Thymus

(G & H Chap 12, pp 285-291)

The primary function of the thymus is to instruct immuno-incompetent T-cells to achieve immuncompetence and to allow them to divide and multiply before going off to populate secondary lymphatic organs.

The thymus produces T lymphocytes which migrate to the spleen and lymphoid organs, where they can reproduce themselves and differentiate further after stimulation by antigen.

The thymus plays a crucial role in the development of immunological competence. As examples of its main functions, it controls:

1. the capacity to reject skin grafts

2. the ability to synthesize antibodies against foreign material. In fact, when the thymus is removed from young animals, they become incapable of mounting an immune response, and they usually die of infections.

3. the thymus exerts a primary effect on the development of other lymphoid organs, i.e. the spleen, lymph nodes and later, on the levels of circulating blood lymphocytes.

The thymus undergoes its most rapid change and development before the end of the second postnatal year, when its growth rate begins to slow down. However it is largest at puberty, after which it gradually involutes and most of the lymphoid tissue is replaced by fat and connective tissue.

Structure

The thymus is located on the superior mediastinum. It is a bilobed structure; the lobes are joined and covered by a thin connective tissue capsule that is composed of collagen and connective tissue fibers. Septae from the capsule penetrate into the gland and divide it into lobules, which are incompletely separated from each other. Each lobule is composed of a cortex and a medulla. The cells making up the stroma of the thymus are epithelial-reticular cells, while the cells making up the parenchyma are largely T-lymphocytes.

The cortex is at the periphery of each lobule, and contains a densely packed concentration of T lymphocytes of all sizes, as well as macrophages and the epithelial-reticular cells. Epithelial reticular cells also completely surround the cortex, isolating it from the medulla.

The medulla is also made up of T lymphocytes, but because their concentration is less dense, the epithelial-reticular cells are more obvious. The medulla also contains structures called Hassall's corpuscles which are comprised of concentrically arranged, flattened epithelial-reticular cells that degenerate and become filled with keratohyalin granules and cytokeratin granules. They increase with age, but their function is unknown.

Macrophages are quite prominent and are necessary to clean up the debris resulting from the death of all those T lymphocytes. Mast cells are usually abundant in association with the capsule and the septa. Although a few plasma cells are present, they do not produce antibody as they do in the spleen. As the thymus ages, fat cells increase and gradually replace the parenchyma.

The thymus, in contrast to lymph nodes, contains no lymph sinuses or afferent lymphatic vessels. Arteries enter the thymus through the capsule and follow the connective tissue septae. At the border of the cortex with the medulla, arterioles leave the septae to supply both the cortex and medulla. The arterioles and capillaries terminate in thin walled venules which pass into the connective tissue septae, and leave the thymus through the capsule. Efferent lymphatic vessels arise in the medulla and join to form longer vessels, which accompany the arteries and veins in the septae, eventually emptying into the mediastinal lymph nodes.

Small vessels and capillaries of the cortex are surrounded by a sheath of epithelial-reticular cells that form a blood-thymus barrier. The capillaries are non-fenestrated and the endothelial cells produce a very thick basal lamina. Thus T lymphocytes of the thymus are separated from the blood supply by five structures:

1) pericytes;

2) the epithelial-reticular cells;

3) the basal lamina of the epithelial-reticular cells;

4) basal lamina of the endothelial cells;

5) non-fenestrated endothelial cells.

