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Зміст14.2 Passive barriers to infection
14.3 Self and non-self
14.4 The natural immune system
14.4 The natural immune system 265
What triggers the inflammatory response?
Lymphocytes circulate continuously through the tissues
14.5 The adaptive immune system
There are five classes of antibody
Antigen processing and presentation
14.6 Disorders of the immune system
14.6 Disorders of the immune system
Principles of cellular and molecular immunology.
Textbook of medicine
The adaptive immune system
Defense against infection: inflammation and immunity
As animals move through their environment to feed and reproduce, they are inevitably brought into contact with other organisms. Some of these will be food while others may attempt to invade the body. Of those that invade the body, some will live in harmony with the host. When this is of benefit to the host, it is known as mutualism. If it is neither beneficial nor harmful, it is called commensalism. When the presence of the invading organism compromises the health of the host, the relationship is known as parasitism. All infectious diseases are due to parasites of one kind or another. In the developed countries, most infections are caused by bacteria, fungi, and viruses but infections by protozoa and worms of various kinds are also very common in poorer regions of the world.
To defend themselves against infections, animals have two basic strategies: they use passive barriers to prevent parasites entering the body and they actively attack those organisms that have become lodged in the tissues. To eliminate an invading organism, the host must first be able to distinguish it from its own cells. Secondly, it must neutralize or kill it. Finally, it must dispose of the remains in such a way that does no further harm. These functions are performed by the immune system, which may be conveniently divided into the natural immune system and the adaptive immune system.
The immune system is a complex network of organs, cells, and circulating proteins. The principal organs of the immune system are the bone marrow, the thymus, the spleen, the lymph nodes, and the lymphoid tissues associated with the epithelia that line the gut and airways (known as mucosa-associated lymphatic tissue or MALT). Collectively they are known as the lymphoid organs (Fig. 14.1). The cells of the immune system include the leukocytes of the blood (Chapter 13), mast cells, and various accessory cells which are scattered throughout the body. The accessory cells include phagocytic cells that are found in many organs, including the lungs, liver, spleen, and kidneys, and cells known as antigen-presenting cells which are particularly associated with the lymphoid organs. The proteins of the immune system are antibodies and complement.
The cells of the immune system recognize foreign materials by their surface molecules. Those molecules that generate an
Fig. 14.1 The location of the major lymphoid organs. The thymus and bone marrow are the primary lymphoid tissues, the remainder are secondary lymphoid tissues.
immune response are called antigens. The recognition may be relatively nonspecific (e.g. the binding of complement to bacterial cell walls) or highly specific, in which a small part of a particular molecule is precisely recognized. This type of interaction is characteristic of the antibodies secreted by the cells of the adaptive immune system in response to a particular antigen.
The first barrier encountered by an invading organism is the skin. Its pseudostratified and keratinized epidermis forms an effective physical barrier to infiltration by micro-organisms. In addition, the sweat glands and sebaceous glands secrete fatty acids which inhibit the growth of bacteria on the skin surface. When the skin is broken either by abrasion or by burns, infection may become a significant problem.
line the airways, gut, and urogenital tract. The epithelia of these membranes are less rugged than that of the skin but they still
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example, the epithelia that line the airways are protected by a thick layer of mucus that traps many bacteria and viruses and prevents them adhering to the underlying cells. The mucus is then eliminated via the mucociliary escalator and coughed up (Section 16.8).
Other regions that are vulnerable to infection are regularly flushed by sterile fluid (e.g. the urinary tract) or by fluids that contain bactericidal agents. For example, the external surface of the eyes are washed by fluid from the tear glands which both flushes the surface to remove foreign materials and contains the bactericidal enzyme lysozyme. Orher body secretions such as the semen and milk also contain antibodies and bactericidal substances.
The food we eat is inevitably contaminated by bacteria and other micro-organisms. Indeed, some organisms are deliberately introduced into certain foods, such as cheese, to flavor them. The gut has several stratagems to combat infection arising from this source. The mucous membranes of the mouth and upper gastrointestinal tract are protected by lysozyme and antibodies of the IgA class (see below) secreted by the salivary glands. Many bacteria are killed by the low pH of the gastric juice. The mucosal surface of the gut also possesses mucus glands that secrete a layer of mucus that both lubricates the passage of food and protects the surface epithelium from infection. Despite these barriers, the lumen of the intestine contains a healthy bacterial population. These are commensal organisms which provide the body with a further line of defense. The normal bacterial flora both competes with potential pathogens for essential nutrienrs and secretes inhibitory factors (bacterkidim) that kill invading pathogens.
