Lymphatic and immune system
AN OVERVIEW OF THE ENDOCRINE SYSTEM
The endocrine system includes all the endocrine cells and tissues of the body. As we noted in Chapter 4, endocrine cells are glandular secretory cells that release their secretions into the extracellular fluid. This characteristic distinguishes them from exocrine cells, which secrete their products onto epithelial surfaces, generally by way of ducts. The chemicals released by endocrine cells may affect only adjacent cells, as in the case of most paracrine factors, or they may affect cells throughout the body.
The components of the endocrine system are introduced in Figure 18-1 . This figure also lists the major hormones produced in each endocrine tissue and organ. Some of these organs, such as the pituitary gland, have endocrine secretion as a primary function; others, such as the pancreas, have many other functions in addition to endocrine secretion. We shall consider the structure and functions of these endocrine organs in detail in chapters dealing with other systems. Examples include the hypothalamus, the adrenal medullae, the heart , the thymus, the pancreas and digestive tract, the kidneys, the reproductive organs, and the placenta.
THE PITUITARY GLAND
Figure 18-8 details the anatomical organization of the pituitary gland, or hypophysis. This small, oval gland lies nestled within the sella turcica, a depression in the sphenoid bone. The pituitary gland hangs inferior to the hypothalamus, connected by the slender infundibulum (funnel). The base of the infundibulum lies between the optic chiasm and the mamillary bodies. The pituitary gland is cradled by the sella turcica and held in position by the diaphragma sellae, a dural sheet that encircles the infundibulum. The diaphragma sellae locks the pituitary in position and isolates it from the cranial cavity.
The pituitary gland can be divided into posterior and anterior divisions on the basis of function and developmental anatomy. Nine important peptide hormones are released by the pituitary gland—seven by the anterior pituitary and two by the posterior pituitary. All nine hormones bind to membrane receptors, and all nine use cAMP as a second messenger. Table 18-2 summarizes key information about these hormones. Refer to this table as our discussion proceeds.
The anterior pituitary, or adenohypophysis, contains a variety of endocrine cell types. The anterior pituitary can be subdivided into three regions: (1) a pars distalis (distal part), which is the largest portion of the entire pituitary gland; (2) an extension called the pars tuberalis, which wraps around the adjacent portion of the infundibulum; and (3) a slender pars intermedia (intermediate part), which forms a narrow band bordering the posterior pituitary (Figure 18-8 ). An extensive capillary network radiates through these regions, so every endocrine cell has immediate access to the circulatory system.
The production of hormones in the anterior pituitary is controlled by the hypothalamus through the secretion of specific regulatory factors. At the median eminence, a swelling near the attachment of the infundibulum, hypothalamic neurons release regulatory factors into the surrounding interstitial fluids. Their secretions enter the circulation quite easily, because the endothelial cells lining the capillaries in this region are unusually permeable. These fenestrated capillaries ( fenestra, window) allow relatively large molecules to enter or leave the circulatory system. The capillary networks in the median eminence are supplied by the superior hypophyseal artery.
Before leaving the hypothalamus, the capillary networks unite to form a series of larger vessels that spiral around the infundibulum to reach the anterior pituitary gland. Once within the anterior pituitary, these vessels form a second capillary network that branches among the endocrine cells (Figure 18-9 ).
This is an unusual vascular arrangement. A typical artery conducts blood from the heart to a capillary network, and a typical vein carries blood from a capillary network back to the heart. The vessels between the median eminence and the anterior pituitary, however, carry blood from one capillary network to another. Blood vessels that link two capillary networks are called portal vessels, and the entire complex is termed a portal system.
Portal systems provide an efficient means of chemical communication by ensuring that all the blood entering the portal vessels will reach the intended target cells before it returns to the general circulation. The communication is strictly one-way, however, because any chemicals released by the cells "downstream" must do a complete tour of the circulatory system before they reach the capillaries at the start of the portal system. Portal vessels are named after their destinations, so this particular network of vessels is known as the hypophyseal portal system.
Hypothalamic Control of the Anterior Pituitary
There are two classes of regulatory hormones: (1) releasing hormones and (2) inhibiting hormones. A releasing hormone (RH) stimulates synthesis and secretion of one or more hormones at the anterior pituitary, whereas an inhibiting hormone (IH) prevents the synthesis and secretion of hormones from the anterior pituitary. An endocrine cell in the anterior pituitary may be controlled by releasing hormones, inhibiting hormones, or some combination of the two. The regulatory hormones released at the hypothalamus are transported directly to the anterior pituitary by the hypophyseal portal system.
The rate of regulatory hormone secretion by the hypothalamus is controlled by negative feedback. The primary regulatory patterns are diagrammed in Figure 18-10a, b; we will reference them as we examine specific pituitary hormones.
We will discuss seven hormones whose functions and control mechanisms are reasonably well understood: thyroid-stimulating hormone, adrenocoricotropic hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, and melanocyte-stimulating hormone. Of the six hormones produced by the pars distalis, four regulate the production of hormones by other endocrine glands. The names of these hormones indicate their activities, but many of the phrases are so long that abbreviations are often used instead.
The hormones of the anterior pituitary are also called tropic hormones (tropé, a turning), because they turn on endocrine glands or support the functions of other organs. (Some references use trophic hormones [trophé, nourishment] to refer to these hormones.)
Thyroid-Stimulating Hormone (TSH)
Thyroid-Stimulating Hormone (TSH), or thyrotropin, targets the thyroid gland and triggers the release of thyroid hormones. TSH is released in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. As circulating concentrations of thyroid hormones rise, the rates of TRH and TSH production decline (Figure 18-10a ).