This system prevents circulating antigens from reaching the thymic cortex, where T lymphocytes are being formed. Stem cells originating in the bone marrow leave the circulation through capillary walls, enter the cortex, become immunologically competent T lymphocytes and re-enter the circulation. There is no blood-thymus barrier in the medulla

Functions of the Thymus

The thymus is important to the proper functioning of the immune system. Its fundamental immunologic role is dependent on its production and release of T lymphocytes. Its primary function is to instruct immuno-incompetent T cells to achieve immunocompetence. The developing T cells proliferate extensively in the cortex, begin to express their surface markers and are tested for their ability to recognize self-MHC molecules and self-epitopes. T cells incapable of recognizing self-MHC I and self-MHC II molecules as “self” are destroyed. 98% of T-cells die in the cortex and are phagocytized by macrophages. Additionally those T lymphocytes whose T-cell receptors are programmed against self-macromolecules are also destroyed. The process of testing for MHC molecules and self-epitopes is believed to be a function of epithelial reticular cells, because they express both classes of epitope-MHC molecule complex on their surface.

The T lymphocytes begin their development as stem cells in the bone marrow, and migrate into the thymus during embryonic and prepubertal development. In the special thymic microenvironment they undergo intense proliferation and further differentiation. Although most (98%) of these lymphocytes die in the cortex and are removed by macrophages, some migrate to the medulla and enter the blood stream through the walls of venules. They are carried to peripheral lymphoid organs such as the spleen and lymph nodes where they occupy special T lymphocyte-dependent regions. It is in these regions that they wait to be challenged by antigen, after which further specialization will occur. Such regions also occur in structures such as the tonsils, Peyer's patches (in the ileum) and the appendix. Without the thymus, these organs develop poorly (why?).

The epithelial reticular cells of the thymus also produces several protein growth factors (thymosin, thymopoietin, thymolin and thymic humoral factor) that stimulate T lymphocyte proliferation and differentiation.

SPLEEN

(G & H Chap. 12 ,pp. 291-296)

The spleen is the organ that is designed to facilitate immune responses to antigens that have gained access to blood. Thus, the spleen ‘filters’ blood just as the lymph nodes filter lymph.

The spleen is the largest collection of lymphoid tissue in the body. It has important roles in the immune response:

As is true of all lymphoid organs, the spleen is the formation site for activated lymphocytes, which pass into the blood.
it plays a major role in the destruction of damaged and aged red blood cells, and
in the phagocytosis of particulate matter in the blood
in the storage of blood (and in blood cell formation during early fetal development).

All of the body's blood is filtered through the spleen. Thus circulating blood comes into close contact with macrophages and lymphocytes which are abundant in this organ. The spleen is therefore an important contributor to both cellular (T lymphocyte mediated) and humoral (B lymphocyte mediated) responses.

Structure of the spleen

The spleen is surrounded by a capsule of dense connective tissue, from which trabeculae extend into the organ, where they branch into thin reticular fibers. The spleen's inner framework (stroma) is composed of reticular cells and associated fibers as well as some collagen fibers. Both the capsule and trabeculae contain some smooth muscle cells and elastic fibers. The smooth muscle allows for slow contractions that can control the volume of blood in the spleen. The capsule is thickest at the hilum where the splenic artery, vein and nerves enter and leave the organ. Lymphatic vessels which originate in the spleen leave via the hilum.

The substance of the spleen, consists of splenic pulp. This is divided into white pulp which consists of lymphoid tissue and red pulp, which makes up the greatest mass of the spleen and which is rich in blood, some lymphoid tissue and specialized structures called splenic cords and splenic sinuses (or sinusoids). In a fresh section of the spleen the white pulp is seen as circular or elongated gray areas, surrounded by the red pulp. Red pulp has a spongy stroma composed of reticular fibers and dendritic reticular cells. A framework of reticular fibers forms a continuous foundation for both the white and red pulp.

Red pulp is a reticular tissue whose stroma consists of splenic cords and splenic sinuses.

Splenic cords are aggregations of lymphoid tissue which lie between the splenic sinuses. In addition to reticular cells and fibers, red pulp contains macrophages, lymphocytes, plasma cells and many blood elements (erythrocytes, granulocytes and platelets). Blood gets into the red pulp via branches of the central artery.

