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8 Immunity: defence against disease KEY KNOWLEDGE This chapter is designed to enable students to: • understand that the immune system provides a defence against invasion by micro-organisms and other foreign material • demonstrate a knowledge of the non-specific defence mechanisms present in the body and distinguish these from specific immunity system and their ability to detect ‘self’ from ‘non-self’ molecules • appreciate that the body can acquire specific immunities, some of which last for life • understand that some reactions of the immune system may have adverse results • enhance their knowledge and understanding of membrane receptors on cells of the immune • demonstrate an understanding of the defence mechanisms that plants have against disease. Figure 8.1 The Triumph of Death, a copy by Jan Breughel estimated that up to three-quarters of the population of Asia and Europe died when a plague pandemic spread through those areas from 1347 to 1351. In this chapter we explore defences against disease, including cells and functions of the immune system, disorders of the immune system and the mechanisms of immunity. (1568–1625) of the painting by his father, Pieter (c. 1517–1569). This painting depicts a street scene during a plague epidemic. A common plague was bubonic plague, which was also called ‘black death’ because bleeding under the skin developed into black blotches on the skin of an infected person close to death. Bubonic plague still exists in many countries. It has been 244 NATURE OF BIOLOGY BOOK 1 A vaccine for cervical cancer The cervix is the lower part, or neck, of the uterus and opens into the vagina. Cervical cancer is the eighth most common cancer in Australian women and is responsible for more than 300 deaths each year. One significant risk factor associated with cervical cancer is infection with the common human papilloma virus (HPV). HPV (figure 8.2) usually causes warts on hands and feet but also is a common sexually transmitted disease that causes genital warts. Cigarette smoking is another risk factor associated with cervical cancer. Cervical cells develop abnormalities, many of which are due to common infections that are ‘cured’ by the body. Others persist and may develop further into cervical cancer. The Pap test, introduced in Australia in 1991 in the National Cervical Screening Program, can detect cervical cell abnormalities that lead to cancer. It is recommended that women have a Pap test every two years until age 70, commencing a year or two after they become sexually active. If an abnormality is detected, appropriate treatment is available and further development into cancer may be avoided. Figure 8.2 Computer artwork (left) and coloured transmission electron micrograph (TEM, right) of human papilloma virus (HPV). The protein coats, or capsids (red), enclose the genetic material. The capsids are studded with surface proteins (blue). For further information on cervical cancer go to www.betterhealth.vic. gov.au. Although the Pap smear is currently the best means of preventing the development of cervical cancer, a new treatment is on the horizon. Professor Ian Frazer, who leads the University of Queensland’s Centre for Immunology and Cancer Research, has been recognised as Australian of the Year for 2006 (figure 8.3). Professor Frazer’s award acknowledges his work toward the development of a vaccine against HPV. Use of his vaccine in worldwide trials has shown that it prevents papilloma virus infection, and reduces Pap smear abnormalities by ninety per cent. The vaccine is expected to be on the market about a year after publication of this book and will assist the prevention of cervical cancer in more than half a million women world wide each year. In this chapter, we explore defences against disease, including the use of vaccines, cells of the immune system, and their characteristics and functions. We also examine some disorders of the immune system. Figure 8.3 Professor Ian Frazer, recognised as Australian of the Year 2006 for his work in developing a vaccine against the papilloma virus IMMUNITY: DEFENCE AGAINST DISEASE 245 Immunity Infection is entry into the body of a micro-organism that may cause disease. Infection does not necessarily lead to disease. The immune system is able to distinguish foreign material from material that is made by the body. Material made by the body’s cells is called ‘self’. Foreign material is called ‘non-self’ and includes material such as snake venom, dust, pollen, viruses and micro-organisms, such as bacteria. Normally, the immune system has the ability to distinguish ‘non-self’ material from ‘self’ material. If a person becomes infected with foreign material, the immune system is activated and attempts to remove the foreign material before it causes harm to tissues in the body. The immune system has two kinds of response to the entry of foreign material. One response involves natural or innate immunity, which is non-specific. It acts in the same way for every infection. Non-specific immunity involves many physical and chemical barriers to infection and is not affected by prior contact with a particular micro-organism. It has no ‘memory’ of a prior infection. The other response involves acquired or adaptive immunity, which is highly specific. Specific immunity involves the production of specialised cells and chemical substances known as antibodies which act against a particular infection. Specific immunity has a ‘memory’ so that when another infection from the same organism occurs, an increased response is obtained. This is why a childhood infection of diphtheria results in lifelong immunity against a further infection. The two kinds of response of the immune system (see table 8.1) interact together to provide immunity for an individual. Table 8.1 The immune system has Non-specific responses two kinds of response, non-specific and specific. react in the same way to all infections react in a specific way to each infection have no ‘memory’ about prior infections have a ‘memory about prior infections level of response same for each infection of the same organism much greater response on a second infection by the same organism Specific responses Non-specific immunity Assume that you come into contact with Clostridium tetani, a bacterial species that affects the nervous system and causes a muscle rigidity called tetanus. A number of features of your body prevent entry of bacteria. The first line of defence The best action against micro-organisms is to prevent their entry into the body altogether. This first line of defence against infection takes place at the body surfaces (see figure 8.4). Skin Alimentary canal Respiratory system Mucus Salt Cilia Acid Figure 8.4 The first line of defence against infection is the body surface which acts as a barrier. Chemicals on the body surface also inhibit infective organisms. 246 NATURE OF BIOLOGY BOOK 2 Acid Normal bacterial flora Gut Lungs Fatty acids Mucus Urinary and reproductive systems ODD FACT Sometimes hair follicles and glands become infected by the bacterial species Staphylococcus aureus, the ‘golden staph’, which leads to a highly contagious skin infection called impetigo. Skin An intact skin acts as a barrier against entry by micro-organisms. A cut or abrasion will allow entry of bacteria or viruses. Glands in the skin secrete fatty acids and sweat contains salt, both of which inhibit bacteria. Mucous membranes Mucus secreted by the cells lining your respiratory tract traps bacteria which are then swept upward to the back of the throat by the action of cilia which line much of the respiratory tract. Some of the mucus and bacteria are swallowed. Some are removed when you blow your nose. Some bacteria are also removed from the respiratory tract when you cough or sneeze. Mucus that lines the digestive tract forms a protective barrier and makes it difficult for micro-organisms to penetrate the cells beneath. Natural secretions Bactericidal = capable of killing bacteria Many secretions of the body contain bactericidal agents. Tears and saliva contain lysozyme, an enzyme that causes bacteria to lyse or burst. Acid in the stomach kills many bacteria. Milk contains lactoperoxidase and semen contains spermine. Natural flora Many different bacteria are normally found on the skin, in the gut and (in females) in the vagina. These bacteria are the natural flora of the body and are generally non-pathogenic in those areas. The presence of these bacteria inhibits the growth of pathogenic bacteria in those places because they compete more successfully for the space and nutrients that are available. In special circumstances, such as when a person takes antibiotics, the natural flora may be disturbed. Pathogenic organisms are then able to move in. This type of infection is called an opportunistic infection. The second line of defence Assume that your first line of defence has failed. Your skin has been cut and Clostridium tetani bacteria enter your body. A second line of defence has a number of parts as outlined below. Phagocytes and killer cells Figure 8.5 Human blood showing different kinds of blood cells. Red blood cells are pink. Various white blood cells have densely staining nuclei. (Also look at figure 8.10a.) Cells called phagocytes move to the point of entry of the bacteria. Phagocytes are white blood cells (see figure 8.5) that engulf and destroy micro-organisms and other foreign materials that enter the body in much the same way as an amoeba engulfs its food. Phagocytes are produced by cells in the bone marrow and include neutrophils (see figure 8.6a), the most common of the white blood cells, and monocytes, the largest of the white blood cells. When monocytes leave the bloodstream, they become macrophages (figure 8.6b) which gather in various tissues. They occur throughout connective tissue, in the lungs, liver, spleen, kidneys, the brain and bone. Macrophages are particularly active against micro-organisms that can live inside the cells of the person they infect. Immediately a bacterium or other micro-organism is engulfed by a phagocyte, enzymes and other factors are released into the vacuole containing the bacterium and the bacterium is killed. Some material may be used by the cell, and unwanted material from the dead bacterium is released by the phagocyte. Some white blood cells that kill virus-infected body cells are called natural killer (NK) cells. Other white blood cells attach to, and help destroy, larger blood parasites such as worms that are too large to be engulfed (phagocytosed). IMMUNITY: DEFENCE AGAINST DISEASE 247 (a) (b) Figure 8.6 (a) Neutrophil cells that have ingested bacteria. The