Introduction

The lymphatic system is an important and often underappreciated component of the circulatory, immune, and metabolic systems. It is composed of lymphatic fluid, lymphatic vessels, and lymphatic cells. Lymphatic cells include macrophages, dendritic cells, lymphocytes, as well as lymphatic organs such as the spleen and thymus. There are three primary functions of the lymphatic system: first is the maintenance of fluid balance, second is the facilitation of the absorption of dietary fats from the gastrointestinal tract to the bloodstream for metabolism or storage, and third is the enhancement and facilitation of the immune system. The lymphatic vessels reabsorb interstitial fluid from the periphery to return it to the intravascular space, which prevents fluid build up in peripheral tissues. The lymphatics allow for the immune system to function properly as it carries antigens to lymph nodes, and also carries immune cells, such as macrophages to sites of infection to begin the immune process.[1]

Cellular Level

The lymphatic transport system can subdivide into five components: capillaries, collecting vessels, lymph nodes, trunks, and ducts. The initial point of entry into the lymphatic system is through the capillaries, which are a single layer of partially overlapping endothelial cells creating a valve. These overlapping junctions form a "button-like" opening, which allows fluid into the capillary when the pressure outside of the vessel is greater than the pressure inside of the vessel. The capillaries subsequently feed fluid into the collecting vessels, in which an endothelial layer with many tight junctions forms a "zipper-like" structure. These collecting vessels also have intraluminal valves as well as pericytes. The pericytes contain alpha-smooth muscle actin, which functions to contract the vessel and pump the fluid further through the system. The valves prevent the backflow of the lymphatic fluid and ensure the unidirectional flow of fluid.[2]

There are three portions of a lymph node, including the medulla, paracortex, and cortex, which in combination, form the house of lymphocytes, antigen-presenting cells, and macrophages. Research has determined that there are approximately 450 lymph nodes in the human body. Each lymph node has lymph sinuses surrounding the lymphoid lobules, all encased by a capsular tissue. The medulla has a reticular meshwork that is very dense and allows antigen-presenting cells, lymphocytes, and macrophages to occupy this space. The paracortex is where T cells function to interact with the dendritic antigen-presenting cells. The B cells of the body are present in the follicles, which comprise the lymph node cortex. The architecture of a lymph node is one of the primary reasons the immune system can function so effectively and efficiently.[3]

After visiting the lymph nodes, the lymphatic fluid flows into efferent lymphatic collecting vessels into larger lymphatic trunks and then into the lymphatic ducts. The lymphatic ducts allow the entry of the lymphatic fluid into the venous system bilaterally via the opening found at the intersection of the subclavian and internal jugular vein.[4]

Development

The embryologic development of the lymphatic system begins with the embryonic veins. Lymphatic endothelial cell (LEC) progenitors develop throughout the venous system and bud from the veins to form the early lymphatic system. The LEC progenitors are produced in the superficial venous plexuses, inter-somatic veins, and cardinal veins. The buds off of the veins create sacs as they enlarge, and eventually evolve to form the lymphatic vasculature. This process starts during week nine and is complete by week 16 of embryonic development.[5]

Throughout disease processes, the lymphatic vessels undergo remodeling to promote the optimal functioning of the body. When lymphangiogenesis occurs, the diameter of the new vessels have larger diameters and have less permeability. This decreased permeability is the result of a change in the cell to cell junctions forming more of a “zipper” and less of a “button” shape.[1] 

Organ Systems Involved

Lymphatic tissues are found in nearly every organ of the body, including the eye and the brain.[6] In the skin, the lymphatic and blood vessels supply the oxygen, nutrients, and cells via a system deep to the epidermal layer. The blood capillaries which supply the epidermal keratinocytes and melanocytes leak plasma into the interstitial space. This fluid, as well as the macromolecules and immune cells, are reabsorbed via the lymphatic system.[2]

Function

The general function of the lymphatic system is to maintain fluid balance, absorption, and transport of dietary fats, and assist the immune system in providing a transport medium. It is through the lymphatic system that antigens, antibodies, and immune cells are delivered to lymph nodes providing adaptive immune protection.[1]

Mechanism

Lymphatic flow in the body is a unique process, which happens to occur in a way that is different from any other bodily fluid. In the interstitial space, the fluid composed of plasma and proteins leaked from the vascular system, cell debris, microorganisms, and immune cells is reabsorbed via the lymphatic capillaries. The overlapping endothelial cells create the “button-like” microvalves found in the blunt-ended lymphatic capillaries allowing only for unidirectional fluid flow. The fluid is under a pressure imbalance and flows into the capillaries secondary to the net hydrostatic and oncotic pressure between the interstitial space and the lymphatic capillaries. Along with the fluid pressure gradient, there is external pressure applied via the contraction of the surrounding tissues when the body is in motion.[2]