Splenic sinuses are long vascular channels with a unique endothelium and basement membrane. The structure is such that it permits the easy passage of blood cell elements. The endothelial cells of the sinusoids are elongated and have slit-like spaces between them. The basement membrane of the endothelial cells is perforated by large, regular, uniform fenestrae. The endothelial cells are wrapped in reticular fibers. The entire arrangement resembles a barrel in which the wooden staves correspond to the endothelium and the hoops correspond to the reticular fibers. The slits constitute a major space in the vascular pathway through the spleen. Blood filters through the splenic cords, passes through the slits into the lumen of the splenic sinuses and then into the splenic veins.

Blood circulation

In order to understand the structure and function of the spleen, it is necessary to understand the blood circulation in this organ. The splenic artery divides as it penetrates the hilum, branching into trabecular arteries that follow the course of the connective tissue trabeculae. When they leave the trabeculae to enter the parenchyma, they are known as central arteries and are surrounded by white pulp (i.e. l;ymphoid tissue). The central artery divides into numerous radial branches that supply the surrounding lymphoid tissue. After leaving the white pulp the central artery divides to form several relatively straight arterioles called penicillar arterioles. These arterioles may be surrounded by concentrically arranged macrophages; they are then called sheathed arterioles. The arterioles continue as arterial capillaries that carry blood to the sinusoids of the red pulp. The sinusoids drain into branches of the pulp veins that then join together and re-enter the trabeculae, forming the trabecular veins. These finally join to form the splenic vein which leaves the spleen through the hilum.

As the central arteries leave the trabeculae, and enter the red pulp, they are immediately surrounded by a sheath of lymphocytes. This is known as the periarterial lymphatic sheath (PALS). PALS are cylindrical and consist mostly of T lymphocytes. At intervals along their course, PALS may show localized formation of lymphatic nodules with germinal centers. Nodules are the territory of B lymphocytes, and the germinal center of a nodule is the site where B lymphocytes complete their maturation into plasma cells in response to antigenic challenge. The PALS, and the associated lymphatic nodules, are collectively known as the white pulp. Surrounding the nodule is an area known as the marginal zone which consists of many sinuses and loose lymphoid tissue and is populated by large numbers of macrophages. Many of the pulp arterioles derived from the central artery empty into sinuses of the marginal zone. This area thus plays a significant role in filtering blood and in initiating an immune response. If the appropriate B cells, T cells and antigen are present, an immune response will be initiated. Activated B cells migrate to the center of the white pulp nodule and give rise to plasma cells, which migrate to the splenic cords and release antibodies into the sinuses. The marginal zone is also an area where macrophages may phagocytize blood-borne antigen, or where antigen may contact the surface of dendritic reticular cells.

Because all of the body's blood is filtered through the spleen, the manner in which blood circulates through it is important. Arterial and venous systems are usually connected by a direct passage between arterial and venous capillaries, in which the endothelium is continuous and the vascular lumen is completely closed. The connection in the spleen is different, and how these hookups are made is still debatable. Three main theories have been proposed: 1) the open circulation theory suggests that the arterial dump blood directly into the red pulp from where it trickles gradually into the venous sinuses; 2) the closed circulation theory suggests that the arterial capillaries communicate directly with the with the lumen of the venous sinuses; 3) a compromise view holds that both types of circulation are present, depending upon physiological demand.

The spleen is a complex organ both structurally and functionally. Both T and B lymphocytes are present in the. T lymphocytes, which effect cellular immune responses are located primarily in PALS. B lymphocytes, which are involved in humoral immunity (antibody synthesis) are located in nodules. Antigens that are blood-borne are first trapped and phagocytized by macrophages in the red pulp and marginal zones. Unlike lymph nodes, which filter lymph and therefore respond to more regional influences, the entire blood supply of the body filters through the spleen and it therefore responds to blood-borne foreign material that is less regional. While the spleen is an important immune organ, life can go on without it, due to the amazing compensatory properties of other organs of the lymphomyeloid complex, such as lymph nodes and bone marrow.