The secondary lymphatic organs are sites that capture pathogens limiting their spread through out the body, as well as facilitate activation of acquired immune responses. These organs contain nodules (B cells) and diffuse lymphatic tissue (T cells) as well as APC rich regions in which antigens are bound for delivery to B cells and T cells. The secondary lymphatic organs include Peyer’s Patches of the ileum, tonsils, lymph nodes and spleen. Their development begins during fetal life and it is completed around the time of birth when they are populated by a mass migration of lymphocytes.
Peyer’s Patches is a cluster of lymphatic nodules found in the ileum of the small intestine. Like all secondary lymphatic organs, this structure develops before birth, is controlled by antigen (soluble or microorganisms), and contains T and B lymphocyte zones (Fig 4). The APC cells include microfold (M cells) and dendritic cells.
Figure 4. Diagram of Peyer’s Patch. Taken from Nature Reviews Immunol 2008, 8:767.
Tonsils are comprised of partially encapsulated groups of nodules supplied with lymphatic vessels and blood vessels. Three distinct tonsil masses form an incomplete ring at the oropharynx (entrance to the throat) and include the palantine, lingual, and pharyngeal (clinically the adenoids). The palantine and lingual tonsils are covered with stratified squamous epithelium. In the young, the pharyngeal tonsil is covered with pseudostratified ciliated columnar epithelium with goblets; in adults it is covered by a stratified squamous epithelium. The surface epithelium of the tonsil invaginates into the underlying connective tissue to form crypts. The walls of these crypts are lined with nodules, primary and secondary. The tonsils are drained by efferent lymphatic vessels; there are no afferent lymphatic vessels.
As you learned in the Blood Vessels lecture, lymphatic vessels comprise a one way drainage system from the periphery of the body towards the heart. They start as blind capillaries under the skin and mucous surfaces, join with larger caliber drainage vessels and eventually merge with the blood circulation at the thoracic duct and right lymphatic duct (Fig 1). En route, the lymph, a filtrate of the blood plasma, passes through at least one lymph node. The lymph node acts as a filter. Here cell-bound and soluble antigens are removed from the lymph thereby limiting the spread of pathogens within the body. Lymph nodes range in size from 1 mm to over 1 cm in diameter and often occur in a group or chains (Fig 1).
Lymph nodes are compact organs encased by a connective tissue capsule (Fig. 5). At the concave aspect, there is a thicker area of connective tissue that partially penetrates into the organ called the hilus. From the capsule, strands of connective tissue called trabeculae (finger-like) extend into the interior of the organ. These trabeculae, in turn are connected to a network of reticular cells and extracellular reticular fibers that support the parenchyma (small lymphocytes).
Multiple afferent lymphatic vessels pierce the capsule to deliver lymph to the node. Beneath the capsule and along the trabeculae there are sinuses (large diameter lymphatic vessels) with perforated endothelium permitting the lymph to percolate throughout the organ. The lymph enters first into the subcapsular sinus and then runs along the trabecular sinuses towards the interior of the node. These trabecular sinuses eventually anastomose into one (or two) efferent lymphatic vessel(s) which exits the node at the hilus.
The parenchyma, small lymphocytes, is separated into a cortex and a medulla (Fig. 5). The cortex lies immediately beneath the subcapsular sinus. The cortex contains nodules called follicles of B lymphocytes and diffuse lymphatic tissue called the paracortical region (or tertiary cortex). The paracortical region consists of T lymphocytes. Adjacent to the cortex is the medulla, the central region of the node.
Lymph enters at the capsule via the afferent lymphatic vessels. The lymph percolates slowly across the cortex and then drains into the medulla. There are no nodules in the medulla. The medulla contains lymphocytes, macrophages, and plasma cells organized into strands, called medullary cords. The cords are separated by sinuses. The lymph exits the node via an efferent lymphatic vessel at the hilus.
Figure 5. Diagram of a lymph node. The left side of the diagram shows the parenchyma. The
right side shows the blood supply and
lymphatic vessels. Adapted from Ross, Kaye & Pawlina, Histology: A Text and Atlas.
An artery enters the lymph node at its hilus. Subsequently it branches into arterioles which pass through the medullary cords to enter the cortex as small capillaries (Fig. 5). The capillaries perfuse the nodules and then drain into venules in the paracortical region. These post capillary venules have high cuboidal endothelium and are called high endothelial venules (HEV). Here small lymphocytes can leave the blood, cross the HEV endothelium, and enter directly into lymph. Eventually blood cells exit the node at the hilus in a single efferent vein.
Lymph nodes function in immune reactions
The lymph node is the site where pathogens are trapped and acquired immunity develops in a confined space as lymphocytes and immunoglobulins are added to the lymph and circulating small lymphocytes are recruited from the blood circulation (at HEVs). When you are fighting an infection, nearby lymph nodes get bigger (up to 2-3 times normal size) and become tender. They will slowly return to normal 2 to 4 weeks after the infection is resolved. The time course of changes in a lymph node after stimulation with a T cell-dependent antigen is shown in Figure 6. The timed events are as follows:
(1) Antigen presentation occurs 24-48 hours after infection: Foreign antigens that enter a lymph node via afferent lymphatic vessels are taken up by macrophages and APCs lurking in the subcapsular sinus, cortex and/or in the medulla within minutes after infection. Most of this foreign antigen becomes degraded by macrophages which display the antigen on their cell surfaces for presentation to T lymphocytes in the diffuse cortex. Some intact antigen may be retained by follicular reticular cells in the nodule region of the cortex for presentation to B cells.
(2) T and B cell activation occurs 2-3 days after infection: Small T lymphocytes enter the lymph node through high endothelial venules (HEV), encounter the processed antigen and differentiate to large T lymphocytes within the diffuse cortex. These cells divide and give rise to clones of memory T cells and TH cells. Some TH cells migrate into the nodule (follicle). Here, small B cells with appropriate receptor specificities react with the processed antigen of TH cells. These activated B cells divide giving rise to memory and effector cells of the B cell lineage. The focus of dividing TH and B cells, as well as active macrophages, builds up to form a germinal center that compresses the rest of the nodule into a crescent around it called a mantle (Fig 6).