Human_Histology

Connective Tissue Framework

Except at the hilum, the surface of the spleen is covered by a layer of peritoneum (referred to as the serous coat). Deep to the serous layer the organ is covered completely by a capsule (Plate 9.2).

Trabeculae arising from the capsule extend into the substance of the spleen. As they do so the trabeculae divide into smaller divisions that form a network.

The capsule and trabeculae are made up of fibrous tissue in which elastic fibers are abundant. In some animals they contain much smooth muscle, but this is not a prominent feature of the human spleen.

The spaces between the trabeculae are pervaded by a network of reticular fibers, embedded in an amorphous matrix.

Fibroblasts (reticular cells) and macrophages are also present in relation to the reticulum. The interstices of the reticulum are pervaded by lymphocytes, blood vessels and blood cells, and by macrophages.

Parenchyma

On examination with unaided eye, the interior of the spleen shows round white areas (white pulp) surrounded by red matrix (red pulp).

The White Pulp

The white pulp is made up of aggregations of lymphocytes that surround a small artery or arterioles. As a result it is in the form of cord-like aggregations of lymphocytes that follow the branching pattern of the arterioles. The cords appear to be circular in transverse section.

At places the cords are thicker than elsewhere and contain lymphatic nodules similar to those seen in lymph nodes. These nodules are called Malpighian bodies.

Each nodule has a germinal center and a surrounding cuff of densely packed lymphocytes.

The nodules are easily distinguished from those of lymph nodes because of the presence of an arteriole in each of them. The arteriole is placed eccentrically at the margin of the germinal center (between it and the surrounding cuff of densely packed cells). More than one arteriole may be present in relation to one germinal center (Plate 9.2).

The functional significance of the white pulp is similar to that of cortical tissue of lymph nodes. Lymphatic nodules of the white pulp are aggregations of B-lymphocytes. The germinal centers are areas where B-lymphocytes are dividing. Lymphocytes surrounding the arteriole are referred to as peri-arterial lymphatic sheath (PALS). Lymphocytes of the PALS are chiefly T-lymphocytes.

The Red Pulp

Red pulp is a modified lymphoid tissue infiltrated with all the cells of circulating blood. It is like a sponge permeated by spaces (splenic sinusoids) lined by reticular cells. The intervals between the spaces are filled by

Chapter 9 Lymphatics and Lymphoid Tissue 99

B-lymphocytes as well as T-lymphocytes, macrophages, and blood cells. These cells appear to be arranged as cords (splenic cords, of Billroth). The cords form a network.

The zone of red pulp immediately surrounding white pulp is the marginal zone. This zone has a rich network of sinusoids. Numerous antigen-presenting cells are found close to the sinusoids. This region seems to be specialized for bringing antigens confined to circulating blood (e.g. some bacteria) into contact with lymphocytes in the spleen so that an appropriate immune response can be started against the antigens. (Such contact does not take place in lymph nodes. Antigens reach lymph nodes from tissues, through lymph). Surgical removal of the spleen (splenectomy) reduces the ability of the body to deal with blood borne infections.

Circulation through the Spleen

On reaching the hilum of the spleen, the splenic artery divides into about five branches that enter the organ independently.

Each branch divides and subdivides as it travels through the trabecular network. Arterioles arising from this network leave the trabeculae to pass into the inter-trabecular spaces. For some distance each arteriole is surrounded by a dense sheath of lymphocytes. These lymphocytes constitute the white pulp of the spleen.

The arteriole then divides into a number of straight vessels that are called penicilli. Penicillar arterioles either open into the red pulp (Open circulation) or they open into the splenic sinusoids (Closed circulation) (Fig. 9.5). Veins from these sinusoids and the red pulp end in the trabecular veins.

100 Textbook of Human Histology

The sinusoids of the spleen are lined by a somewhat modified endothelium. The endothelial cells here are elongated and are shaped like bananas. They are referred to as stave cells. With the EM a system of ultramicroscopic fibrils is seen to be present in their cytoplasm. The fibrils may help to alter the shape of the endothelial cells thus opening or closing gaps between adjoining cells.

The spleen acts as a filter for worn out red blood cells. Normal erythrocytes can change shape and pass easily through narrow passages in penicilli and ellipsoids. However, cells that are aged are unable to change shape and are trapped in the spleen where they are destroyed by macrophages.