Once the lymph travels from the lymphatic capillaries to the collecting lymphatic vessels through passive motion aided by intraluminal valves, simple passive movement is not sufficient to return the increasing amounts of lymphatic fluid. The fluid then flows to the lymphatic collecting vessels, which have a lining of pericytes. These cells express alpha-smooth muscle actin, which allows for contraction in a peristaltic manner along the length of the collecting vessel. These vessels also have unique valves created by the tight adhesions between the cells making “zipper-like” junctions. A stretch in the wall of the collecting vessel causes the pericytes to stretch and allows for the propulsion of fluid from one collecting duct to the next until the fluid enters the lymph node.[2]

The intrinsic pump comprised of the pericytes and valves generates two-thirds of the lymphatic flow at rest. The remaining one-third of the flow of the 8 to12 liters of lymphatic fluid and protein that the system transports each day comes from compression of skeletal muscles.[6]

From the collecting lymphatic vessels, the lymph travels to the lymph nodes, entering through afferent lymphatic collecting vessels. Under non-inflammatory conditions, lymph flows around the outer portion of the lymphatic lobules through the subcapsular sinus. Along the floor of the sinus, there are endothelial cells which express cytokine receptors, such as CCL21 and CCR7. The binding of these receptors increases dendritic cell mobilization into the lymph nodes during the immune response.[7] Dendritic cells in peripheral tissues monitor their local environment and, when an infection is present, are mobilized. Uptake into the lymphatic system results in transportation to lymph nodes, where they bind CCL21 and CCR7 receptors. The dendritic cells then enter the lymph node, where the antigen is presented to T cells, resulting in activation of the immune system.[8]

From the lymph node sinus, the fluid exits via the efferent collecting vessels, which are in function very similar to the afferent lymphatic vessels. The major difference at this point is a significant change in the composition of the fluid as it has been acted on by the immune cells in the lymph node. Via the lymphovenous valve, the fluid enters the blood at the junction of the thoracic duct and the subclavian vein.[7]

Related Testing

Lymphoscintigraphy is a nuclear medicine study, where radionucleotide guided imaging can display absent and delayed lymphatic channels filling. This is the gold-standard choice when diagnosing lymphedema if the diagnosis cannot be made from history and physical exam. If lymphatic vessels have delayed or absent filling is shown in this study, the edema a patient is experiencing is likely secondary to lymphatic obstruction.[9]

Pathophysiology

Edema is a buildup of interstitial fluid in the extracellular/interstitial space that is secondary to an imbalance of capillary filtration related to lymphatic drainage. There can be increased capillary hydrostatic pressure, decreased plasma oncotic pressure, increased capillary permeability, increased plasma volume, or, most notably, regarding lymphatics, a lymphatic obstruction.[9] Build-up can be secondary to weak lymphatic contractions through the lymphatic vessels, chronically distended lymphatic vessels, and valvular incompetence.[6]

During inflammatory, malignant, infectious, or autoimmune disease states, the lymph node can change in size or consistency, which is referred to as lymphadenopathy. Lymph nodes in the popliteal, iliac, or supraclavicular lymph nodes should be considered abnormal if they are greater than 5 mm. If lymph nodes become fixed, or immobile, and have a hardened texture, there is likely malignancy or infection present within the body.[10]

During inflammatory states, the lymphatic pumping becomes reduced secondary to cytokines producing vasoactive substances and altering the contractile functioning of the vessel. Therefore, it is likely that during inflammatory disease processes, the associated edema can, in part, be secondary to decreased lymphatic pumping.[1]

Lymphatic tissues play a significant role in cancer metastases and disease progression. Lymph node metastases can be a significant indicator of the prognosis and patient survival in many neoplasms. Research has found that lymph node metastasis is worsened further due to tumor lymphangiogenesis through inappropriate molecular signaling. Vascular endothelial growth factor (VEGF)-C overexpression can increase lymphatic flow, which in part increases tumor metastases.[2]

Clinical Significance

Lymphedema can be managed clinically with complex decongestive physiotherapy, consisting of compressive bandages and manual lymphatic massage. Compression is provided using 30 to 40 mm Hg compression stockings as well as pneumatic compression devices. If lymphedema is refractory to traditional compression and massage management, surgery with bypass or debulking procedures may resolve lymphedema.[9]