bacteria appear as the smaller purple rod shapes inside the cells. (b) Radioactively labelled macrophages and a few lymphocytes Complement Bacteria Phagocyte Bacteria lysis attracts coats Figure 8.7 Complement proteins lyse many bacterial species. This attracts phagocytes to the site of infection. Bacteria which have been coated by other complement proteins are readily ingested by the phagocytes. Complement proteins How do your phagocytes recognise and attach to the Clostridium tetani cells so that they can engulf them? Blood proteins called complement proteins assist in this task (see figure 8.7). There are about 20 different complement proteins. Most complement proteins are made in the liver and circulate in the blood in an inactive state. When infection occurs, antibody–antigen complexes form and these activate complement proteins. The activation of one kind of complement protein results in a cascade effect where each activated complement protein then activates another, and so on down the chain. Complement proteins assist in the second line of defence in a number of ways. Some complement proteins stick to invading micro-organisms that then become more readily identifiable as foreign to phagocytes. Some stimulate phagocytes to become more active. Some attract phagocytes to the site of infection. Other complement proteins destroy the membranes of invading micro-organisms. Complement proteins also play a role in acquired immunity (see page 263). Interferon Another group of proteins important in immunity are interferons. Interferons are secreted by some cells when they are infected by virus particles. These interferons act on uninfected cells making them more resistant to the virus. Interferons are produced very early during a viral infection and are particularly important in our ability to resist some viral infections. They cause dozens of antivirol proteins to be made. Different viruses infect different tissues. The further a virus must travel to reach its target cell then the more likely it is to be destroyed before it gets there. Interferons are particularly important if a virus hasn’t far to travel. This is the case with cold and influenza viruses that infect cells in the nose or throat. Because infection occurs quickly, the body sometimes doesn’t have the time to develop antibodies against these viruses and relies on interferon for its defence. If a person develops a cold or flu, interferon has failed to prevent infection. Cytokines Cytokines are protein molecules that act as messengers between cells. They are produced by virtually all cells of the immune system, but particularly by certain 248 NATURE OF BIOLOGY BOOK 2 T cells. Hence, cytokines act as the messengers between cells of the immune system in much the same way that hormones act as the messengers within the endocrine system. Cytokines also communicate with cells in other body systems, including the nervous system. As in other cellular communicating systems, a cell can respond to a message from a cytokine only if it has an appropriate receptor. A cell must also regulate the duration of its response to cytokines in order to maintain its proper functioning. SOCS3 (figure 8.8) is a member of a family of proteins that suppress the signalling of a variety of cytokines, including growth hormone. Abnormalities in SOCS3 are associated with a variety of inflammatory diseases. Figure 8.8 Two views of a Inflammation ribbon diagram (three-dimensional structure) of SOCS3. The two views are related by 180°. You may have noticed a reddening or inflammation around the cut in your skin where the Clostridium tetani have entered. Inflammation is a reaction to the infection and occurs when arterioles in the area around the cut dilate, resulting in an increased blood supply to the area. Inflammation is controlled by a number of plasma enzyme systems and other compounds, including serotonin, produced by mast cells, platelets and basophils. Serotonin increases dilation of arterioles and permeability of vascular tissue. The blood carries phagocytes to the area. Phagocytes also move from nearby tissues towards the cut (see figure 8.9). Chemicals released by damaged cells Bacteria enter on sliver of glass Epidermis (a) Abscess starting to form (c) (b) Platelet Monocyte Capillary wall Bacterium Erythrocyte Neutrophil Basophil Macrophage Blood vessel Dermis Nerve (d) Blood clot Subcutaneous Bacterium Figure 8.9 Inflammation occurs if bacteria enter a cut. (a) Injury to an otherwise healthy skin (b) Vasodilation and increased permeability (c) Phagocyte migration from capillaries to cut area (d) Phagocytosis of bacteria and other cellular debris by neutrophils and macrophages Neutrophil Capillary walls in the area become more permeable to phagocytes which move out of the capillaries into the surrounding area. Phagocytes that arrive early at the scene of the injury release chemicals such as histamine that attract more and more phagocytes to the infection. As the invading Clostridium tetani bacteria are killed and engulfed by the phagocytes, material that has leaked from the capillaries will form a clot around the infection and prevent its spread. You will probably also have pus in the inflamed area. Pus contains white blood cells that are dead as a result of the many bacteria they have engulfed. It also contains living white blood cells as well as other cell debris. IMMUNITY: DEFENCE AGAINST DISEASE 249 Eventually the pus and other dead or damaged cells are reabsorbed by other cells of the body or released from the skin and tissue repair occurs. Your skin heals and all outward signs of the infection disappear. All of the features discussed in this section are non-specific in their action. Exactly the same responses would have operated whatever micro-organism or foreign material you encountered and whether or not you had been previously infected by the organism. KEY IDEAS • The defence system of the body is called the immune system. • The immune system is able to identify ‘non-self’ material from ‘self’. • The immune system can produce two kinds of response to invading foreign material, namely non-specific and specific. • Micro-organisms are prevented from entering the body by a number of non-specialised features. This is the first line of defence. • There is a second line of defence against foreign material that enters the body. QUICK-CHECK 1 What is meant by the terms ‘self’ and ‘non-self’? 2 Indicate one way in which a non-specific immune response differs from a specific response. 3 Give an example of the first line of defence of the body against infection. 4 List two kinds of cells that form part of the second line of defence of the body. 5 What is complement protein? How does it act as part of the second line of defence? 6 What is interferon? How does it act as part of the second line of defence? 7 What roles do cytokines play in the immune system? Specific immunity Once a micro-organism enters your body, the presence of this foreign material initiates a response known as the third line of defence. This line of defence involves a specific response by the immune system to that particular infection and results in adaptive or acquired immunity. The specific immunity acquired is generally long lasting, often for life. The third line of defence involves special white blood cells known as lymphocytes. They recognise invading cells or particles, react to that invasion and ‘remember’ the particular type of invader. If the same infection occurs again, the response to it occurs more rapidly. Cells of the third line of defence Two main groups of lymphocytes are involved in specific immunity. All lymphocytes are produced in the bone marrow (figure 8.10a). Some mature in the bone marrow into B lymphocytes or B cells. Other lymphocytes leave the bone marrow before they are fully developed and travel to the thymus gland where they differentiate into mature T lymphocytes or T cells. (T cell stands for ‘thymusdependent’ cell.) There are different kinds of B and T cells (figure 8.10b). 250 NATURE OF BIOLOGY BOOK 2 Figure 8.10 (a) Blood cells all (a) Bone marrow cell develop from special cells, called stem cells, in the bone marrow. Stem cells continually reproduce by mitosis and then differentiate. Of the differentiated cells, all are white blood cells except the red blood cells and platelets. (b) Different kinds of B and T lymphocytes. Th = helper T cells, Tc = cytotoxic T cells. Stem cell Stem cell Stem cell Monocyte Red blood cell Platelets Basophils and mast cells B lymphocyte and plasma T lymphocyte cell Neutrophil Eosinophils Stem cell in bone marrow (b) B cell progenitor Humoral response Maturation occurs in bone marrow T cell progenitor Cell mediated response Maturation occurs in thymus Trachea Many different kinds of B cells formed Antibody different on each kind of B cell Each kind of B cell can give rise to Thymus Heart Antigenbinding receptor of antibody T cell Th cells Tc cells B memory cells Plasma cells that produce antibodies Activated Th cell Th memory cell Activated Tc cell Tc memory cell IMMUNITY: DEFENCE AGAINST DISEASE 251 COLONY STIMULATING FACTORS — CSFs 252 NATURE OF BIOLOGY BOOK 2 10 White cell count x 10–9/L Neutrophils and monocyte-macrophages are of special importance in protecting the body against acute infection. These cells are produced by cells in bone marrow which reproduce continually because the cells in the blood have a relatively short life. Scientists were able to show that the continued growth of bone marrow cells did not occur spontaneously but was regulated by some factor that was given the name of colony stimulating factor (CSF). Professor Donald Metcalf (see figure 8.11b), an Australian scientist at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, discovered CSF. CSF is detectible in the serum and urine and in extracts of a variety of tissues. From the late 1960s until 1984, work was carried out to try and isolate CSF. Special methods of cell culture and purification of cell products were developed. By 1984, four different CSFs had been isolated. Only very small amounts of CSF had been obtained and it was calculated that 200 million mice would be required to produce one gram of purified CSF. Scientists used new DNA technology to clone CSF genes that were then inserted into bacteria, yeast or mammalian cells. These cells were cultured and relatively large amounts of CSF became available. It was shown that injections of CSF into mice and primates stimulated production of neutrophils and macrophage formation without significant toxic effects. Clinical trials commenced in 1987, and today two of the CSFs are available to treat people who have very low levels of white cells in their blood. What application has this discovery had? In some diseases, and as a result of certain forms of treatment, such as chemotherapy for cancer, the number of neutrophils and macrophages produced by the body declines significantly. This reduction in immune cells means reduced resistance against infection. The CSFs are now used to prevent the fall in neutrophils and prevent the infection that can otherwise occur following treatment with chemotherapy. Leukaemia is a cancer, or malignancy, of the blood. Acute myeloid leukaemia is a cancer in which a person produces faulty white blood cells. Something has gone wrong with the blood-forming tissue. There is no point in giving CSF to patients with faulty bone marrow. They would respond by making even more of the faulty cells. Other treatment must be given before injection with CSF. Treatment of patients with acute myeloid leukaemia is really a three-step process. The first step is to irradiate the patient to kill the faulty bone marrow cells. In the second step, the patient is given a transplant of compatible bone marrow cells, often from a relative. 