related to the lymphatic vasculature are ripe to be addressed. However, too little is known about the mechanisms at play to maintain normal physiology of the vessels at present. Some of these mechanisms no doubt relate to the properties of the vessels themselves and the response to local mediators; others may relate to the status of neighboring immune cells 73 , 80 , Still others may relate to mechanisms that operate at a distance—via neural communication, for instance.

Why does the application of an inflammatory mediator like IL-1b in the vicinity of a collecting vessel cause markedly enhanced permeability in the analogous contralateral collecting vessel of the same experimental subject ? Is there a neural cue? Many an experimental design would assume that the contralateral tissue is the ideal control, yet even such basic assumptions require close examination. Clearly, much remains to be learned. Some of the more straightforward tasks may include comprehensive profiling of lymphatic endothelium from different organs and parts of the network.

We have a hint, mostly derived from work in the lymph node, that lymphatic vessel diversity exists and peripheral lymphatic capillaries are distinct from those in the lymph node http: Indeed, such work highlights a number of genes relatively selectively expressed in the lymph node by lymphatic endothelium. Some of these selected genes have already been connected to lymphatic valve formation and maintenance Table 2 , yet lymphatic valves have not been described in lymph nodes.

Other genes suggest connections that might link lymph node lymphatics to osmolyte transport , and pacemaker activity Clearly, there are many new functional connections to be made as we explore lymphatic diversity in full. The tools to do so are at hand. Survey of gene expression profiling in the Immunological Genome Project identifies novel genes selectively expressed by lymphatic endothelial cells in lymph nodes.

The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. National Center for Biotechnology Information , U. Author manuscript; available in PMC Aug Randolph , 1 Stoyan Ivanov , 1 Bernd H.

Zinselmeyer , 1 and Joshua P. Louis, Missouri Find articles by Gwendalyn J. Louis, Missouri Find articles by Stoyan Ivanov. Louis, Missouri Find articles by Bernd H. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Annu Rev Immunol. See other articles in PMC that cite the published article.

The Lymphatic System: Integral Roles in Immunity

Abstract The lymphatic vasculature is not considered a formal part of the immune system, but it is critical to immunity. Open in a separate window. Table 1 Key functional molecules expressed on lymphatic endothelium. Molecule Function Reference s Prox-1 Transcription factor necessary for lymphatic development and maintenance. Also expressed by a subset of macrophages. Also expressed by many stromal cells and podocytes. Unique isoforms of CCL21 distinguish peripheral and lymph node lymphatic endothelia. Lymphatic Collecting Vessels Lymphatic capillaries, specialized for uptake of lymph as described above, coalesce into contractile vessels that are called collecting vessels.

Lymphatics and the Lymph Node Microenvironment A major factor in considering how inflammation affects immunity and antigen transport relates to the profound impact that inflammation can have on the arrangement of lymphatic vessels and sinuses in the lymph nodes, which directly drain the collecting lymphatic vessels. Table 2 Survey of gene expression profiling in the Immunological Genome Project identifies novel genes selectively expressed by lymphatic endothelial cells in lymph nodes.

Gene Functions Reference s Xlr5a X-linked lymphocyte related; unknown function.

1. Overview

Known to be expressed on subset of human lymph node lymphatic endothelium. In the Immgen database www. Previously associated with neurite growth and guidance. Quantifying Memory CD8 T cells reveals regionalization of immunosurveillance. Preferential localization of effector memory cells in nonlymphoid tissue. Visualizing the generation of memory CD4 T cells in the whole body. Roozendaal R, Mebius RE. Stromal cell—immune cell interactions. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity.

Lymphatic transport of high-density lipoproteins and chylomicrons. Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p Steady-state fluid filtration at different capillary pressures in perfused frog mesenteric capillaries. Microvascular fluid exchange and the revised Starling principle. LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans. The diaphragms of fenestrated endothelia: Mehta D, Malik AB.

Signaling mechanisms regulating endothelial permeability. Iijima N, Iwasaki A. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Wiig H, Swartz MA. Interstitial fluid and lymph formation and transport: Secretion of adipokines by human adipose tissue in vivo: Negrini D, Moriondo A.

Lymphatic anatomy and biomechanics. Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching. Interstitial flow as a guide for lymphangiogenesis. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Modest hyperglycemia prevents interstitial dispersion of insulin in skeletal muscle.

Time lag of glucose from intravascular to interstitial compartment in type 1 diabetes.

Estimating plasma glucose from interstitial glucose: Metabolic competition in the tumor microenvironment is a driver of cancer progression. Lymphatic and interstitial flow in the tumour microenvironment: Endothelial nitric oxide synthase regulates microlymphatic flow via collecting lymphatics. Functionally specialized junctions between endothelial cells of lymphatic vessels. Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Clement CC, Santambrogio L. The lymph self-antigen repertoire.

Rapid leukocyte migration by integrin-independent flowing and squeezing. Lammermann T, Sixt M. Pflicke H, Sixt M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node.