Adrenocorticotropic hormone (ACTH)
Adrenocorticotropic hormone (ACTH), also known as corticotropin, stimulates the release of steroid hormones by the adrenal cortex, the outer portion of the adrenal gland. ACTH specifically targets cells that produce hormones called glucocorticoids, which affect glucose metabolism. ACTH release occurs under the stimulation of corticotropin-releasing hormone (CRH) from the hypothalamus. As glucocorticoid levels increase, the rates of CRH release and ACTH release decline (Figure 18-10a ).
Follicle-stimulating hormone and luteinizing hormone are called gonadotropins, because they regulate the activities of the male and female gonads (testes and ovaries, respectively). The production of gonadotropins occurs under stimulation by gonadotropin-releasing hormone (GnRH) from the hypothalamus.
Follicle-Stimulating Hormone (FSH). Follicle-stimulating hormone (FSH), or follitropin, promotes follicle development in women and, in combination with luteinizing hormone, stimulates the secretion of estrogens by ovarian cells. Estradiol is the most important estrogen. In men, FSH stimulates sustentacular cells, specialized cells in the tubules where sperm differentiate. In response, the sustentacular cells promote the physical maturation of developing sperm. FSH production is inhibited by inhibin, a peptide hormone released by cells in the testes and ovaries (Figure 18-10a ). (Disagreement exists as to whether inhibin suppresses the release of GnRH as well as FSH.)
Luteinizing Hormone (LH). Luteinizing hormone (LH), or lutropin, induces ovulation in women and promotes the ovarian secretion of estrogens and the progestins (such as progesterone), which prepare the body for possible pregnancy. In men, LH is sometimes called interstitial cell-stimulating hormone (ICSH), because it stimulates the production of sex hormones by the interstitial cells of the testes. These sex hormones are called androgens (andros, man), the most important of which is testosterone. LH production, like FSH production, is stimulated by GnRH from the hypothalamus. GnRH production is inhibited by estrogens, progestins, and androgens (Figure 18-10a).
Prolactin (pro-, before + lac, milk) (PRL), or mammotropin, works with other hormones to stimulate mammary gland development. In pregnancy and during the nursing period that follows delivery, PRL also stimulates milk production by the mammary glands. The functions of PRL in males are poorly understood, but there is evidence that PRL has an indirect role in the regulation of androgen production. (PRL appears to make interstitial cells more sensitive to LH.)
Prolactin production is inhibited by prolactin-inhibiting hormone (PIH). This hormone is identical to the neurotransmitter dopamine. The hypothalamus also secretes a prolactin-releasing hormone, but the identity of this prolactin-releasing factor (PRF) is a mystery. Circulating PRL stimulates PIH release and inhibits the secretion of prolactin-releasing factor (Figure 18-10b ).
Although PRL exerts the dominant effect on the glandular cells, normal development of the mammary glands is regulated by the interaction of several hormones. Prolactin, estrogens, progesterone, glucocorticoids, pancreatic hormones, and hormones produced by the placenta cooperate in preparing the mammary glands for secretion, and milk ejection occurs only in response to oxytocin release at the posterior pituitary. We shall detail the functional development of the mammary glands.
Growth hormone (GH), or somatotropin (soma, body), stimulates cell growth and replication by accelerating the rate of protein synthesis. Although virtually every tissue responds to some degree, skeletal muscle cells and chondrocytes (cartilage cells) are particularly sensitive to GH levels.
The stimulation of growth by GH involves two different mechanisms. The primary mechanism, which is indirect, is best understood. Liver cells respond to the presence of GH by synthesizing and releasing insulin-like growth factors (IGFs), or somatomedins, which are peptide hormones that bind to receptor sites on a variety of cell membranes (Figure 18-10c). In skeletal muscle fibers, cartilage cells, and other target cells, somatomedins increase the rate of uptake of amino acids and their incorporation into new proteins. These effects develop almost immediately after GH release occurs; they are particularly important after a meal, when the blood contains high concentrations of glucose and amino acids. In functional terms, cells can now obtain ATP easily through the aerobic metabolism of glucose, and amino acids are readily available for protein synthesis. Under these conditions, GH, acting through the somatomedins, stimulates protein synthesis and cell growth.
The direct actions of GH are more selective and tend not to appear until after blood glucose and amino acid concentrations have returned to normal levels:
- In epithelia and connective tissues, GH stimulates stem cell divisions and the differentiation of daughter cells. The subsequent growth of these daughter cells will be stimulated by somatomedins.
- GH also has metabolic effects in adipose tissue and in the liver. In adipose tissue, GH stimulates the breakdown of stored triglycerides by adipocytes (fat cells), which then release fatty acids into the blood. As circulating fatty acid levels rise, many tissues stop breaking down glucose and start breaking down fatty acids to generate ATP. This process is termed a glucose-sparing effect. In the liver, GH stimulates the breakdown of glycogen reserves by liver cells. These cells then release glucose into the circulation. Because most other tissues are now metabolizing fatty acids rather than glucose, blood glucose concentrations begin to climb, perhaps to levels significantly higher than normal. The elevation of blood glucose levels by GH has been called a diabetogenic effect, because diabetes mellitus, an endocrine disorder we will consider later in the chapter, is characterized by abnormally high blood glucose concentrations.
Control of Growth Hormone Production. The production of GH is regulated by growth hormone-releasing hormone (GH-RH, or somatocrinin) and growth hormone-inhibiting hormone (GH-IH), or somatostatin) from the hypothalamus. Somatomedins stimulate GH-IH and inhibit GH-RH (Figure 18-10c ).