Lymph Vessels of the Spleen

Traditionally, it has been held that in the spleen lymph vessels are confined to the capsule and trabeculae. Recent studies have shown, however, that they are present in all parts of the spleen. Lymphocytes produced in the spleen reach the bloodstream mainly through the lymph vessels.

Functions

Like other lymphoid tissues the spleen is a center where both B-lymphocytes and T-lymphocytes multiply, and play an important role in immune responses. As stated above, the spleen is the only site where an immune response can be started against antigens present in circulating blood (but not present in tissues).

The spleen contains the largest aggregations of macrophages of the mononuclear phagocyte system. In the spleen the main function of these cells is the destruction of red blood corpuscles that have completed their useful life. This is facilitated by the intimate contact of blood with the macrophages because of the presence of an open circulation. Macrophages also destroy worn out leukocytes, and bacteria.

In fetal life the spleen is a center for production of all blood cells. In later life only lymphocytes are produced here.

The spleen is often regarded as a store of blood that can be thrown into the circulation when required. This function is much less important in man than in some other species.

Clinical Correlation

Splenomegaly

Enlargement of spleen is termed as splenomegaly. It occurs in a wide variety of disorders which increase the cellularity and vascularity

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of the organ. Many of the causes are exaggerated forms of normal splenic function.

Causes of splenomegaly

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' *" + obstruction, Splenic vein obstruction.

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Diseases with abnormal erythrocytes: Thalassaemias, Spherocytosis, Sickle cell disease.

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Miscellaneous: Amyloidosis, Primary and metastatic splenic tumors.

THE THYMUS

The thymus is an organ that is a hazy entity for most students. This is because of the fact that the organ is not usually seen in dissection hall cadavers (because of atrophy in old people, and because of rapid autolysis after death). The organ is also not accessible for clinical examination (as it lies deep to the manubrium sterni). At birth the thymus weighs 10–15 grams. The weight increases to 30–40 grams at puberty. Subsequently, much of the organ is replaced by fat. However, the thymus is believed to produce T-lymphocytes throughout life.

The thymus consists of right and left lobes that are joined together by fibrous tissue. Each lobe has a connective tissue capsule. Connective tissue septa passing inwards from the capsule incompletely subdivide the lobe into a large number of lobules (Plate 9.3).

Each lobule is about 2 mm in diameter. It has an outer cortex and an inner medulla. Both the cortex and medulla contain cells of two distinct lineages as described below. The medulla of adjoining lobules is continuous.

The thymus has a rich blood supply. It does not receive any lymph vessels, but gives off efferent vessels.

Epithelial Cells (Epitheliocytes)

Embryologically these cells are derived from endoderm lining the third pharyngeal pouch. The cells lose all contact with the pharyngeal wall. Later they become flattened and may branch. The cells join to form sheets that cover the internal surface of the capsule, the surfaces of the

septa, and the surfaces of blood vessels. The epithelial cells lying deeper in the lobule develop processes that join similar processes of other cells to form a reticulum. It may be noted that this reticulum is cellular, and has no similarity to the reticulum formed by reticular fibers in lymph nodes and spleen. Epithelial cells of the thymus are not phagocytic.

It has been suggested that the sheets of epithelial cells present deep to the capsule, around septa, and around

blood vessels form an effective blood-thymus barrier that prevents antigens (present in blood) from reaching lymphocytes present in the thymus. Epitheliocytes also promote T-cell differentiation and proliferation.

On the basis of structural differences several types of epitheliocytes are recognized. Type 1 epitheliocytes line the inner aspect of the capsule, the septa and blood vessels. These are the cells forming the partial hemothymic barrier mentioned above. Type 2 and type 3 cells are present

102Textbook of Human Histology

in the outer and inner parts of the cortex respectively. Type 4 cells lie in the deepest parts of the cortex, and also in the medulla. They form a network containing spaces that are occupied by lymphocytes. Type 5 cells are present around corpuscles of Hassall (see below).

Cortical epitheliocytes are also described as thymic nurse cells. They destroy lymphocytes that react against self antigens.