8 6 4 •• 2 • • 0 (a) • • •• • • • •• •• • •• • • •• • • • • •• • • 5 10 15 20 25 Days after marrow transfusion 30 (b) Figure 8.11 (a) Patients (15) who received a bone marrow transplant after irradiation of their own marrow were injected with CSF. The upper curve shows the average production of white blood cells in these patients. The lower curve shows the average white cell production in a sample of patients (18) before CSF was available. Most of the increase was due to an increase in neutrophil production. (b) Professor Donald Metcalf, scientist, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Professor Metcalf discovered the CSFs which have been used in the treatment of patients with various diseases. He is a leading scientist whose contribution has made a difference not only in basic knowledge, but also in the treatment of disease in his lifetime. Bone marrow transplants can be very successful. The transplanted marrow behaves as the patient’s own and produces healthy white blood cells. Provided sufficient white blood cells grow, the patient has full resistance against infection. Sometimes the bone marrow cells do not grow at a sufficiently high rate to prevent infection. A third step in the treatment can help to solve this problem. Injection of CSF significantly increases the number of neutrophils and macrophages produced in the bone marrow recipient (see figure 8.11a). This, in turn, significantly increases the chance that a patient will be restored to full health. This was the case with José Carreras, a world-famous opera singer who was one of the first people to be treated with CSF. Australians can be proud that the work of their medical scientists has led to these exciting advances. The box on pages 260–3 outlines other work being carried out at WEHI. In another world-first, scientists and physicians in Melbourne discovered that the CSFs cause cells that are normally resident in the bone marrow to move into the blood. This was completely unexpected. They then also discovered that these blood cells could be used instead of bone marrow cells in bone marrow transplantation (but now really ‘blood cell’ transplantation). This is much safer as blood can be collected instead of bone marrow, which removes the requirement of an anaesthetic. In addition, these blood cells work much better than the bone marrow cells and recovery is much faster after transplantation. For these reasons, blood cell transplantation has overtaken bone marrow transplantation around the world. Australians can be proud of this important medical research. How do B cells and T cells identify foreign material? Proteins on cell membranes are determined by genes. These genes are called the major histocompatibility complex (MHC) and the proteins produced by these genes are called markers. All cells have MHC markers on their surfaces. Distinguishing ‘self’ from ‘non-self’ In humans, two major groups of MHC markers exist. Class 1 markers are found on all cells of the body except red blood cells. Class 2 markers are found only on T cells, B cells and some macrophages. MHC markers produced in a person are called ‘self’. Markers that are not produced within a person are called ‘non-self’. B cells and T cells recognise and ignore cells that have the same MHC markers as themselves. When material such as pollen, or infecting agents, such as bacteria and viruses, enter a person, the B cells and T cells recognise the MHC markers on those as foreign or ‘non-self’ and react. Foreign material may also be a toxic chemical such as snake venom. The material (or marker) that triggers a response from a B cell or a T cell is called an antigen (see figure 8.12). Antigens are usually proteins, but can also include carbohydrate. Figure 8.12 Antigens (black dots marked by curved arrow) on the surface of the motile protozoan Leishmania, which causes leishmaniasis, a disease with symptoms that can resemble malaria. This is a transverse section in the region of the flagella. Antigens have been stained with gold particles. Bar equals 1 µm. IMMUNITY: DEFENCE AGAINST DISEASE 253 Like all cells, immune cells such as T cells and B cells have their own antigens that are called self antigens. In addition, they have receptor sites (figure 8.12). Some of these receptors are self receptors; that is, they determine if a molecule or cell the immune cell comes into contact with has the appropriate structures that show it is part of the same organism. Other receptors are for non-self receptors; that is, they identify molecules or cells that are ‘foreign’ to those of the immune cell. If they are identified as foreign, an immune response occurs. Self antigens Immune cell Figure 8.13 Immune cells have self antigens on their surfaces. In addition, they have receptors. Some are self receptors that identify self antigens. Some are non-self receptors. Receptors for self Receptors for non-self Because B cells and T cells can recognise ‘non-self’, they must have some mechanism for detecting the millions of different kinds of ‘non-self’ MHC markers that exist. This occurs in a very specific way. Many kinds of B cells Antigen binding sites B cell membrane Nucleus Antigen Surface immunoglobulin antibody Figure 8.14 Immunoglobulins on the surface of B cells identify antigens (not to scale). Each B cell identifies one kind of antigen only. ODD FACT A clone of cells is a group of cells, each identical with the cell from which they have been derived. 254 NATURE OF BIOLOGY BOOK 2 B cells have immunoglobulins on their surfaces. Immunoglobulins are proteins that identify antigens. Immunoglobulins are also called antibodies. The immunoglobulins of each B cell have a specific structure and recognise only one kind of antigen (see figure 8.14). There are millions of antigens to which the body must be able to respond. When B cells are maturing in the bone marrow, a particular part of the genetic material undergoes change and only a few of each kind of B cell are made. In this way millions of different B cells are made with different immunoglobulins on their surfaces. These are able to identify the millions of different antigens with which a person may come into contact. Although B cells combine with antigens, the few B cells specific for any one antigen would not be sufficient to counter a massive infection of bacteria. A person must have some way of producing large numbers of a specific antibody against antigens encountered. When a B cell identifies an antigen, it replicates rapidly to produce large numbers of special cells called plasma cells which produce antibodies and release them into body fluids. Generally, many more cells are produced than are needed. Excess cells die by apoptosis. The clonal-selection theory of antibody production When an antigen enters the body it probably passes many B cells before it meets one with immunoglobulin with which it can combine. In effect, the antigen ‘selects’ the B cell that will lead to its death. The B cell selected by the antigen reproduces rapidly to give rise to a number of identical cells. Each of these cells also reproduces rapidly to produce a large clone of cells. This is called clonal expansion. Cells cloned in this way will all have exactly the same genetic material and the same immunoglobulins. Most of these cells then differentiate into plasma cells and produce the same kind of antibody (see figure 8.15). Antigen Clonal selection Each B cell combines with only one kind of antigen. All recognition sites on a B cell are identical. This B cell has four antibodies on its surface, so it has eight binding sites. Clonal expansion or proliferation Differentiation Clone of plasma cells Memory cells Figure 8.15 Clonal selection. Each B cell produces a clone of plasma cells which make only one kind of antibody. Note the antigen fits only one of the surface receptors (immunoglobulins) shown here. Memory cells also form. Production of antibody An Australian, Sir Macfarlane Burnet, first proposed the clonal selection theory in 1955. There is a delay in this type of immune response because clonal expansion is necessary before sufficiently large amounts of antibodies can be made. This means that, if the infecting bacteria are able to reproduce to form relatively large numbers, a person may become quite ill before antibodies are produced that can react with the bacteria. Some of the B cells produced differentiate into other cells called B-memory cells. B-memory cells also have the same antibody–antigen specificity as the parent B cell. Plasma cells survive for only a few days but memory cells can survive for several years and, in some cases, for life. If a second infection of the bacterium occurs, the B-memory cells react faster and more vigorously than the initial B-cell reaction to the first infection. There is not usually a noticeable effect from a second infection by the same antigen because the body reacts very quickly to eliminate the ‘non-self material’. The person is said to be immune to the particular disease. When recovery from infection is complete, fewer plasma cells and antibodies are produced. Because most of the cells produced by clonal expansion are no longer required after recovery from the infection, they die by apoptosis. How much antibody is produced? Look at figure 8.16. It shows the level of antibody production after infection by an organism for the first time. This is called the primary antibody response. Note the decline in antibody level after the infection has cleared. On a second infection by the same organism, there is a secondary antibody response. In this, the immune system