The pars intermedia may secrete two forms of melanocyte-stimulating hormone (MSH), or melanotropin. As the name indicates, MSH stimulates the melanocytes of the skin, increasing their production of melanin, a brown, black, or yellow-brown pigment. MSH release is inhibited by an inhibiting hormone now known to be dopamine. MSH is important in the control of skin pigmentation in fishes, amphibians, reptiles, and many mammals other than primates. The pars intermedia in adult humans is virtually nonfunctional, and the circulating blood usually does not contain MSH. However, MSH is secreted by the human pars intermedia (1) during fetal development, (2) in very young children, (3) in pregnant women, and (4) in some disease states. The functional significance of MSH secretion under these circumstances is not known. Administration of a synthetic form of MSH causes darkening of the skin, and it has been suggested as a means of obtaining a "sunless tan."
The posterior pituitary is also called the neurohypophysis, or pars nervosa (nervous part), because it contains the axons of hypothalamic neurons. Neurons of the supraoptic and paraventricular nuclei manufacture antidiuretic hormone (ADH) and oxytocin, respectively. These products move by axoplasmic transport along axons in the infundibulum to the basement membranes of capillaries in the posterior pituitary gland.
Antidiuretic hormone (ADH), also known as vasopressin or arginine vasopressin (AVP), is released in response to a variety of stimuli, most notably a rise in the electrolyte concentration in the blood or a fall in blood volume or blood pressure. A rise in the electrolyte concentration stimulates the secretory neurons directly. Because they respond to a change in the osmotic concentration of body fluids, these neurons are called osmoreceptors. ADH secretion after a fall in blood volume or pressure occurs under the stimulation of another hormone, angiotensin II (angeion, vessel + teinein, to stretch).
The primary function of ADH is to decrease the amount of water lost at the kidneys. With losses minimized, any water absorbed from the digestive tract will be retained, reducing the concentration of electrolytes in the extracellular fluid. In high concentrations, ADH also causes vasoconstriction, a constriction of peripheral blood vessels that helps elevate blood pressure. ADH release is inhibited by alcohol, which explains the increased fluid excretion that follows the consumption of alcoholic beverages.
In women, oxytocin (oxy-, quick + tokos, childbirth), or OT, stimulates smooth muscle tissue in the wall of the uterus, promoting labor and delivery. After delivery, oxytocin stimulates the contraction of myoepithelial cells around the secretory alveoli and the ducts of the mammary glands, promoting the ejection of milk.
Until the last stages of pregnancy, the uterine smooth muscles are relatively insensitive to oxytocin, but sensitivity becomes more pronounced as the time of delivery approaches. The trigger for normal labor and delivery is probably a sudden rise in oxytocin levels at the uterus. There is good evidence, however, that the oxytocin released by the posterior pituitary plays only a supporting role and that most of the oxytocin involved is secreted by the uterus and fetus.
Oxytocin secretion and milk ejection are part of the neuroendocrine reflex diagrammed in Figure 18-6e . The stimulus is an infant suckling at the breast, and sensory nerves innervating the nipples relay the information to the hypothalamus. Oxytocin is then released into the circulation at the posterior pituitary, and the myoepithelial cells respond by squeezing milk from the secretory alveoli into large collecting ducts. This "milk let-down" reflex can be modified by any factor that affects the hypothalamus. For example, anxiety, stress, and other factors can prevent the flow of milk, even when the mammary glands are fully functional. In contrast, nursing mothers can become conditioned to associate a baby's crying with suckling. These women may begin milk let-down as soon as they hear a baby cry.
Although the functions of oxytocin in male and female sexual activity remain uncertain, it is known that circulating concentrations of oxytocin in both genders rise during sexual arousal and peak at orgasm. There is evidence that in men oxytocin stimulates smooth muscle contractions in the walls of the sperm duct (ductus deferens) and prostate gland. These actions may be important in emission, the ejection of prostatic secretions, sperm, and the secretions of other glands into the male reproductive tract before ejaculation. There are indications that the oxytocin released during intercourse in females may stimulate smooth muscle contractions in the uterus and vagina that promote sperm transport toward the uterine tubes.
Table 18-2 summarizes important information concerning the hormonal products of the pituitary gland. Review these carefully before considering the structure and function of other endocrine organs.
THE PINEAL GLAND
The pineal gland, part of the epithalamus, lies in the posterior portion of the roof of the third ventricle. The pineal gland contains neurons, glial cells, and special secretory cells called pinealocytes. These cells synthesize the hormone melatonin from molecules of the neurotransmitter serotonin. Collaterals from the visual pathways enter the pineal gland and affect the rate of melatonin production. Melatonin production is lowest during daylight hours and highest at night.
Several functions, including the following, have been suggested for melatonin in humans:
- In a variety of other mammals, melatonin slows the maturation of sperm, eggs, and reproductive organs by reducing the rate of GnRH secretion. The significance of this effect remains uncertain, but there is circumstantial evidence that melatonin may play a role in the timing of human sexual maturation. For example, melatonin levels in the blood decline at puberty, and pineal tumors that eliminate melatonin production will cause premature puberty in young children.
- Melatonin is a very effective antioxidant; it may protect CNS neurons from free radicals, such as nitric oxide (NO) or hydrogen peroxide (H2O2), that may be generated in active neural tissue.
- Because of the cyclical nature of pineal activity, the pineal gland may also be involved with the establishment or maintenance of basic circadian rhythms, daily changes in physiological processes that follow a regular pattern. Increased melatonin secretion in darkness has been suggested as a primary cause for seasonal affective disorder (SAD). This condition, characterized by changes in mood, eating habits, and sleeping patterns, can develop during the winter in people who live at high latitudes, where sunshine is scarce or lacking altogether.
CONCEPT CHECK QUESTIONS
1. If a person were suffering from dehydration, how would this condition affect the level of ADH released by the posterior pituitary gland?