Clearly, these passive mechanisms do nor always prevent the ingress of pathogens. The skin can be penetrated by ectoparasites such as ticks and mosquitoes which may themselves be infected with micro-organisms such as Plasmodium (the organism that causes malaria). Small pathogens such as bacteria and viruses may penetrate the body's defenses via the internal epithelia, such as those of the airways. Those that enter the gut may overwhelm the defenses afforded by the natural commensal bacteria, for example in typhoid fever. When infection occurs, the active processes of immuniry come into play.
Before the body can mount a defense against infection, it first needs to know the difference between the normal cells of the body and those of invading parasites. How does the immune system recognize 'self from 'non-self? It is now known that mammalian cells possess markers on their surface that identify
them as host cells. So, just as red cells possess surface proteins
that determine particular blood groups, orher cells possess
cells. By using these markers, the immune system can distinguish host cells from those of invading organisms. The mole-characteristic are called nonspecific, while those that can detect a particular invading organism amongst the thousands of possible candidates are called specific recognition molecules. As we shall see, nonspecific recognition is characteristic of the natural immune system while the adaptive immune system can identify and destroy a specific type of invading organism.
The proteins that identify host cells are known as the major histocompatibility complex, or MHC. Their rather unfortunate name arises from the history of their discovery. They were first detected as the proteins responsible for the rejection of tissue grafts between a donor and a recipienr animal. In human immunology the MHC complex is known as the HLA complex (for human leukocyte antigen). It is now known that MHC consists of a large number of genes which encode several families of proteins. MHC class I proteins are integral membrane proteins found on all nucleated cells and platelets (but not red cells). MHC class II proteins are found only on certain lymphocytes (mostly В cells, see below), macrophages, monocytes, and antigen-presenting cells. These proteins function to expose parts of foreign proteins to a class of lymphocytes known as T cells to stimulate an immune response to infection. MHC class III proteins include complement, which plays an important part in the body's defense against micro-organisms.
The natural immune system consists of the innate defense mechanisms that do not change very much either with age or following infections. It consists of four kinds of cells and three different classes of proteins. The cells of the natural immune system are:
The classes of protein are:
The principal phagocytes of the natural
immune system are the neutrophils and
The neutrophils are the most common white cell in the blood (Section 13-3). They contain two main types of granule called
the primary azurophil granules and the secondary specific granules. The primary azurophil granules contain an enzyme called
14.4 The natural immune system
myeloperoxidase, a range of bactericidal proteins, and a protease called cathepsin G. The secondary specific granules contain lysozyme, alkaline phosphatase, and a peculiar form of cytochrome (cytochrome £558) which can be inserted in the plasma membrane.
Neutrophils are able to pass from the blood into the intercellular spaces by diapedesis (see below) and actively phagocytose and engulf disease-producing bacteria. The enzymes within the cytoplasmic granules then kill the invading organisms and digest them. As a result of this action, the neutrophils form the first line of defense against infection.
The macrophages are formed in the bone marrow and released into the blood as monocytes. Within 2 days they migrate to tissues such as the spleen, lungs, and lymph nodes where they mature. Macrophages contain a large number of lysosomes and phagocytic vesicles containing the remains of ingested materials. They are found in all tissues, even in the brain where they are known as microglia (Fig. 14.2). Macrophages are situated around the basement membrane of small blood vessels and line both the spleen sinusoids and the medullary sinuses of the lymph nodes, where they are able to remove particulate matter from circulation. In the liver they are known as Kupffer cells.
The phagocytosis and killing of microbes
Before a phagocyte can kill an invading bacterium, it must first recognize it as a foreign body and engulf it. This is the process of phagocytosis which was described in Section 4.5. Phagocytes are nonspecific immune cells and will attack a wide variety of invading organisms and cell debris.
After a bacterium has been engulfed the phagocyte will kill it. This is achieved by a variety of methods. Following phagocytosis,
Fig. 14.2 The mononuclear phagocyte system. Monocytes are formed in the bone marrow where they mature before being released into the circulation. They migrate to tissues such as the spleen, liver, lungs, and lymph nodes where they take up residence as mature macrophages. The neutrophils (the other main class of phagocyte) remain in the circulation until they participate in an inflammatory reaction.
the macrophage or neutrophil produces a number of reactive oxygen intermediates via cytochrome £558. Molecular oxygen is first converted to the superoxide anion which, under the influence of an enzyme called superoxide dismutase, gives rise to hydrogen peroxide. The hydrogen peroxide then gives rise to a number of highly reacrive intermediates which kill the bacteria that lie within the phagosome (Fig. 14.3). These events cause a marked increase in oxygen uptake by the activated cell. This increase is called a respiratory burst. Both macrophages and neutrophils also produce nitric oxide and other reactive nitrogen intermediates to kill bacteria. In addition, the bactericidal proteins (called defensins) become inserted in the bacterial cell membrane and cause it to rupture. Various enzymes then digest the remains.