responds much more quickly because there IMMUNITY: DEFENCE AGAINST DISEASE 255 Figure 8.16 An initial infection or vaccination causes a primary response which occurs about 10 days after infection and results in a low level of antibody production. A second exposure to the same organism results in the secondary antibody response which is faster to appear and more effective than the primary response. Natural infection Primary antibody response Antibody production and response (arbitrary units) Initial infection or vaccination Secondary antibody response Time is no need for clonal expansion. The concentration of antibodies rises much more rapidly than during the primary response and many more antibodies are released. In addition, note that the antibody level after a second infection has cleared remains much higher for much longer than after the primary response. Even if the time between a primary and a secondary infection is several years, the presence of even low numbers of B-memory cells produces a rapid and increased secondary response. Structure of an antibody The two ‘arms’ of an antibody have the same shape. An antibody molecule has four polypeptide chains, two long heavy chains and two shorter light chains joined together (see figure 8.17a). The free ends where the light and heavy chains are adjacent to each other are the regions that combine with antigen. These areas are called the ‘antigen-binding sites’ and differ in different antibodies. The hinge area allows the antibody to bend if necessary to maintain a better link with the antigen to which it binds. The way in which the combining sites of an antibody and its antigen match is shown in figure 8.17b. (a) (b) Antibody binds to antigen at these positions. Light chain Hinge region Heavy chain Different antibodies have different shaped antigen-binding sites. Figure 8.17 (a) The basic antibody has two identical light polypeptide chains and two identical heavy polypeptide chains linked together. There are five different kinds of heavy chains. Why do antibodies have a hinge region? (b) Computer-generated image of an antigen (left-hand side) and its antibody (right-hand side). The surfaces come close together when the antigen–antibody complex forms. The polypeptide chains of the antibody are colour coded, heavy chains red and light chains blue. 256 NATURE OF BIOLOGY BOOK 2 There are five different kinds of heavy chains and this results in five different classes of antibody molecules (see table 8.2) — also known as immunoglobulins (Ig). Different classes of antibodies are made of different numbers of basic antibody units. IgG, IgD and IgE each comprise a single molecule; IgA has two and IgM has five molecules. Immunity involving antibodies in body fluids is called humoral immunity. Table 8.2 Some of the characteristics of the different types of antibodies found in body fluids Type of antibody IgG IgA IgM IgD IgE approx. concentration in serum (mg/mL) 12 2 1 0.04 0.000.02 ability to cross placenta yes no no no no present in saliva and tears no yes no no no present in milk yes yes no no no active against viruses yes yes some no no active against some bacteria yes yes yes no no involved in allergy reactions no no no no yes KEY IDEAS • If non-specialised defences fail to prevent infection, specialised responses occur. • All cells have protein markers on their surfaces. • Non-self markers on cells entering a person are called antigens. • A number of different kinds of cell are involved in specific immunity. • The phenotype is the physical, biochemical or physiological expression of the genotype. • Some cells produce antibodies that circulate in body fluids and react with specific antigens. QUICK-CHECK 8 What are the two main groups of cells involved in specific immunity and where do they mature? 9 What role do protein markers on foreign cells play in the immune response? 10 What is an immunoglobulin? Where would you find one? 11 What cells are produced by the cloning of B cells? What is their function? 12 Why is cloning of B cells important in the immune response? 13 What are the main features of the primary antibody response? 14 In what ways does the secondary antibody response differ from the primary antibody response? 15 Are all maternal antibodies equally important for a fetus? Explain. IMMUNITY: DEFENCE AGAINST DISEASE 257 Different kinds of antibodies IgM and IgG antibodies activate macrophages and the complement system and are particularly active against bacteria and their toxins. IgA antibodies play an important role in surfaces that are vulnerable to infection and are present in saliva, tears, the lungs and along the lining of the gut. IgE antibodies activate mast cells which release histamines. These are important in allergies (see page 269). The function of IgD antibodies is unknown. Because the basic antibody unit has two antigen-binding sites, it can bind to two antigens. A lattice is built up of the antibody and its specific antigen bound together, and the antigen is ‘disarmed’. The antigen is no longer able to damage host cells (see figure 8.18). This is what happens when an antivenom is injected into a person after a snakebite. The antivenom combines with the venom and the venom can no longer act against cells. ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ Antibody ■ ■ ■ ■ ■ ■ ■ ■ Antigen ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ Antigen ■ Cross-linking of antigens on different cells ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ Figure 8.18 Antibodies react with specific antigens. An antigen involved in such a response is no longer able to damage host cells. If an invading micro-organism has different antigens on the surface membrane then, for each different antigen, a different kind of B cell will be activated and a different kind of antibody made. ■ ■ ■ ■ ■ ■ ■ ■ Ig = immunoglobulin Antigen–antibody complex may be agglutination of cells If the antigen is a bacterium, additional help is required to remove the antibody–antigen complex. Macrophages have receptors that identify the part of the antibody where the ends of the two heavy chains come together. Macrophages bind to that part of the antibody–antigen complex (see figure 8.19) and engulf and digest the antibody and its associated antigen. Microbe Receptor site Figure 8.19 Antibody reacts with a microbe to give antibody–antigen complex. This is identified by a macrophage which engulfs and digests the antibody– antigen complex. Macrophage Antibody and antigen complex T cells When T cells mature in the thymus, many different kinds of T cells are produced which recognise many different antigens. As with B cells, only a few of each kind are produced. After encountering their specific antigens, T cells reproduce rapidly in the same way as B cells, and T-memory cells also form. T cells do not make antibodies. There are different types of T cells and each type reacts with other cells in the immune response. Immunity involving T cells and phagocytes is called cellular immunity. Helper T cells Phagocytes that have ingested foreign material carry some of the foreign antigen on their surfaces as well as their usual class 2 marker proteins. One type of 258 NATURE OF BIOLOGY BOOK 2 Th = helper T cells T cells, called helper T cells (Th), recognises these antigens and stimulates B cells (see figure 8.20). B cells will not reproduce and form plasma cells without this assistance from Th cells. Th cells also secrete a protein that stimulates other T cells and B cells. (a) Figure 8.20 (a) When phagocytes ingest antigens, some of the antigen attaches to the phagocyte surface. (b) Helper T cells help B cells to recognise foreign antigen on the surface of phagocytes. (c) The B cells reproduce to form plasma cells which produce antibodies against the antigen. (b) (c) Help Antigen Th Proliferation of plasma cells B Antibody secretion Phagocyte Cytotoxic T cells Tc = cytotoxic T cells Some scientists suggest that there is a third kind of T cell, known as suppressor T cells, which act as an infection recedes. ODD FACT Plasma leaking from blood capillaries into the surrounding tissues forms tissue fluid. When tissue fluid moves into the lymphatic vessels it is called lymph. Lymph nodes, tonsils and adenoids Lymph nodes in axilla (armpit) Lymphoid tissue in lungs, bronchi, gut and urogenital tract Another type of T cell, cytotoxic T cells (Tc), kills body cells that have been infected with a virus. In this case the infected body cell has foreign antigen on its surface as well as class 1 protein markers. A Tc cell identifies its antigen, in this case a viral protein coat that is left outside the infected cell, and the class 1 marker and kills the infected cell before the virus has time to replicate. Tc cells kill the infected cell by secreting proteins that punch holes in the membrane of the cell and the contents ooze out. Tc cells cannot kill isolated virus particles. They can kill the virus only when it is inside a cell. Some Tc cells also destroy cancer cells. T cells and B cells travel around the body B cells and T cells develop from primary lymphoid tissues: bone marrow and thymus respectively. They enter the bloodstream, then leave it and move around the body. The immune system also contains a number of other lymphoid tissues and organs, including the spleen, tonsils and lymph nodes (see figure 8.21), which are connected by a network of lymphatic Thymus vessels. White blood cells of many types are packed together in these lymphatic tissues. Lymphatic vessels contain lymph, which drains from nearby tissues. Memory T and B cells, in particular, circulate in the lymph, Bone marrow ready to react with their antigens. Antigens that enter the body are carried in lymph to a lymphatic organ where there is a high concentration of white cells. If the antigen Spleen hasn’t been destroyed along the way, the immune response begins when it comes into contact with cells in the lymph nodes. Your lymph nodes can sometimes be swollen and Gut-associated sore, indicating that you have an infection lymph nodes of some kind. Lymph nodes in groin Figure 8.21 Distribution of lymphoid organs and tissues which make up the immune system IMMUNITY: DEFENCE AGAINST DISEASE 259 KEY IDEAS • The immune response produces different kinds of T cells. • Different kinds of T cells have different functions. • The immune system contains many lymphoid organs and tissues. QUICK-CHECK 16 17 18 19 Explain why immunity involving T cells is called cellular immunity. What is the function of cytotoxic cells? What does lymph contain? Name three lymphoid tissues or organs. THE WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH Melbourne’s Walter and Eliza Hall Institute (WEHI), founded in 1915, was Australia’s first medical research institute. From the beginning, the Institute has been closely associated with the Royal Melbourne Hospital and today it is located in a striking building (figure 8.22) adjacent to the hospital in Parkville. It is also closely linked to The University of Melbourne. The Institute first came on to the world stage in virology and immunology under the leadership of Sir Macfarlane Burnet (Director 1944–64), who was awarded the Nobel Prize in 1960 (figure 8.23; see page 212). Renowned immunologist Sir Gustav Nossal, Director from 1965 to 1996, greatly expanded and diversified the Institute’s research programs and today, led by molecular biologist Professor Suzanne Cory, the Institute has major programs in cancer, haematology and inflammation, immunology and autoimmunity, and infectious diseases. Figure 8.22 The Walter and Eliza Hall Institute at dusk Figure 8.23 WEHI has had three directors — Sir Macfarlane Burnet (left) (Director 1944–64), Sir Gustav Nossal (Director 1965–96) and Professor Suzanne Cory (Director 1996 to present [2006]). 