2. A blood sample shows elevated levels of somatomedins. What pituitary hormone would you expect to be elevated as well?
3. What effect would elevated circulating levels of cortisol, a steroid hormone from the adrenal cortex, have on the pituitary secretion of ACTH?
across the anterior surface of the trachea just inferior to the thyroid
("shield-shaped") cartilage, which forms most of the anterior
surface of the larynx (Figure 18-12a ). The two lobes of the thyroid gland are united by a slender
connection, the isthmus isthmus . You can easily feel the gland with your fingers. When
something goes wrong with it, the thyroid gland typically becomes visible as it
swells and distorts the surface of the neck. The size of the gland is quite
variable, depending on heredity and environmental and nutritional factors, but
its average weight is about
The thyroid gland contains large numbers of thyroid follicles. Individual follicles are spheres lined by a simple cuboidal epithelium (Figure 18-12c,d ). The follicle cells surround a follicle cavity. This cavity holds a viscous colloid, a fluid containing large quantities of suspended proteins. A network of capillaries surrounds each follicle, delivering nutrients and regulatory hormones to the glandular cells and accepting their secretory products and metabolic wastes.
Follicular cells synthesize a globular protein called thyroglobulin and secrete it into the colloid of the thyroid follicles (Figure 18-12d ). Each thyroglobulin molecule contains the amino acid tyrosine, the building block of thyroid hormones. The formation of thyroid hormones involves three basic steps:
1. Iodide ions are absorbed from the diet at the digestive tract and delivered to the thyroid gland by the circulation. Carrier proteins in the basal membrane of the follicle cells transport iodide ions (I-) into the cytoplasm. The follicle cells normally maintain intracellular concentrations of iodide that are many times higher than those in the extracellular fluid.
2. The iodide ions diffuse to the apical surface of each follicle cell, where they are converted to an activated form of iodide (I+) by an enzyme called thyroid peroxidase. This reaction sequence also attaches either one or two of these iodide ions to the tyrosine molecules of thyroglobulin.
3. Tyrosine molecules to which iodide ions have been attached are paired, forming molecules of thyroid hormones that remain incorporated into thyroglobulin. The pairing process is probably performed by thyroid peroxidase. The hormone thyroxine, also known as tetraiodothyronine, or simply T4, contains four iodide ions. Triiodothyronine, or T3, is a related molecule containing three iodide ions. Eventually, each molecule of thyroglobulin contains 4-8 molecules of T3 or T4 hormones or both.
The major factor controlling the rate of thyroid hormone release is the concentration of TSH in the circulating blood (Figure 18-13 ). TSH stimulates iodide transport into the follicle cells and stimulates the production of thyroglobulin and thyroid peroxidase. TSH also stimulates the release of thyroid hormones. Under the influence of TSH, the following steps occur:
4. Follicle cells remove thyroglobulin from the follicles through endocytosis.
5. Lysosomal enzymes then break the protein down, and the amino acids and thyroid hormones enter the cytoplasm. The amino acids are recycled and used to synthesize thyroglobulin.
6. The released molecules of T3 and T4 diffuse across the basement membrane and enter the circulation. Thyroxine (T4) accounts for roughly 90 percent of all thyroid secretions, and triiodothyronine (T3) is secreted in comparatively small amounts.
7. Roughly 75 percent of the T4 and 70 percent of the T3 molecules entering the circulation become attached to transport proteins called thyroid-binding globulins (TBGs). Most of the rest of the T4 and T3 in the circulation is attached to transthyretin, also known as thyroid-binding prealbumin (TBPA), or to albumin, one of the plasma proteins. Only the relatively small quantities of thyroid hormones that remain unbound—roughly 0.3 percent of the circulating T3 and 0.03 percent of the circulating T4—are free to diffuse into peripheral tissues.
An equilibrium exists between the bound and unbound thyroid hormones. At any moment, free thyroid hormones are being bound to carriers at the same rate at which bound hormones are being released. When unbound thyroid hormones diffuse out of the circulation and into other tissues, the equilibrium is disturbed. The carrier proteins then release additional thyroid hormones until a new equilibrium is reached. The bound thyroid hormones thus represent a substantial reserve, and the bloodstream normally contains more than a week's supply of thyroid hormones.
TSH plays a key role in both the synthesis and the release of thyroid hormones. In the absence of TSH, the thyroid follicles become inactive, and neither synthesis nor secretion occurs. TSH binds to membrane receptors and, by stimulating adenylate cyclase, activates key enzymes.
Functions of Thyroid Hormones
Thyroid hormones readily cross cell membranes, and they affect almost every cell in the body. Inside a cell, they bind to (1) receptors in the nucleus, (2) receptors on the surfaces of mitochondria, and (3) receptors in the cytoplasm. Thyroid hormones bound to cytoplasmic receptors are essentially held in storage. If intracellular levels of thyroid hormones decline, the bound thyroid hormones are released into the cytoplasm.
The thyroid hormones binding to mitochondria increase the rates of mitochondrial ATP production. The binding to receptors in the nucleus activates genes that control the synthesis of enzymes involved with energy transformation and utilization. One specific effect is accelerated production of sodium-potassium ATPase, the membrane protein responsible for the ejection of intracellular sodium and the recovery of extracellular potassium. As we noted in Chapter 3, this exchange pump consumes large amounts of ATP.
Thyroid hormones also activate genes that code for the synthesis of enzymes involved in glycolysis and ATP production. This effect, coupled with the direct effect of thyroid hormones on mitochondria, increases the metabolic rate of the cell. Because the cell consumes more energy and because energy use is measured in calories, the effect is called the calorigenic effect of thyroid hormones. When the metabolic rate increases, more heat is generated. In young children, TSH production increases in cold weather; the calorigenic effect may help them adapt to cold climates. (This response does not occur in adults.) In growing children, thyroid hormones are also essential to normal development of the skeletal, muscular, and nervous systems.