Natural killer cells and the interferons
Viruses lack the ability to replicate by themselves. Instead, they subvert the genetic machinery of host cells to make copies of themselves. For this reason, it is important that those cells that become infected with a virus are destroyed before the virus has time to replicate and infect neighboring cells. The cells that perform this vital function are known as natural killer cells. They are large, granular lymphocytes which are believed to recognize virus-infected cells from modified cell surface markers (compare this with T-cell recognition of infected cells, Section 14.5). When a natural killer cell has recognized a target, it is activated and positions specific granules between its nucleus and the
Fig. 14.3 The processes leading to the generation of reactive oxygen intermediates by the phagocytes. The host cell is protected by various mechanisms from damage (e.g. vitamins С and E, glutathione, and the enzyme catalase).
14 Defense against infection: inflammation and immunity
target cell. The granule contents are then released by exocytosis onto the target cell which responds by undergoing a preprogrammed cell death (apoptosis) thar prevents viral replication. When cells are infected by a virus they make interferons (of which there are many different kinds) and secrete them into the extracellular fluid. The interferons then bind to receptors on neighboring cells which respond by reducing their rate of mRNA translation. This results in the infected cell being surrounded by a layer of cells that cannot replicate the virus so that a barrier is formed which prevents the spread of the infection. Finally, the natural killer cells seek out and destroy any infected cells.
Eosinophils are the least numerous of the white cells of the blood. The granules that take up the dye eosin (eosinophil specific granules) contain a protein rich in arginine residues called major basic protein. The cells are also able to secrete membrane-penetrating proteins called performs and a battery of enzymes including peroxidase and phosphohpase D.
Eosinophils appear to play an important role in combating helminth infections. These organisms are too large to be phagocy-tosed by a single cell so that they must be attacked extracellularly. Eosinophils are particularly attracted to parasites whose outer membranes have been coated with antibody of the IgE class (see below). Major basic protein, performs, peroxidase, and phospholi-pase D attack the outer membrane of the parasites to inactivate or kill them. Eosinophils are attracted to sites of infection or inflammation by chemical signals (interleukins) released from mast cells and are found in the connective tissues underlying the epithe-lia of the skin, bronchi, gut, and other hollow organs.
Complement is the name given to a group of about 20 plasma proteins that play an important part in the control of infections, particularly those caused by bacteria and fungi. Like the clotting factors, the complement proteins are a series of enzymes that can be sequentially activated either by microbial cell surfaces or by antibody secreted by the lymphocytes. The major component of the complement system is known as C3, which can be activated in a variety of ways (Fig. 14.4). Once activated, C3 generates a fraction known as C3b which binds to the surface of microbes and so facilitates their uptake by phagocytes. The same fragment initiates a series of reactions that can lead to lysis of the invading bacterium. A smaller fragment called C3a can activate phagocytes to kill phagocytosed particles and interact with other complement proteins. Both fragments, together with another complement fraction known as C5, play an important role in the initiation of the inflammatory response (see below).
The acute-phase proteins are a group of plasma proteins synthesized by the liver that show a huge increase in concentration during an infection. They include C-reactive protein and mannose-
Fig. 14.4 An outline of the complement system showing the pathways of activation and involvement in the immune response.
binding protein, both of which bind to the surface of invading organisms This surface coating is known as opsonization. Both complement and antibodies also opsonize foreign organisms. As the phagocytes have receptors for the coating proteins, they are able'to recognize opsonized particles and engulf them.
The acute inflammatory response
When the body becomes injured or infected, a number of physiological changes occur in the affected area. There is a local vasodilatation, increased permeability of the capillaries, and infiltration of the damaged tissues by white cells. These changes constitute the inflammatory response which appears to be geared to bringing plasma proteins and cells to the point of injury. Inflammation can be caused by a variety of stimuli, including traumatic injury, infection, and cellular necrosis.
For an injury to the skin the stages of the inflammatory response are as follows:
1. There is a reddening of the skin at the site of injury which results from vasodilatation. This is known as the acute vascular response. This is followed rapidly by local tissue swelling due to the accumulation of fluid by the affected tissues. The skin of the surrounding area becomes flushed
(the flare). These three components of the inflammatory response constitute the triple response discussed in Section 8.3.
The processes involved in the inflammatory response are summarized in Fig. 14.5. In the first stages of a response to infection, the invading organism becomes coated with small amounts of complement C3b which is found in normal plasma. The immobilized C3b then generates a form of complement called C3 convertase. This complex splits C3 into C3a and C3b. The C3b molecules bind to the organism that triggered the initial response (a positive feedback loop). It also activates another complement component called C5. Together with СЗа, С5 stimulates the tissue mast cells to degranulate and release their contents into the interstitial space.