260 NATURE OF BIOLOGY BOOK 2 The Institute has a staff of over 600 scientists and support staff with diverse skills. The team leaders include biochemists, molecular biologists, cell biologists, structural biologists, bioinformaticians, geneticists and medicinal chemists. Some commenced their careers in science, others in medicine. Postdoctoral fellows, postgraduate students and technicians all play important roles in their research laboratories, supported by core technologists such as computer scientists, librarians, animal technicians, veterinarians, photographers, administrators, accountants and engineers. Research opportunities are provided for undergraduate students to enable them to taste life in the research world. WEHI pioneered the innovative GTAC program (named for the four letters of the genetic code), which introduces molecular and cell biology to primary and secondary school students from all over Victoria. GTAC’s exciting facility (figures 8.24 and 8.25) is located at University High School, right next door to WEHI, and many WEHI PhD students serve as demonstrators and mentors in GTAC programs. You and your school can find out more about GTAC programs by going to www.gtac.edu.au. Figure 8.25 The DNA helix on the floor of the Australian Genome Research Facility Figure 8.24 The GTAC building with WEHI in the background WEHI’s talented science animator Drew Berry (figure 1.34 on page 27) was a major contributor to the amazing film DNA interactive, which was made to celebrate the 50th anniversary of the discovery of DNA by James Watson and Francis Crick. This film won an Emmy and also an award from the British Academy of Film and Television Arts. Excerpts of Drew’s work have been exhibited at the Museum of Modern Art in New York and at the Pompidou Centre in Paris. ‘This is an incredibly exciting time to be a scientist,’ says Professor Suzanne Cory, Director of the Institute. ‘The DNA revolution and the Human Genome Project [figure 8.25] have opened up amazing opportunities for identifying the critical molecular mistakes underlying many diseases. This is enabling scientists to target these lesions and develop more effective therapies.’ ‘The human body is a very complex machine,’ she continues, ‘with multiple interactive component parts. If one component malfunctions, this can have devastating consequences for the entire system. At WEHI, our major focus is the body’s self-defence system. This complex system is derived from a single rare stem cell in the bone marrow. We are studying how this amazing cell can generate its diverse repertoire of white and red blood cells and how these cells function in health and disease. ‘The immune system can protect us from innumerable pathogens. It swiftly recognises ‘foreign’ macromolecules (antigens) and mounts an offensive to destroy them. Three main cell types are involved: B and T lymphocytes, and dendritic cells. Dendritic cells process foreign proteins into bite-size bits (antigens) and ‘present’ them on a halo of tentacles (figure 8.26) to T cells, galvanising them into action. One type of T cell then ‘helps’ B cells make antibodies to neutralise foreign proteins, while another type of T cell attacks infected cells. (continued) IMMUNITY: DEFENCE AGAINST DISEASE 261 ‘Leukaemias and lymphomas are cancers of lymphocytes. Occasionally, the normal process of DNA rearrangement that goes on in a lymphocyte to produce an antigen receptor goes awry and activates an oncogene: that is, a gene with the potential to cause cancer. Most oncogenes cause cells to overproliferate, but others stop cells from dying when they should. Cell death occurs by a process known as apoptosis (figure 8.27). Our scientists are world experts in apoptosis and are using this knowledge to develop new and more effective cancer therapies. (a) Figure 8.27 A normal lymphocyte and one undergoing programmed cell death, apoptosis. Note the ‘blebs’ on the dying cell. ‘Occasionally, immune cells are provoked to attack normal cells or tissues, producing devastating autoimmune disorders. Scientists at WEHI are studying several of these diseases, particularly diabetes, multiple sclerosis, coeliac disease and autoimmune arthritis. Their goal is to develop more effective treatments and preventative vaccines. ‘The malaria parasite infects red blood cells and changes them to evade the immune system (figure 8.28). Malaria is a devastating disease that kills up to 3 million people every year, most of whom are children under 5 years of age. Our malaria (b) Figure 8.26 (a) Antigen-presenting dendritic cell, which stimulates the body’s immune response (b) Dendritic cell stained for antigen-presenting molecules (green), nucleus (DNA, blue) and endosomes (red) ‘The cells communicate via a complex maze of surface molecules called cytokines and chemokines; rather like television, radio, telephone and e-mail operating all at once. Furthermore, within each cell, there are equally complicated signalling links between the cell surface, the nucleus and the genes. It is, therefore, very hard to predict what might happen if the balance is altered by, say, injecting a drug or vaccine. One of our groups is developing computer models for predicting the outcome to better manipulate this vital defence system. 262 NATURE OF BIOLOGY BOOK 2 Figure 8.28 A Drew Berry (see page 27) illustration of malaria parasites, Plasmodium falciparum, (green) invading red blood cells researchers are hot on the trail of the evasion strategy used by malaria to develop an effective vaccine and better antimalarial drugs. They have links in many endemic areas — Papua New Guinea, Malawi, Indonesia and Vietnam — and run international workshops to help train researchers from these countries (see figure 8.29). ‘One of the most exciting recent discoveries from WEHI is the identification of the cell that makes the breast. Our breast cancer researchers used an instrument called a laser-driven, fluorescence-activated cell sorter (FACS) to fractionate cells labelled with different fluorescent antibodies. They found a very rare cell capable of regenerating complete breast tissue when transplanted into another mouse (refer to chapter 16, page 641). Indeed, when the female becomes pregnant, the regenerated breast tissue even makes milk! This is the first time the breast stem cell has been isolated. The scientists are now trying to isolate breast stem cells from human tissue and are looking at breast cancers to see if they are derived from altered stem cells.’ If you would like to learn more about the research being done at WEHI, go to www.wehi.edu.au and click on the WEHI link for this chapter. Macfarlane Burnet once said, ‘Science to me is the finest sport in the world.’ Perhaps you would like to play one day! Figure 8.29 Hamish Scott (left), Pauline Crewther, Chelsee Hewitt, Ping Cannon, Catherine Carmichael and Joelle Michaud (from the Scott Laboratory based at WEHI) discuss results. Acquiring specific immunity A person makes antibodies against a disease-causing organism only after coming into contact with the organism. Because of the presence of specific antibodies, a person is able to resist infection and is said to be immune to further infection by that organism. This kind of immunity is called specific immunity. Antibodies are acquired and so the term acquired immunity is also used. Specific immunity is also acquired when antibodies are received from an outside source. This is called passive immunity. The term active immunity is used when antibodies are produced within a person. Active and passive immunity can be achieved in different ways. Active immunity Active immunisation involves the production of antibodies within a person in response to exposure to a particular antigen. In addition, B-memory cells and T cells are produced that react quickly if another encounter occurs with the same organism. Active immunity can be acquired in two ways: naturally or induced. Natural active immunity When a person comes into contact with a particular disease-causing organism for the first time, no antibodies against the organism (the antigen) will be present. It IMMUNITY: DEFENCE AGAINST DISEASE 263 ODD FACT In 1885, Alfred Russell Wallace (1823–1913), who held many of the same ideas about evolution as Darwin, published a pamphlet claiming vaccination to be both useless and dangerous. takes a few days for the appropriate plasma cells and antibodies to form (note the primary response shown in figure 8.16) and during that time the person begins to show symptoms of the disease. The antibodies formed have identical sites for binding to the foreign material. As the amount of antibody increases, the infecting micro-organisms begin to be destroyed and the person starts to recover. If sufficient antibodies are made to destroy all the infecting micro-organisms, the person recovers completely. This type of immunity is called naturally acquired active immunity. It is called active because the immune system in the infected individual has made the antibodies and continues to do so. The immunity was acquired naturally after infection. In some cases, the level of infection is sufficient to activate the immune system and yet there may be no outward visible sign that the person has a disease. Such an infection is called a sub-clinical infection and results in antibody formation in the same way as an obvious infection. Both situations result in immunity against further infection with that disease and the individual would show a secondary response similar to that outlined in figure 8.16. In some cases, if the infecting organism or