Two pairs of parathyroid glands are
embedded in the posterior surfaces of the thyroid gland (Figure 18-14a ). The gland cells are separated by the dense capsular fibers of the thyroid. All together the four parathyroid
glands weigh a mere
Like the C cells of the thyroid, the chief cells monitor the circulating concentration of calcium ions. When the Ca2+ concentration of the blood falls below normal, the chief cells secrete parathyroid hormone (PTH), or parathormone. The net result of PTH secretion is an increase in Ca2+ concentration in body fluids. Parathyroid hormone has four major effects:
1. It stimulates osteoclasts, accelerating mineral turnover and the release of Ca2+ from bone.
2. It inhibits osteoblasts, reducing the rate of calcium deposition in bone.
3. It reduces urinary excretion of Ca2+.
4. It stimulates the formation and secretion of calcitriol at the kidneys. In general, the effects of calcitriol complement or enhance those of PTH, but one major effect of calcitriol is the enhancement of Ca2+ and PO43- absorption by the digestive tract. We will consider calcitriol in a later section.
A yellow, pyramid-shaped adrenal gland, or suprarenal gland (supra-, above + renes, kidneys), sits on the superior border of each kidney (Figure 18-16a ). Each adrenal gland lies at roughly the level of the twelfth rib and is firmly attached to the superior portion of each kidney by a dense fibrous capsule. The adrenal gland on each side nestles between the kidney, the diaphragm, and the major arteries and veins that run along the dorsal wall of the abdominopelvic cavity. The adrenal glands project into the peritoneal cavity, and their anterior surfaces are covered by a layer of parietal peritoneum. Like other endocrine glands, the adrenal glands are highly vascularized.
A typical adrenal gland weighs about
The linings of the digestive tract, the liver, and the pancreas produce a variety of exocrine secretions that are essential to the normal breakdown and absorption of food. Although the pace of digestive activities can be affected by the ANS, most digestive processes are controlled locally. The various components of the digestive tract communicate with one another by means of hormones that we will consider in Chapter 24. One digestive organ, the pancreas, produces two hormones with widespread effects.
The thymus is located in the mediastinum, generally just posterior to the sternum.
In newborn infants and young children, the thymus is relatively large,
commonly extending from the base of the neck to the superior border of the
heart. Although the thymus continues to increase in size throughout childhood,
the body as a whole grows even faster, so the size of the thymus relative to
that of the other organs in the mediastinum gradually decreases. The thymus
reaches its maximum absolute size, at a weight of about
The thymus produces several hormones that are important to the development and maintenance of normal immunological defenses ( Table 18-4 ). Thymosin is the name originally given to a thymic extract that promotes the development and maturation of lymphocytes, the white blood cells responsible for immunity. The thymic extract actually contains a blend of several different, complementary hormones—thymosin-, thymosin-ß, thymosin V, thymopoietin, thymulin, and several others. The term thymosins is now used to refer to all thymic hormones.
lies within the abdominopelvic cavity in the J-shaped
loop between the stomach and the small intestine (Figure 18-19
It is a slender, pale organ with a nodular (lumpy) consistency. The adult
pancreas is 20-
The endocrine pancreas consists of small groups of cells scattered among the exocrine cells. The endocrine clusters are known as pancreatic islets , or the islets of Langerhans. Pancreatic islets account for only about 1 percent of the pancreatic cell population. Nevertheless, a typical pancreas contains roughly 2 million pancreatic islets.
Lymphatic and immune system
ORGANIZATION OF THE LYMPHATIC SYSTEM
The lymphatic system consists of the following:
1. A network of lymphatic vessels that begin in peripheral tissues and end at connections to the venous system.
2. Lymph, a fluid that resembles plasma but contains a much lower concentration of suspended proteins.
3. Lymphoid organs connected to the lymphatic vessels and containing large numbers of lymphocytes.
The three primary functions of the lymphatic system are:
1. The production, maintenance, and distribution of lymphocytes. Lymphocytes are produced and stored within (1) lymphoid tissues and organs, such as the spleen and thymus, and (2) areas of red bone marrow.
2. The return of fluid and solutes from peripheral tissues to the blood. Capillaries normally deliver more fluid to the tissues than they carry away. The return of tissue fluids through lymphatic vessels maintains normal blood volume and eliminates local variations in the composition of the interstitial fluid.
3. The distribution of hormones, nutrients, and waste products from their tissues of origin to the general circulation. Substances that originate in the tissues but are for some reason unable to enter the bloodstream directly may do so by way of the lymphatic vessels. For example, lipids absorbed by the digestive tract commonly fail to enter the circulation at the capillary level. They reach the bloodstream only after they have traveled along lymphatic vessels (a process we shall explore further in Chapter 24).
Lymphatic vessels, often called lymphatics, carry lymph from peripheral tissues to the venous system. The smallest lymphatic vessels are called lymphatic capillaries.
The lymphatic network begins with the lymphatic capillaries, or terminal lymphatics, that branch through peripheral tissues. They differ from blood capillaries in that lymphatic capillaries (1) originate as blind pockets, (2) are larger in diameter, (3) have thinner walls, and (4) in sectional view typically have a flattened or irregular outline (Figure 22-2). Although lined by endothelial cells, they have no underlying basement membrane. The endothelial cells of a lymphatic capillary are not tightly bound together, but they do overlap. The region of overlap acts as a one-way valve. It permits the entry of fluids and solutes, even those as large as proteins, but it prevents their return to the intercellular spaces (Figure 22-2).
Lymphatic capillaries are present in almost every tissue and organ in the body. Prominent lymphatic capillaries in the small intestine are called lacteals; these are important in the transport of lipids absorbed by the digestive tract. Lymphatic capillaries are absent in areas that lack a blood supply, such as the cornea of the eye. There are also no lymphatics in the CNS.