Lymphocytes of the Thymus (Thymocytes)

In the cortex of each lobule of the thymus the reticulum formed by epithelial cells is densely packed with lymphocytes. Stem cells formed in bone marrow travel to the thymus. Here they come to lie in the superficial part of the cortex, and divide repeatedly to form small lymphocytes. Lymphatic nodules are not present in the normal thymus.

The medulla of each lobule also contains lymphocytes, but these are less densely packed than in the cortex. As a result the epithelial reticulum is more obvious in the medulla than in the cortex. As thymocytes divide they pass deeper into the cortex, and into the medulla. Ultimately, they leave the thymus by passing into blood vessels and lymphatics. For further details of thymic lymphocytes (see below).

Macrophages

Apart from epithelial cells and lymphocytes the thymus contains a fair number of macrophages (belonging to the mononuclear phagocyte system). They are placed subjacent to the capsule, at the corticomedullary junction, and in the medulla. The subcapsular macrophages are highly phagocytic. Deeper lying macrophages are dendritic cells. Their significance is considered below.

Corpuscles of Hassall

These are small rounded structures present in the medulla of the thymus. Each corpuscle has a central core formed by epithelial cells that have undergone degeneration. These cells ultimately form a pink staining hyaline mass. Around this mass there is a wall formed by concentrically arranged epithelial cells. These cells also stain bright pink with hematoxylin and eosin. The central mass of the corpuscle may also contain degenerating macrophages. The functional significance of the corpuscles of Hassall is not understood.

Functions of the Thymus

The role of the thymus in lymphopoiesis has been discussed earlier. Stem cells (from bone marrow) that reach the superficial part of the cortex divide repeatedly to form smaller lymphocytes. It has been postulated that during these mitoses the DNA of the lymphocytes undergoes numerous random mutations, as a result of which different lymphocytes acquire the ability to recognize a very large number of different proteins, and to react to them. As it is not desirable for lymphocytes to react against the body’s own proteins, all lymphocytes that would react against them are destroyed. It is for this reason that 90% of lymphocytes formed in the thymus are destroyed within three to four days. The remaining lymphocytes, that react only against proteins foreign to the body, are thrown into the circulation as circulating, immunologically competent T-lymphocytes. They lodge themselves in secondary lymph organs like lymph nodes, spleen, etc., where they multiply to form further T-lymphocytes of their own type when exposed to the appropriate antigen.

From the above it will be understood why the thymus is regarded as a primary lymphoid organ (along with bone marrow). It has been held that, within the thymus, lymphocytes are not allowed to come into contact with foreign antigens, because of the presence of the bloodthymic barrier. It has also been said that because of this thymocytes do not develop into large lymphocytes or into plasma cells, and do not form lymphatic nodules. While these views may hold as far as the thymic cortex is concerned, they do not appear to be correct in respect of the medulla. Recently it has been postulated that the medulla of the thymus (or part of it) is a separate “compartment”. After thymocytes move into this compartment they probably come into contact with antigens presented to them through dendritic macrophages. Such contact may be a necessary step in making T-lymphocytes competent to distinguish between foreign antigens and proteins of the body itself.

The proliferation of T-lymphocytes and their conversion into cells capable of reacting to antigens, probably takes place under the influence of hormones produced by epithelial cells of the thymus. T-lymphocytes are also influenced by direct cell contact with epitheliocytes. Hormones produced by the thymus may also influence lymphopoiesis in peripheral lymphoid organs. This influence appears to be specially important in early life, as lymphoid tissues do not develop normally if the

thymus is removed. Thymectomy has much less influence after puberty as the lymphoid tissues have fully developed by then.

A number of hormones produced by the thymus have now been identified as follows. They are produced by epitheliocytes.

Thymulin enhances the function of various types of T-cells, specially that of suppressor cells.

Thymopoietin stimulates the production of cytotoxic T-cells. The combined action of thymulin and thymopoietin allows precise balance of the activity of cytotoxic and suppressor cells.

Thymosin alpha 1 stimulates lymphocyte production, and also the production of antibodies.

Thymosin beta 4 is produced by mononuclear phagocytes.

Thymic humoral factor controls the multiplication of helper and suppressor T-cells.

Apart from their actions on lymphocytes, hormones (or other substances) produced in the thymus probably influence the adenohypophysis and the ovaries. In turn, the activity of the thymus is influenced by hormones produced by the adenohypophysis, by the adrenal cortex, and by sex hormones.