toxin acts quickly before the immune system can make sufficient antibodies, a person can die. Induced active immunity Today we can make use of the body’s immune response to induce actively acquired immunity. Vaccines, which contain dead or treated living microorganisms, are used to activate the immune system to produce antibodies against specific disease-causing organisms without actually causing the disease. This is possible because bacteria and viruses can be killed or treated in some way so that they are no longer able to cause disease (see figure 8.30). Because the same antigens are present on these treated micro-organisms they will produce an immune response if they are used in vaccines. Organisms that are not killed by the special treatment given during the preparation of a vaccine are said to be attenuated. They can still reproduce, but the special treatment has removed their disease-causing capability. ▲ ■ ■ ■ ■ ■ ▲ ▲ ■ ▲ ▲ Remove capsule ■ ▲ ■ ▲ A bacterium with a capsule causes disease. ■ ▲ ▲ ▲ ■ ■ ■ ▲ ▲ ■ ▲ bacterium may remove its diseasecausing characteristic without affecting its antigens. The immune system responds to the antigens in the same way it would to a fully virulent organism. Some vaccines contain live attenuated microorganisms. The advantage of this is that the bacterium continues to reproduce initially and stimulates a much higher level of antibody production. ■ Figure 8.30 Treatment of a ▲ Immunisation = vaccination = injection of dead or attenuated micro-organisms Without its capsule, the bacterium no longer causes disease, but still acts as an antigen. When a vaccine is injected into a person, the immune system shows a primary antibody response similar to that shown in figure 8.16. A second injection of vaccine produces a secondary antibody response. The antibody is specific for the treated micro-organism used in the vaccine, so if the person comes into contact with the live organisms at some future date, memory cells and antibodies will be ready to act and the person is immune to infection. Some micro-organisms cause disease by secreting toxins or poisonous substances. These toxins can be treated to form toxoids. Toxoids are made of the same material as the toxin, and so act as antigens, but are unable to cause disease. Some vaccines contain toxoids. A summary of the various types of acquired immunity is shown in figure 8.35. Read about work to develop a vaccine against malaria on page 117. 264 NATURE OF BIOLOGY BOOK 2 ODD FACT Since 1977 no naturally transmitted cases of smallpox have been recorded anywhere in the world. Figure 8.31 Prior to the 1980s, Australians travelling abroad had to carry vaccination booklets to prove they had been immunised against smallpox. Eradicating a disease by vaccination Before the 1960s, smallpox, a disease caused by the variola virus, was widespread in many countries. Australians travelling overseas were required to carry a vaccination certificate (see figure 8.31) to show that they had been vaccinated against the disease. The World Health Organization (WHO) began an extensive vaccination program against smallpox in 1959 and, by December 1979, they announced that the disease had been eradicated. Because of the widespread vaccination against smallpox, the infecting virus could no longer find appropriate hosts who were not immune. Although support had been given to a WHO proposal that all live stocks of smallpox virus be destroyed by 30 June 1999, Russia and the United States confirmed in May 1999 that they did not intend to proceed with the destruction. Claims have been made that scientific opportunities will be lost if all stocks are destroyed. Australians no longer have to be vaccinated against smallpox. If they travel to some parts of South America or Africa they would still be vaccinated against yellow fever, a viral infection that is transmitted from person to person by the Aedes aegypti mosquito. In Australia, the viral disease poliomyelitis has been eliminated. Vaccination against polio began in 1956 and still continues, usually in the form of ‘OPV’ — oral poliomyelitis vaccine (Sabin type). A standard injection-type vaccine against polio is also available, but the oral vaccine has two advantages: 1. It contains attenuated poliovirus which becomes established in the intestine and in the blood so antibodies are formed in both locations giving additional protection to the individual. 2. It is much easier to administer than an injection which requires sterile needles and swabbing of the skin. The incidence of a number of other diseases — the bacterial diseases diphtheria (caused by Corynebacterium diphtheriae), tetanus (Clostridium tetani), and pertussis (also known as whooping cough and caused by Bordetella pertussis) and the viral diseases measles, mumps and rubella (also called German measles) — has also been significantly decreased by the use of vaccines. A range of immunisations are recommended for Australian children by the National Health and Medical Research Council (NHMRC). Those provided free by the Victorian Government under that program are given in table 8.3. The national program also includes special vaccines not relevant in Victoria. In Victoria, each child starting primary school must have a school entry immunisation certificate unless they have special dispensation. If a pregnant woman is infected with the rubella virus, the development of the fetus may be affected. Defects in sight, hearing or other characteristics may occur. This is why the NHMRC recommends vaccination against rubella for teenage girls. The immunity they acquire will remain with them in adulthood. IMMUNITY: DEFENCE AGAINST DISEASE 265 Why do we continue to get colds and flu? Cold and flu viruses are continually changing to give new strains of the viruses. These act as new antigens. Look at the influenza virus in figure 8.32. Haemagglutinin and neuraminidase are the antigens. These proteins can change to give rise to new forms and hence new antigens. Although we may have antibodies specific for a previous cold or flu infection, they will not act against the new type of antigen. The immune system has to learn how to make specific antibodies for the new antigen, but the infection develops before sufficient antibodies are made. Figure 8.32 An electron micrograph of influenza virus particles. a and b = entire particles showing outer layer of neuraminidase (N) and haemagglutinin (H) spikes, c = disintegrating particle and d = partly disrupted influenza virus particle showing coiled nucleoprotein folded in parallel repeating bands surrounded by an outer membrane or envelope to which N and H spikes are attached. The coiled nucleoprotein does not change from year to year, whereas N and H spikes do. Antibody concentration (arbitrary units) The majority of the 20 million people who died during the influenza pandemic of 1918–1919 were young adults. This was unusual because it is usually the very young and the very old that suffer most in an influenza epidemic. It has been suggested that old people may have survived because they had been exposed to a similar influenza virus when they were young. If so, they would have made antibodies to that particular strain and were immune. The anti-flu drug, Relenza, that was discussed in chapter 4 reduces the severity and length of an influenza infection. Because of the availability of the drug, future outbreaks of the disease should result in fewer deaths than epidemics of the past. Passive immunity Approximately 2–3 weeks Time Antibodies injected Figure 8.33 Introduced antibodies (passive immunity) give immediate protection against infection but their action lasts for a relatively short time. 266 NATURE OF BIOLOGY BOOK 2 Antibodies produced in one person and introduced into another can react with antigens to provide immunity. When this occurs, the individual receiving the antibodies has passive immunity — it is called passive because the antibodies have not been made by the user. You will recall that in active immunity, an individual continues to make a particular antibody, often for life. The advantage of passive immunity is that it gives immediate protection to the person receiving the antibodies. However, you will see from figure 8.33 that introduced antibodies decline relatively quickly and do not provide long lasting immunity to the receiver. Passive immunity can be acquired in two ways: naturally or induced. Natural passive immunity Birth 1200 Immunoglobulin (mg/100 mL) 1100 Maternal IgG 1000 Total antibody 900 800 Infant IgG 700 600 500 Newborn IgG 400 300 IgM 200 IgA 100 0 2 4 6 8 0 2 4 6 8 10 12 Months Figure 8.34 The immune system does not complete development until sometime after birth. A fetus obtains IgG antibodies from the mother before birth. These maternal IgG antibodies will gradually disappear from the baby’s body after birth. At birth, a baby makes a low level of its own IgM. By 12 months of age, an infant produces about 60 per cent of its adult level of IgG, 75 per cent of its adult IgM level and 20 per cent of its adult IgA level. A developing fetus receives maternal antibodies across the placenta. Look at table 8.2 on page 257. What kind of antibodies are these? These antibodies provide important protection for the fetus and baby because the baby’s immune system does not mature fully until after birth (see figure 8.34). A baby also acquires antibodies through the mother’s milk. Colostrum is the thick yellowish milk the mother produces for the first two or three days after the birth and this is particularly rich in antibodies. One of the reasons breast feeding is recommended is because of the protection against infection that the mother’s antibodies give the baby. Induced passive immunity Assume a member of your family develops infectious hepatitis (hepatitis A). You will be at risk of also being infected. If you immediately receive an injection of antibodies specific for hepatitis A then infection may be avoided. The antibodies used in such injections are obtained from blood collected from voluntary donors by the Australian Red Cross Society. The antibodies, or immunoglobins, are extracted from the blood plasma collected from persons known to have had hepatitis A. The plasma will contain many different antibodies including those against hepatitis A. We can now summarise the ways in which immunity can be acquired (see figure 8.35). Acquired immunity Active Natural Antibodies made after exposure to infection Figure 8.35 A summary of different types of acquired immunity Passive Induced Antibodies made after immunisation with toxoid or with killed or treated organisms Memory B cells and T cells Natural Antibodies acquired by baby across placenta or in