From the lymphatic capillaries, lymph flows into larger lymphatic vessels that lead toward the trunk. The walls of these lymphatic vessels contain layers comparable to those of veins, and, like veins, the larger lymphatic vessels contain valves (Figure 22-3). The valves are quite close together, and at each valve the lymphatic vessel bulges noticeably. As a result, large lymphatics have a beaded appearance (Figure 22-3). The valves prevent the backflow of lymph within lymph vessels, especially those of the limbs. Pressures within the lymphatic system are minimal, and the valves are essential to maintaining normal lymph flow toward the thoracic cavity.
Lymphatic vessels commonly occur in association with blood vessels (Figure 22-3). Note the differences in relative size, general appearance, and branching pattern that distinguish the lymphatic vessels from arteries and veins. There are also characteristic color differences that are apparent on examining living tissues. Most arteries are bright red, veins dark red, and lymphatic vessels a pale golden color. In general, a tissue will contain many more lymphatics than veins, but the lymphatics are much smaller.
Two sets of lymphatic vessels collect blood from the lymphatic capillaries: superficial lymphatics and deep lymphatics. Superficial lymphatics are located in the subcutaneous layer beneath the skin; in the loose connective tissues of the mucous membranes lining the digestive, respiratory, urinary, and reproductive tracts; and in the loose connective tissues of the serous membranes lining the pleural, pericardial, and peritoneal cavities. Deep lymphatics are larger lymph vessels. They accompany deep arteries and veins supplying skeletal muscles and other organs of the neck, limbs, and trunk and the walls of visceral organs.
Superficial and deep lymphatics converge to form larger vessels called lymphatic trunks that in turn empty into two large collecting vessels: the thoracic duct and the right lymphatic duct. The thoracic duct collects lymph from the body inferior to the diaphragm and from the left side of the body superior to the diaphragm. The smaller right lymphatic duct collects lymph from the right side of the body superior to the diaphragm.
The thoracic duct is formed inferior to the diaphragm at the level of vertebra L2. The base of the thoracic duct is an expanded, saclike chamber called the cisterna chyli (Figure 22-4). The cisterna chyli receives lymph from the lower abdomen, pelvis, and lower limbs via the right and left lumbar trunks and the intestinal trunk.
The inferior segment of the thoracic duct lies anterior to the vertebral column. From the second lumbar vertebra, it penetrates the diaphragm at the aortic hiatus and ascends along the left side of the vertebral column to the level of the left clavicle. After collecting lymph from the left bronchomediastinal trunk, the left subclavian trunk, and the left jugular trunk, it empties into the left subclavian vein near the left internal jugular vein (Figure 22-4). Lymph collected from the left side of the head, neck, and thorax, as well as lymph from the entire body inferior to the diaphragm, re-enters the venous system in this way.
Right Lymphatic Duct
The right lymphatic duct is formed by the merging of the right jugular, right subclavian, and right bronchomediastinal trunks in the area near the right clavicle. This duct empties into the right subclavian vein, delivering lymph from the right side of the body superior to the diaphragm (Figure 22-4).
Lymphocytes account for 20-30 percent of the circulating white blood cell population. However, circulating lymphocytes are only a small fraction of the total lymphocyte population. The body contains some 1012 lymphocytes, with a combined weight of over a kilogram.
There are three classes of lymphocytes in the blood: (1) T (thymus-dependent) cells, B (bone marrow-derived) cells, and NK (natural killer) cells. Each type has distinctive biochemical and functional characteristics.
Approximately 80 percent of circulating lymphocytes are classified as T cells. There are many different types of T cells, including the following:
- Cytotoxic T cells, which attack foreign cells or body cells infected by viruses. Their attack commonly involves direct contact. These lymphocytes are the primary cells involved in the production of cell-mediated immunity, or cellular immunity.
- Helper T cells, which stimulate the activation and function of both T cells and B cells.
- Suppressor T cells, which inhibit the activation and function of both T cells and B cells.
The interplay between suppressor and helper T cells helps establish and control the sensitivity of the immune response. For this reason, these cells are also known as regulatory T cells.
These are the T cells that we will examine in the course of this chapter. It is not a complete list, however; there are other types of T cells that participate in the immune response. For example, inflammatory T cells stimulate regional inflammation and local defenses in an injured tissue, and suppressor/inducer T cells suppress B cell activity but stimulate other T cells.
B cells account for 10-15 percent of circulating lymphocytes. When stimulated, B cells can differentiate into plasma cells. Plasma cells, introduced in Chapter 4, are responsible for the production and secretion of antibodies, soluble proteins that are also known as immunoglobulins. These proteins react with specific chemical targets called antigens. Most antigens are pathogens, parts or products of pathogens, or other foreign compounds. Most antigens are proteins, but some lipids, polysaccharides, and nucleic acids can also stimulate antibody production. When an antibody binds to its target antigen, a chain of events begins that leads to the destruction of the target compound or organism. B cells are responsible for antibody-mediated immunity, which is also known as humoral ("liquid") immunity because antibodies occur in body fluids.
The remaining 5-10 percent of circulating lymphocytes are NK cells, also known as large granular lymphocytes. These lymphocytes will attack foreign cells, normal cells infected with viruses, and cancer cells that appear in normal tissues. Their continuous policing of peripheral tissues has been called immunological surveillance.
Life Span and Circulation of Lymphocytes
Lymphocytes are not evenly distributed in the blood, bone marrow, spleen, thymus, and peripheral lymphoid tissues. The ratio of B cells to T cells varies with the tissue or organ considered. For example, B cells are seldom found in the thymus, and in the blood T cells outnumber B cells by a ratio of 8:1. This ratio changes to 1:1 in the spleen and 1:3 in the bone marrow.