Clinical Correlation

Enlargement of the thymus is often associated with a disease called myasthenia gravis. In this condition there is great weakness of skeletal muscle. In many such cases the thymus is enlarged and there may be a tumor in it. Removal of the thymus may result in considerable improvement in some cases.

Myasthenia gravis is now considered to be a disturbance of the immune system. There are some proteins to which acetyl choline released at motor end plates gets attached. In myasthenia gravis antibodies are produced against these proteins rendering them ineffective. Myasthenia gravis is, thus, an example of a condition in which the immune system begins to react against1 * % autoimmune diseases.

MUCOSA-ASSOCIATED LYMPHOID TISSUE

As discussed significant aggregations of lymphocytes seen in relation to the mucosa of the respiratory, alimentary and urogenital tracts are referred to as mucosa-associated lymphoid tissue (MALT). The total volume of MALT is more or less equal to that of the lymphoid tissue present in lymph nodes and spleen. Mucosa associated aggregations of lymphoid tissue have some features in common as follows:

Chapter 9 Lymphatics and Lymphoid Tissue 103

These aggregations are in the form of one or more lymphatic follicles (nodules) having a structure similar to nodules of lymph nodes. Germinal centers may be present. Diffuse lymphoid tissue (termed the parafollicular zone) is present in the intervals between the nodules. The significance of the nodules and of the diffuse aggregations of lymphocytes are the same as already described in the case of lymph nodes. The nodules consist predominantly of B-lymphocytes, while the diffuse areas contain T-lymphocytes.

These masses of lymphoid tissue are present in very close relationship to the lining epithelium of the mucosa in the region concerned, and lie in the substantia propria. Larger aggregations extend into the submucosa. Individual lymphocytes may infiltrate the epithelium and may pass through it into the lumen.

The aggregations are not surrounded by a capsule, nor do they have connective tissue septa. A supporting network of reticular fibers is present.

As a rule these masses of lymphoid tissue do not receive afferent lymph vessels, and have no lymph sinuses. They do not, therefore, serve as filters of lymph. However, they are centers of lymphocyte production. Lymphocytes produced here pass into lymph nodes of the region through efferent lymphatic vessels. Some lymphocytes pass through the overlying epithelium into the lumen.

Mucosa-associated Lymphoid Tissue in the

Respiratory System

In the respiratory system the aggregations are relatively small and are present in the walls of the trachea and large bronchi. The term bronchial-associated lymphoid tissue

(BALT) is applied to these aggregations.

Mucosa-associated Lymphoid Tissue in the

Alimentary System

This is also called gut-associated lymphoid tissue (GALT). In the alimentary system examples of aggregations of lymphoid tissue are tonsils, Peyer’s patches and lymphoid nodules in vermiform appendix.

TONSILS

Near the junction of the oral cavity with the pharynx there are a number of collections of lymphoid tissue that are referred to as tonsils. The largest of these are the right and left palatine tonsils, present on either side of the oropharyngeal isthmus (In common usage the word tonsils refers to the palatine tonsils). Another midline collection

Fig. 9.6: Coronal section of palatine tonsil (Schematic representation)

of lymphoid tissue, the pharyngeal tonsil, is present on the posterior wall of the pharynx. Smaller collections are present on the dorsum of the posterior part of the tongue (lingual tonsils), and around the pharyngeal openings of the auditory tubes (tubal tonsils).

PLATE 9.4: Palatine Tonsil

Clinical Correlation

Tonsillitis is the infection of palatine tonsils. The palatine tonsils are often infected. It is a common cause of sore throat. Frequent infections can lead to considerable enlargement of the tonsils, specially in children. Such enlarged tonsils may become a focus of infection and their surgical removal (tonsillectomy) may then become necessary.

The nervous system may be divided into the central nervous system (CNS), made up of the brain and spinal cord, the peripheral nervous system (PNS), consisting of the peripheral nerves and the ganglia associated with them, and the autonomic nervous system, consisting of the sympathetic and the parasympathetic nervous systems. The brain consists of the cerebrum (made up of two large cerebral hemispheres), cerebellum, midbrain, pons, and medulla oblongata. The midbrain, pons, and medulla together form the brainstem. The medulla is continuous below with the spinal cord (Flowchart 10.1).