mother’s milk Induced Antibodies acquired through injection of immunoglobulins No memory cells Rabbits as antibody-making machines Horses are also used to make antivenoms. When a person receives antivenom against the venom injected into them during a snakebite, they are receiving antibodies that act specifically against the snake venom and so they are given immediate protection. The antivenom combines with the venom, which is no longer free to damage body cells. The antivenom is produced in rabbits which receive injections of venom. Why aren’t the rabbits killed? Initially, only a very small dose of venom is injected into each rabbit. The dose is so small that the rabbits survive and are able to produce antivenom. A slightly higher dose of venom is then injected into the rabbits, which respond by producing a higher level of antivenom. At an appropriate time, blood is taken from the rabbits, the antivenom is extracted and used in vaccines for people and other animals that are bitten by snakes. Taking blood from the rabbits is like taking blood from people. It will be replenished by the rabbit, the rabbit continues to make antivenom and more blood can be taken from the rabbit at another time. The rabbits are antivenom- or antibody-making machines that help to save human lives. IMMUNITY: DEFENCE AGAINST DISEASE 267 Table 8.3 The immunisation schedule recommended for Australians by the NHMRC Age Disease Vaccine birth • hepatitis B • hepB 2 months • • • • • hepatitis B diphtheria, tetanus and pertussis Haemophilus influenzae type b poliomyelitis pneumococcal infections • • • • • hepB DTPa Hib IPV 7vPCV 4 months • • • • • hepatitis B diphtheria, tetanus and pertussis Haemophilus influenzae type b poliomyelitis pneumococcal infections • • • • • hepB DTPa Hib IPV 7vPCV 6 months • • • • • hepatitis B1 diphtheria, tetanus and pertussis Haemophilus influenzae type b1 poliomyelitis pneumococcal infections • • • • • hepB DTPa Hib IPV 7vPCV 12 months • • • • hepatitis B Haemophilus influenzae type b measles, mumps and rubella meningococcal infections • • • • hepB Hib MMR MenCCV 18 months • chickenpox • VZV 4 years • diphtheria, tetanus and pertussis • measles, mumps and rubella • poliomyelitis • DTPa • MMR • IPV year 7 • hepatitis B • chickenpox • hepB • VZV year 10 • diphtheria, tetanus and pertussis • DTPa non-immune women shortly after delivery • measles, mumps and rubella • MMR 50 years • diphtheria and tetanus • ADT 50 years and over (Aboriginal and Torres Strait Islander people) • influenza (annual) • pneumococcal infections • influenza • 23PPV 65 years and over • influenza (annual) • pneumococcal infections • influenza • 23PPV 1All immunisations on the table except these are provided free by the Victorian Government. DTPa = diphtheria–tetanus–pertussis infant/child formulation ADT = diphtheria–tetanus adult formulation IPV = inactivated poliomyelitis vaccine MMR = measles–mumps–rubella vaccine VZV = varicella zoster vaccine 7vPCV = 7-valent pneumococcal conjugate vaccine 23vPP = 23-valent pneumococcal polysaccharide vaccine MenCCV = meningococcal C conjugate vaccine Schedules vary between regions. Contact your state or territory health department for details. Source: Immunise Australia Program, Department of Health and Ageing (2005) and Immunisation Program, Department of Human Services Victoria 268 NATURE OF BIOLOGY BOOK 2 KEY IDEAS • Specific immunity can be acquired in different ways. • In actively acquired immunity, the immune system of a person produces antibodies in response to antigens. • In passively acquired immunity, a person receives antibodies from an outside source. • Both active and passive immunity can be acquired naturally or artificially. QUICK-CHECK 20 A child develops the disease tuberculosis and later recovers. Explain whether the child is likely to have immunity to the disease five years later. 21 Not all adults have been vaccinated against tetanus. One such person stands on a rusty nail and is at risk of developing the disease. The person receives an injection of antitoxin shortly after the accident. Explain whether the person is likely to have an immunity to tetanus five years later. 22 Explain the main differences between non-specific immunity and specific immunity. 23 Outline one way in which vaccines or antivenoms are made. ODD FACT One of the Australian fur seals, Arctocephalus pusillus, at the Melbourne Zoo is allergic to pollen and has been trained to receive injections for the condition. ODD FACT People who are allergic to red strawberries develop itching and swelling in the mouth and throat. These people are often able to eat white strawberries so the allergy is probably related in some way to the red pigment. Adverse events associated with immunity Allergies Mast cells are immune cells involved in allergic responses. Mast cells are fixed cells found around blood vessels, in connective tissue, near the lining of the gut and in the lungs. Circulating basophil cells are also involved in allergic responses, but to a much lesser extent. Both kinds of cells contain large granules of histamine. You will recall that there are five different types of antibody. One type is IgE, which binds to mast cells and, to some extent, to basophils. IgE antibodies are made against antigens such as dust, pollen and plant spores. If a person contains IgE antibodies for a particular antigen, they are said to be sensitised to that antigen. If the person is further exposed to the same antigen, cross links are formed between the antibody on the mast cells and the antigen. These antibody– antigen cross links trigger mast cells to release active agents such as histamine. Histamine causes contraction of smooth muscle, including the muscle around tubules leading to the lungs. The diameter of the tubules decreases and this leads to difficulty in breathing, as in asthma. Histamine also causes blood vessels to dilate allowing cells and serum to move into the surrounding tissue causing swelling and inflammation. An allergic response can occur very quickly and can be fatal, particularly if it is widespread in the body. Treatment includes use of antihistamine drugs. Read Trent’s story on page 270. Trent has an allergy to peanuts and dairy products. Allergic responses can be avoided in some cases if the person is desensitised. This occurs by treating the person with small doses of the antigen to which they IMMUNITY: DEFENCE AGAINST DISEASE 269 TRENT — ALLERGIC TO PEANUTS AND DAIRY PRODUCTS Trent and his mother each tell a story. Mother’s story We have redefined ‘normal’ in our house. We have endeavoured to treat Trent as normal but just with different restrictions. There are two important factors when it comes to a person with allergies. 1. The diet must be restricted, especially so when you need to exclude things like dairy and peanuts. Dairy is the big one. Dairy includes cheese, butter, ice cream and milk. 2. The risk in eating something wrong is always present. An anaphylactic reaction happens in minutes and is life threatening. A restricted diet means that often Trent can’t eat what other children do. We always ensure Trent has the equivalent food wherever possible and never misses out. He gets safe alternatives. We don’t think we should raise him to feel any more deprived or precious than other children; it just comes down to the fact that he (and we) need to make different choices. It is normal, just different from most other people. Going out is difficult. At other people’s houses, we always take food, as most times people don’t know what to offer Trent. At restaurants, we sometimes take his food from home or something he can eat; for example, a McDonalds ‘happy meal’ can be bought on the way and is fortunately seen as a real treat by Trent. This, of course, is easier to do for a young child but may become more difficult for Trent as he gets older and really wants to be the same as others. He can eat at a restaurant only if they can guarantee there are no dairy products or peanuts in the food. Most restaurants try to be helpful as they don’t want to be the cause of any ‘accidents’. Trent usually takes his own food to a birthday party; I check with the hosting mother and send along something similar to what the other children are eating. Occasionally, if I am sure about the brand of foods being served, he will share in some of what is offered to the other children. Trent is always very wary of this, though, and looks for my reassurance that it will be OK for him to eat. Having an anaphylactic reaction is the other worry. If Trent somehow eats the wrong thing, is there someone present to administer the Epipen? An Epipen is a selfinjecting shot of adrenaline that would probably save his life. It is not difficult to administer but requires a certain technique. The reaction develops very quickly and the Epipen injection would need to be given even before an ambulance arrived. I really need to trust the 270 NATURE OF BIOLOGY BOOK 2 people at his school, where Trent stays or where he goes to play. Emotionally, this is all rather enormous for a 7-yearold to worry about. The restrictions and risks greatly impose on his life but Trent handles it so well. We are extremely proud of him. Food is something you can never really get away from. Many celebrations and occasions are planned around food, yet Trent finds fun in where he goes and what he does in life. Trent can do many things well; he loves school and sport. He has a positive attitude about his allergies and has always handled it with a sense of maturity and wisdom. Even as a small child, he never had a tantrum when he couldn’t have what the other children were having. He always appreciated his own ‘treat’ and was excited to have that. He is wary of food and never eats something without checking with his Mum and Dad first. Trent realises that he is indeed fortunate. Many children are born with worse illnesses and disabilities. He thinks having allergies is no big deal, as you will read below. Trent’s story Hi, my name is Trent. I am 7 and I am allergic to dairy and peanuts. It is a little bit hard with allergies because: • I get lots of hayfever. [Mum’s note: Hayfever is also an allergic/immune response that goes hand in hand with food allergies.] • I can’t eat certain foods. • Everyone in my class eats chocolate and I don’t. Good stuff about allergies: • My Mummy gives me treats instead of the stuff I can’t have. • I also trust Mum and Dad to give me the right food. I have had allergies for a long time. It is like a normal life. At school, I love sport, art, maths and writing stories. Having allergies doesn’t mean you can’t do stuff like other people because I can still play football really, really