The lymphocytes within these organs are visitors, not residents. All types of lymphocytes move throughout the body. They wander through a tissue and then enter a blood vessel or lymphatic vessel for transport to another site.
T cells move relatively quickly. For example, a wandering T cell may spend about 30 minutes in the blood, 5-6 hours in the spleen, and 15-20 hours in a lymph node. B cells, which are responsible for antibody production, move more slowly. A typical B cell spends about 30 hours in a lymph node before moving on.
Lymphocytes have relatively long life spans. Roughly 80 percent survive for 4 years, and some last 20 years or more. Throughout your life, you maintain normal lymphocyte populations by producing new lymphocytes in your bone marrow and lymphatic tissues.
In Chapter 19, we discussed hemopoiesis, the formation of the cellular elements of blood. Erythropoiesis (red blood cell formation) in adults is normally confined to the bone marrow, but lymphocyte production, or lymphopoiesis, involves the bone marrow, thymus, and peripheral lymphoid tissues. The relationships are diagrammed in Figure 22-5.
The bone marrow plays the primary role in the maintenance of normal lymphocyte populations. Hemocytoblast divisions in the bone marrow of an adult generate the lymphoid stem cells responsible for the production of all types of lymphocytes. Two distinct populations of lymphoid stem cells are produced in the bone marrow.
One group of lymphoid stem cells remains in the bone marrow (Figure 22-5). Divisions of these cells produce immature B cells and NK cells. B cell development involves intimate contact with large stromal cells (stroma, a bed) in the bone marrow. The cytoplasmic extensions of stromal cells contact or even wrap around the developing B cells. The stromal cells produce an immune system hormone, or cytokine, called interleukin-7, which promotes the differentiation of B cells. (We will consider cytokines and their varied effects in a later section.)
As they mature, B cells and NK cells enter the circulation and migrate to peripheral tissues (Figure 22-5). Most of the B cells move into lymph nodes, the spleen, or other lymphoid tissues. The NK cells migrate throughout the body, moving through peripheral tissues in their search for abnormal cells.
The second group of lymphoid stem cells migrates to the thymus (Figure 22-5). While in the thymus, these cells and their descendants develop further in an environment that is isolated from the general circulation by the blood-thymus barrier. Under the influence of thymic hormones collectively known as thymosins, the lymphoid stem cells divide repeatedly, producing the various kinds of T cells. At least seven thymosins have been identified, including thymosin-, thymosin-ß, thymosin V, thymopoietin, thymulin, thymolymphotropin, and thymic-factor X. Their precise functions and interactions have yet to be determined.
The T cells and B cells that migrate from their sites of origin retain the ability to divide. Their divisions produce daughter cells of the same type; for example, a dividing B cell produces other B cells, not T cells or NK cells. As we shall see, the ability to increase the number of lymphocytes of a specific type is important to the success of the immune response.
Lymphoid tissues are connective tissues dominated by lymphocytes. In a lymphoid nodule, or lymphatic nodule, the lymphocytes are densely packed in an area of loose connective tissue (Figure 22-6). Lymphoid nodules are found in the connective tissue beneath the epithelia lining the respiratory, digestive, and urinary tracts. Typical nodules average about a millimeter in diameter, but the boundaries are not distinct, because no fibrous capsule surrounds them. They commonly have a central zone called a germinal center, which contains dividing lymphocytes.
The extensive collection of lymphoid tissues linked with the digestive system is called the gut-associated lymphoid tissue (GALT). Clusters of lymphoid nodules beneath the epithelial lining of the intestine are known as aggregate lymphoid nodules, or Peyer's patches (Figure 22-6a). In addition, the walls of the appendix, a blind pouch that originates near the junction between the small and large intestines, contain a mass of fused lymphoid nodules.
Lymph nodes are small, oval lymphoid organs
ranging in diameter from 1 to
The shape of a typical lymph node resembles that of a kidney bean. Blood vessels and nerves attach to the lymph node at the indentation, or hilus (Figure 22-7). Two sets of lymphatic vessels are connected to each lymph node: efferent lymphatics and afferent lymphatics.
Lymph delivered by the afferent lymphatics flows through the lymph node within a network of sinuses, open passageways with incomplete walls. Lymph first enters a subcapsular sinus, which contains a meshwork of branching reticular fibers, macrophages, and dendritic cells. Dendritic cells are involved in the initiation of the immune response, and we shall consider their role in a later section. After passing through the subcapsular sinus, lymph flows through the outer cortex of the node. The outer cortex contains B cells within germinal centers that resemble those of lymphoid nodules.
Lymph then continues through lymph sinuses in the deep cortex (paracortical area). Lymphocytes leave the circulation and enter the lymph node by crossing the walls of blood vessels within the deep cortex. The deep cortical area is dominated by T cells.
After flowing through the sinuses of the deep cortex, lymph continues into the core, or medulla, of the lymph node. The medulla contains B cells and plasma cells organized into elongate masses known as medullary cords. Lymph enters the efferent lymphatics at the hilus after passing through a network of sinuses in the medulla.
A lymph node functions like a kitchen water filter: It filters and purifies lymph before that fluid reaches the venous system. As lymph flows through a lymph node, at least 99 percent of the antigens in the arriving lymph will be removed. Fixed macrophages in the walls of the lymphatic sinuses engulf debris or pathogens in the lymph as it flows past. Antigens removed in this way are then processed by the macrophages and "presented" to nearby lymphocytes. Other antigens bind to receptors on the surfaces of dendritic cells, where they can stimulate lymphocyte activity. This process, called antigen presentation, is generally the first step in the activation of the immune response.