TISSUES CONSTITUTING THE NERVOUS SYSTEM

The nervous system is made up of, predominantly, by a tissue that has the special property of being able to conduct impulses rapidly from one part of the body to another. The specialized cells that constitute the functional units of the nervous system are called neurons. Within the brain and spinal cord neurons are supported by special kind of

connective tissue cells that are called neuroglia. Nervous tissue, composed of neurons and neuroglia, is richly supplied with blood. It has been taught that lymph vessels are not present, but the view has recently been challenged.

The nervous system of man is made up of innumerable neurons. The total number of neurons in the human brain is estimated at more than 1 trillion. Neurons are regarded not merely as simple conductors, but as cells that are specialized for the reception, integration, interpretation, and transmission of information.

Nerve cells can convert information obtained from the environment into codes that can be transmitted along their axons. By such coding the same neuron can transmit different kinds of information.

STRUCTURE OF A NEURON

Neurons vary considerably in size, shape, and other features. However, most of them have some major features in common and these are described below (Figs. 10.1 to 10.5).

Fig. 10.3:

Cell Body/Perikaryon

A neuron consists of a cell body that gives off a variable number of processes (Fig. 10.1). The cell body is also called the soma or perikaryon. Like a typical cell it consists of a mass of cytoplasm surrounded by a cell membrane.

Cytoplasm

The cytoplasm contains a large central nucleus (usually with a prominent nucleolus), numerous mitochondria, lysosomes, and a Golgi complex (Fig. 10.2). In the past it was stated that centrioles are not present in neurons, but studies with the electron microscope have shown that centrioles are present. In addition to these features, the cytoplasm of a neuron has some distinctive characteristics not seen in other cells.

Nissl Substance

The cytoplasm shows the presence of a granular material that stains intensely with basic dyes; this material is the Nissl substance (also called Nissl bodies or granules) (Fig. 10.2). When examined by EM, these bodies are seen to be composed of rough surfaced endoplasmic reticulum (Fig. 10.3). The presence of abundant granular endoplasmic reticulum is an indication of the high level of protein synthesis in neurons. The proteins are needed for maintenance and repair, and for production of neurotransmitters and enzymes.

Neurofibrils

Another distinctive feature of neurons is the presence of a network of fibrils permeating the cytoplasm (Fig. 10.4). These neurofibrils are seen, with the EM, to consist of microfilaments and microtubules. (The centrioles present in neurons may be concerned with the production and maintenance of microtubules).

Pigment Granules

Some neurons contain pigment granules (e.g. neuromelanin in neurons of the substantia nigra). Ageing neurons contain a pigment lipofuscin (made up of residual bodies derived from lysosomes).

Neurites

The processes arising from the cell body of a neuron are called neurites. These are of two kinds. Most neurons give off a number of short branching processes called dendrites and one longer process called an axon.

Dendrites

The dendrites are characterized by the fact that they terminate near the cell body. They are irregular in thickness, and Nissl granules extend into them. They bear numerous small spines that are of variable shape. In a dendrite, the nerve impulse travels toward the cell body (Table 10.1).

Axon

The axon may extend for a considerable distance away from the cell body.

The longest axons may be as much as a meter long.

Each axon has a uniform diameter, and is devoid of Nissl substance.

The cytoplasm within the axon is called axoplasm and its cell membrane is called axolemma.

The axoplasm contains all the cell organelles of neurons cell body except ribosomes. Hence, proteins synthesized in the cell body are continuously transported toward the axon terminals by a process called axoplasmic transport.

In an axon the impulse travels away from the cell body.

Axons constitute what are commonly called nerve fibers. The bundles of nerve fibers found in CNS are called as nerve tracts, while the bundles of nerve fibers found in PNS are called peripheral nerves.

An axon (or its branches) can terminate in two ways. Within the central nervous system, it always terminates by coming in intimate relationship with another neuron, the junction between the two neurons being called a synapse. Outside the central nervous system, the axon may end in relation to an effector organ (e.g. muscle or gland), or may end by synapsing with neurons in a peripheral ganglion.

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Axon Hillock and Initial Segment

The axon is free of Nissl granules. The Nissl-free zone extends for a short distance into the cell body: this part of the cell body is called the axon hillock. The part of the axon just beyond the axon hillock is called the initial segment (Fig. 10.2).