An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs.

CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Lymphoid aggregates remodel lymphatic collecting vessels that serve mesenteric lymph nodes in Crohn disease. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia. Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment.

The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. D6 as a decoy and scavenger receptor for inflammatory CC chemokines. Cytokine Growth Factor Rev. The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Increased inflammation in mice deficient for the chemokine decoy receptor D6. The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6. D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion.

Elevated expression of the chemokine-scavenging receptor D6 is associated with impaired lesion development in psoriasis. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. Immunological functions of hyaluronan and its receptors in the lymphatics. Hyaluronan digestion controls DC migration from the skin. Hyaluronan in tissue injury and repair. Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity.

Lymphatic neoangiogenesis in renal transplants: Antibodies bind to specific antigens in a lock-and-key fashion, forming an antigen-antibody complex. Antibodies are a type of protein molecule known as immunoglobulins. There are five classes of immunoglobulins: The five classes of Ig antibodies. Antibodies are Y-shaped molecules composed of two identical long polypeptide Heavy or H chains and two identical short polypeptides Light or L chains. Function of antibodies includes: Structural regions of an antibody molecule. A unique antigenic determinant recognizes and binds to a site on the antigen, leading to the destruction of the antigen in several ways.

The ends of the Y are the antigen-combining site that is different for each antigen. Click here to learn more about the different classes of antibodies. Formation of an antigen-antibody complex. Helper T cells activate B cells that produce antibodies. Supressor T cells slow down and stop the immune response of B and T cells, serving as an off switch for the immune system. Cytotoxic or killer T cells destroy body cells infected with a virus or bacteria.

Memory T cells remain in the body awaiting the reintroduction of the antigen. A cell infected with a virus will display viral antigens on its plasma membrane. Killer T cells recognize the viral antigens and attach to that cell's plasma membrane. The T cells secrete proteins that punch holes in the infected cell's plasma membrane. The infected cell's cytoplasm leaks out, the cell dies, and is removed by phagocytes. Killer T cells may also bind to cells of transplanted organs. The immune system is the major component of this defense.

Lymphocytes, monocytes, lymph organs, and lymph vessels make up the system. The immune system is able to distinguish self from non-self. Antigens are chemicals on the surface of a cell. All cells have these. The immune system checks cells and identifies them as "self" or "non-self". Antibodies are proteins produced by certain lymphocytes in response to a specific antigen.

B-lymphocytes and T-lymphocytes produce the antibodies. B-lymphocytes become plasma cells which then generate antibodies. T-lymphocytes attack cells which bear antigens they recognize. They also mediate the immune response. Secondary immunity, the resistance to certain diseases after having had them once, results from production of Memory B and T cells during the first exposure to the antigen.

A second exposure to the same antigen produces a more massive and faster response. The secondary response is the basis for vaccination. Vaccination is a term derived from the Latin vacca cow, after the cowpox material used by Edward Jenner in the first vaccination. A vaccine stimulates the antibody production and formation of memory cells without causing of the disease. Vaccines are made from killed pathogens or weakened strains that cause antibody production but not the disease. Recombinant DNA techniques can now be used to develop even safer vaccines.

The immune system can develop long-term immunity to some diseases. Man can use this to develop vaccines, which produce induced immunity. Active immunity develops after an illness or vaccine. Vaccines are weakened or killed viruses or bacteria that prompt the development of antibodies. Application of biotechnology allows development of vaccines that are the protein antigen which in no way can cause the disease.

Passive immunity is the type of immunity when the individual is given antibodies to combat a specific disease. Passive immunity is short-lived. There are 30 or more known antigens on the surface of blood cells. These form the blood groups or blood types. In a transfusion, the blood groups of the recipient and donor must be matched. If improperly matched, the recipient's immune system will produce antibodies causing clotting of the transfused cells, blocking circulation through capillaries and producing serious or even fatal results.

ABO blood types are determined by a gene, I for isoagglutinin. Proteins produced by the A and B alleles are antigenic. Individuals with blood type A have the A antigen on the surface of their red blood cells, and antibodies to type B blood in their plasma. People with blood type B have the B antigen on their blood cells and antibodies against type A in their plasma. Individuals with type AB blood produce have antigens for A and B on their cell surfaces and no antibodies for either blood type A or B in their plasma.

Type O individuals have no antigens on their red blood cells but antigens to both A and B are in their plasma. People with type AB blood can receive blood of any type. Those with type O blood can donate to anyone. If a transfusion is made between an incompatible donor and recipient, the recipient's blood will undergo a cascade of events.

Reaction of antigens on cells and antibodies in plasma will produce clumping that clogs capillaries, other cells burst, releasing hemoglobin that can crystallize in the kidney and lead to kidney failure. Success of organ transplants and skin grafts requires a matching of histocompatibility antigens that occur on all cells in the body.

Chromosome 6 contains a cluster of genes known as the human leukocyte antigen complex HLA that are critical to the outcome of such procedures.

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