In addition to filtering, lymph nodes provide an early-warning system. Any infection or other abnormality in a peripheral tissue will introduce abnormal antigens into the interstitial fluid and thus into the lymph leaving the area. These antigens will then stimulate macrophages and lymphocytes in nearby lymph nodes.
If you wanted to protect a house against intrusion, you might guard all entrances and exits or place traps by the windows and doors. The distribution of lymphatic tissues and lymph nodes follows such a pattern. The largest lymph nodes are found where peripheral lymphatics connect with the trunk, in regions such as the groin, the axillae, and the base of the neck. These nodes are often called lymph glands. Because lymph is monitored in the cervical, inguinal, or axillary lymph nodes, potential problems can be detected and dealt with before they affect the vital organs of the trunk. Aggregations of lymph nodes also exist within the mesenteries of the gut, near the trachea and passageways leading to the lungs, and in association with the thoracic duct (Figure 22-4). These lymph nodes protect against pathogens and other antigens within the digestive and respiratory systems.
A minor injury commonly produces a slight enlargement of the nodes along the lymphatics draining the region. This symptom, often called "swollen glands," typically indicates inflammation or infection of peripheral structures. The enlargement generally results from an increase in the number of lymphocytes and phagocytes in the node in response to a minor, localized infection. Chronic or excessive enlargement of lymph nodes constitutes lymphadenopathy. This condition may occur in response to bacterial or viral infections, endocrine disorders, or cancer.
The thymus lies posterior to the
sternum, in the anterior portion of the mediastinum. It has a pinkish
coloration and a grainy consistency. The thymus reaches its greatest size
(relative to body size) in the first year or two after birth and its maximum
absolute size during puberty, when it weighs between 30 and
The capsule that covers the thymus
divides it into two thymic lobes (Figure 22-8a,b). Fibrous
partitions, or septae, from the capsule
divide the lobes into lobules averaging
Lymphocytes in the cortex are arranged in clusters that are completely surrounded by reticular epithelial cells. These cells, which developed from epithelial cells of the embryo, also encircle the blood vessels of the cortex. The reticular epithelial cells (1) maintain the blood-thymus barrier and (2) secrete the thymic hormones (thymosins) that stimulate stem cell divisions and T cell differentiation.
As they mature, T cells leave the cortex and enter the medulla of the thymus. There is no blood-thymus barrier in the medulla. The reticular epithelial cells in the medulla cluster together in concentric layers, forming distinctive structures known as Hassall's corpuscles (Figure 22-8d). Despite their imposing appearance, the function of Hassall's corpuscles remains unknown. T cells within the medulla can enter or leave the circulation via the blood vessels in this region or within one of the efferent lymphatics that collect lymph from the thymus.
The adult spleen contains the
largest collection of lymphoid tissue in the body. It is about
Functions of the Spleen
On gross dissection, the spleen has a deep red color due to the blood it contains. In essence, the spleen performs the same functions for the blood that lymph nodes perform for lymph. Splenic functions can be summarized as (1) the removal of abnormal blood cells and other blood components through phagocytosis, (2) the storage of iron from recycled red blood cells, and (3) the initiation of immune responses by B cells and T cells in response to antigens in the circulating blood.
Surfaces of the
The spleen has a soft consistency, and its shape primarily reflects its association with the structures around it. It is in contact with the stomach, the left kidney, and the muscular diaphragm. The diaphragmatic surface is smooth and convex, conforming to the shape of the diaphragm and body wall. The visceral surface contains indentations that record the shape of the stomach (the gastric area) and of the kidney (the renal area. Splenic blood vessels and lymphatics communicate with the spleen on the visceral surface at the hilus, a groove marking the border between the gastric and renal depressions. The splenic artery, the splenic vein, and the lymphatics draining the spleen are attached at the hilus.
Histology of the Spleen
The spleen is surrounded by a capsule containing collagen and elastic fibers. (The spleens of dogs and cats have extensive layers of smooth muscle that can contract to eject blood into the circulation;the human spleen lacks those muscle layers and cannot contract). The cellular components within constitute the pulp of the spleen (Figure 22-9c). Areas of red pulp contain large quantities of red blood cells, whereas areas of white pulp resemble lymphoid nodules.
The splenic artery enters at the hilus and branches to produce a number of arteries that radiate outward toward the capsule. These trabecular arteries branch extensively, and their finer branches are surrounded by areas of white pulp. Capillaries then discharge the blood into the red pulp.
The cell population of the red pulp includes all the normal components of the circulating blood, plus fixed and free macrophages. The structural framework of the red pulp consists of a network of reticular fibers. The blood passes through this meshwork and enters large sinusoids, also lined by fixed macrophages. The sinusoids empty into small veins, and these ultimately collect into trabecular veins that continue toward the hilus.
This circulatory arrangement gives the phagocytes of the spleen an opportunity to identify and engulf any damaged or infected cells in the circulating blood. Lymphocytes are scattered throughout the red pulp, and the marginal zone surrounding each area of white pulp has a high concentration of macrophages and dendritic cells. Thus any microorganism or other antigen in the blood will quickly come to the attention of the splenic lymphocytes.
1. Nonspecific defenses do not discriminate between one threat and another. These defenses, which are present at birth, include physical barriers, phagocytic cells, immunological surveillance, interferons, complement, inflammation, and fever. They provide the body with a defensive capability known as nonspecific resistance.
2. Specific defenses protect against particular threats. For example, a specific defense may protect against infection by one type of bacteria but ignore other bacteria and viruses. Many specific defenses develop after birth, as a result of accidental or deliberate exposure to environmental hazards. Specific defenses are dependent on the activities of lymphocytes. The body's specific defenses produce a state of protection known as immunity, or specific resistance.