The mast cell granules contain a wide variety of substances, including histamine, chemotactic agents that attract polymor-phonuclear cells from the blood, and signaling molecules called interleukins. In addition, activated mast cells synthesize prostaglandins and leukotrienes. The histamine and prostaglandins elicit a local vasodilatation and this, coupled with the retraction of the capillary endothelial cells, leads to leakage of plasma into the interstitial space. The plasma contains complement and antibodies, both of which aid the countermeasures against infection (the interstitial fluid normally has very little protein).
The histamine and interleukins modify the surface of the capillary endothelial cells so that the neutrophils adhere to them. The neutrophils then squeeze between the endothelial cells and migrate to the site of infection. Once in position, they begin engulfing the invaders and killing them by means of the mechanisms described earlier.
Fig 14.5 The mechanism by which an invading organism triggers an inflammatory response. The initiation of this series of events begins with the activation of an enzyme known as C3 convertase.
changes constitute the inflammatory response.
5. The trigger for the inflammatory response is mast cell degranulation.
The histamine that is released together with newly synthesized
prostaglandins elicits a local vasodilatation which leads to leakage
of plasma into the interstitial space. The granules also release
chemotactic agents which atttact neutrophils to the site of injury.
266 14 Defense against infection: inflammation and immunity
14.5 The adaptive immune system
It is well known that, while exposute to certain disease-producing organisms (e.g. the chickenpox virus) will cause disease on the first exposure, a subsequent exposure will not generally result in infection. Nevertheless, the resistance to infection does not extend to other diseases. Experience of chickenpox does not prevent infection by the measles virus. These facts highlight two important features of our immune system. First, resistance is acquired by one exposure to an invading organism and then lasts for many years—even for a whole lifetime. Secondly, the resistance is specific for that organism. In immunological terminology, the response is specific and has memory. These characteristics distinguish the response of the adaptive immune system from that of the natural immune system.
The cells of the adaptive immune system are the lymphocytes. The lymphoid system consists of the total mass of tissue associated with the lymphocytes and their function. It is disseminated throughout the body (see Fig. 14.1). The tissues in which the lymphocytes mature (the bone marrow and thymus) are known as primary lympboid tissue, while the lymph nodes, spleen, and other lymphoid tissues are secondary lymphoid tissue. There are two principal classes of lymphocyte, known as В cells and T cells. The В cells mature in the bone marrow and secrete antibody while the T cells mature in the thymus gland and secrete signaling molecules known as cytokines, cytotoxic substances, or both.
Lymphocytes are stimulated by antigens that bind to their surface receptors. Individual lymphocytes respond only to one antigen and when they are stimulated they proliferate by mitosis to form a population of cells with an identical specificity, called a clone. As shown in Fig. 14.6, some of the cells continue to proliferate and carry out their specific immunological function (see below), while others remain in the lymphoid tissue as memory cells, able to respond to a similar challenge in the future.
To monitor the tissues of the body for invading organisms, the lymphocytes circulate continuously throughout the tissues. They migrate from the blood, through the tissues, to the lymph nodes, which they enter by way of the afferent lymphatic vessels (see Section 15.10 for an explanation of the circulation of the lymphatic fluid). After they have entered the lymph nodes they pass into the efferent lymphatics and return to the blood via the thoracic duct. In addition, some lymphocytes enter the lymph nodes directly from the postcapillary venules.
The first stage of a lymphocyte's migration from the blood is its adhesion to the wall of the blood vessel. Normally, like the red cells, the lymphocytes remain in the center of a blood vessel but when they reach a target tissue some of them become
Fig. 14.6 The generation of а В lymphocyte clone. An antigen activates a naive lymphocyte which then proliferates. Some of the clonal cells mature and secrete antibody of the same specificity as that of the receptor (i.e. ir is capable of binding to the initiating antigen) while other cells remain in the lymphoid tissues as memory cells.
attached to the vessel wall. This process is guided by homing receptors which are specific for particular tissues. The cells then flatten and squeeze between the endothelial cells and move into the surrounding tissues (diapedesis).
The lymph nodes consist of an outer capsule beneath which lies the subcapsular sinus which is fed by the afferent lymphatics (Fig. 14.7). Below the subcapsular sinus lies the cortex, which is organized into primary follicles (which contain В cells) and secondary follicles, also known as germinal centers, which appear to contain a class of В cells known as memory cells. The space between the follicles is called the paracortex and is populated by T cells. At the center of the gland lies the medulla, which contains antibody-secreting В cells and macrophages. The arrangement of the lymph nodes allows the afferent lymph to percolate through the tissue to the efferent lymphatic. In this way, any antigens that may be present are exposed to cells which are capable of mounting an appropriate immune response.
В lymphocytes and antibody
A resting В lymphocyte has little cytoplasm, a darkly staining nucleus, and few mitochondria or ribosomes. After it has been stimulated by antigen, it becomes transformed into л plasma cell,
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