well. Figure 8.36 Trent are sensitive. This antigen links with the IgE and so makes less IgE available for any future reaction. The severity of any future reaction will be reduced. Why do we have an antibody that can lead to such problems? It has been suggested that IgE assists in the destruction of infections by larger organisms such as some worms that cannot be engulfed by phagocytes. Some allergies can also be caused by T cells. These reactions occur much more slowly than those involving antibodies and generally no treatment is required. Rhesus incompatibility Human blood can be classified as Rhesus positive or Rhesus negative depending on the presence or absence of the Rhesus protein on red blood cells. The blood group to which an individual belongs is genetically determined (see chapter 9 for more details). Depending on the father’s blood group, it is possible for a Rhesus negative mother to have a Rhesus positive child. In some cases, the activation of an immune response can lead to severe problems in the baby. How does this immune response arise and how can it be prevented? During a first pregnancy in which a Rhesus negative mother has a Rhesus positive child there is generally no problem. Few, if any, blood cells from the fetus move across the placenta into the mother. At the birth of the child, when the placenta separates away from the uterus wall, significant numbers of the baby’s red blood cells may cross into the mother’s bloodstream. The Rhesus protein on the red blood cells is foreign to the mother and this stimulates her immune response. The mother then makes Rhesus antibodies (see figure 8.37). Rh = Rhesus During first pregnancy Placenta Rh-ve mother At first birth Rh-ve mother Shortly after birth Subsequent pregnancy mother is sensitised Rh-ve mother Rh-ve mother B NO TREATMENT anti-Rh Rh+ve red cells anti-Rh Rh+ve fetus Rh+ve fetus Lysis Rh+ve fetus Anti-Rh from mother moves across placenta into fetus — fatal damage may occur Generally no problems Red blood cells of Rh+ve fetus move into mother Mother’s plasma cells produce Rhesus antibodies and continue to do so During first pregnancy At first birth Within 72 hours after birth Subsequent pregnancy no sensitisation Rh-ve mother Rh-ve mother Rh-ve mother Rh-ve mother Placenta Placenta TREATMENT Rh+ve red cells Rh+ve fetus Generally no problems Rh+ve fetus Red blood cells of Rh+ve fetus move into mother Mother receives injection of anti-Rh which react with fetal Rh+ve red blood cells Rh+ve fetus Generally no problems. Mother receives injection of anti-Rh at any subsequent birth Figure 8.37 Haemolytic disease of the newborn can occur when an Rh negative mother has an Rh positive child. Treatment is now available that has led to a significant reduction in incidence of this disease in recent years. IMMUNITY: DEFENCE AGAINST DISEASE 271 If another pregnancy follows in which the mother again has a Rhesus positive child, a problem can arise. Some of the Rhesus antibodies made by the mother pass across the placenta into the fetus where they react with the Rhesus protein on the red blood cells of the Rhesus positive child. If this happens, serious damage occurs to tissues and organs, including the liver. Blood cells are destroyed and their contents, including haemoglobin breakdown products, circulate in the bloodstream giving the baby a yellow jaundiced appearance. The problem increases with each pregnancy and can result in the death of the baby. The disease is called haemolytic disease of the newborn. Treatment is now available for Rhesus negative women who have Rhesus positive babies. Within 72 hours after the birth of the first Rhesus positive baby (or after a miscarriage), the mother is given an injection of immunoglobulin high in Rhesus antibody. She is passively immunised with Rhesus antibodies. These react with and remove fetal red blood cells from the mother’s circulation. This prevents the development of Rhesus antibodies by the mother and the development of memory cells that would give a greater response during the next pregnancy. The injection is repeated in any subsequent pregnancy. These events are summarised in figure 8.37. How does a fetus survive the mother’s immune system? We have seen, in the case of Rhesus incompatibility, that antibodies made by the mother in specific response to a fetal protein can cross the placenta and react with cells within the fetus. Antibodies that pass through the placenta are generally maternal IgG antibodies. Half the genetic material of a fetus is inherited from the father and so many of the compounds made by a fetus are foreign to the mother and are capable of acting as antigens. Some of these antigens cross the placenta from the fetus into the mother and result in the production of antibodies by the mother. This occurs with increasing frequency as pregnancy proceeds. Why don’t these antibodies cross the placenta back into the fetus and cause a massive rejection of the fetus by the mother’s body? This doesn’t happen because the placenta acts as a selective barrier to antibodies. The placenta allows only some antibodies to cross from the mother into the fetus. Generally, anti-fetus antibodies made in the mother are absorbed by cells in the placenta and so are prevented from crossing into the fetus. In addition, an antibody ‘blocking factor’ is found in maternal serum that inhibits the function of maternal lymphocytes that have been sensitised by fetal antigens. Some women have repeated spontaneous miscarriages without apparent cause. Some of these miscarriages may be due to a rejection of the fetus because anti-fetal antibodies have crossed the placenta and reacted with fetal cells. Some of the women who have repeated miscarriages have reduced levels of ‘blocking factor’. In some cases, when a woman with a history of recurrent miscarriages is immunised against the white blood cells of the father of the children, the fetus seems to be protected against rejection. Maternal antibodies specific for fetal antigens react with cells in the placenta and prevent the passage of fetal antigens which would otherwise initiate an immune response in the mother. Auto-immune diseases Sometimes the ability of the immune system to recognise self from non-self breaks down. When this occurs, the system reacts as if some of the body’s own cells are non-self. In this case B and T cells attack and destroy self cells in the same way that they attack and destroy invading micro-organisms. 272 NATURE OF BIOLOGY BOOK 2 Conditions that develop because of this self attack are called auto-immune diseases. The attack can occur generally throughout the body or against a specific organ. Some auto-immune diseases and their features are listed in table 8.4. Read Rachel’s story on pages 276–7. She has the autoimmune disease systemic lupus erythematosus. Table 8.4 Some auto-immune diseases and their features. In some auto-immune diseases, particular organs are affected more than others. General reactions occur throughout the body in other auto-immune diseases. See pages 276–7 for Rachel’s story about lupus. Disease Features Main site of action Graves’ disease increased production of thyroid hormone thyroid pernicious anaemia vitamin B12 deficiency, abnormal red blood cells stomach insulin-dependent diabetes mellitus diabetes responsive to insulin treatment pancreas rheumatoid arthritis destruction of joint cartilage joints multiple sclerosis progressive paralysis, myelin layers around axons degenerate CNS systemic lupus erythematosus fever, pain in joints, damage to CNS, heart and kidneys kidneys Multiple sclerosis: an auto-immune disease Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). It is thought to be an example of an auto-immune disease, a group of disorders in which the body’s immune cells attack its own tissues. It is also a relatively common disease affecting up to one per 1000 people of northern European origin. In MS there is a breakdown of the fatty myelin sheath that surrounds the processes of nerve cells (see figure 8.38). This myelin sheath is produced by specialised cells called oligodendrocytes and it normally speeds transmission of nerve impulses by electrically insulating nerves from the surrounding environment. Damage to the myelin sheath can short-circuit communication between different parts of the CNS (either within the brain or along the spinal cord). It also impairs the transmission of information between the CNS and the peripheral nerves, that part of the nervous system which sends messages to the muscles and which relays information from the sensory organs. The damage to the myelin sheath is thought to be caused in a stepwise way by immune cells that invade the CNS in discrete waves. The sites of damage are patchy and scattered throughout the CNS. Therefore, different people with MS often have different symptoms, ranging from loss of coordination and muscle weakness, to sensory impairment such as loss of feeling in the arms or legs, or visual defects, and sometimes even problems with various aspects of thinking and memory. For most people the disease starts as a single attack that usually improves. In some patients this is the only attack that they ever experience but for others this is followed by a series of further attacks that also usually get better. Some of these attacks start after infections Figure 8.38 Brain scan. Multiple sclerosis results in extensive damage to the myelin sheaths of nerve processes in the CNS. Compare this brain with the one on page 187. IMMUNITY: DEFENCE AGAINST DISEASE 273 affecting the lungs or urine, presumably caused by activation of immune cells. This includes reactivation of ‘memory’ cells that have previously damaged CNS myelin in earlier attacks. Approximately half of the people who have had discrete attacks enter a progressive phase of the disease. Whereas early in the disease the damage can be repaired, with repeated attacks the tissue injury may become permanent. This leads to multiple plaque-like areas of scarring or sclerosis (hence ‘multiple sclerosis’) within the CNS. During this phase of the disease there is permanent impairment of nerve transmission and worsening disability. Recently, it has been suggested that this progressive phase is a result of damage to the processes of the nerve cells that cross the plaques. In the past, the diagnosis of MS was based on the combined assessment of the patient’s symptoms and of the doctor’s examination findings. However, diagnostic accuracy improved dramatically in the 1990s because of a new way to image the brain that relies on the use of magnetic fields and radio-frequency pulses. This test, known as magnetic resonance imaging, provides a very accurate assessment of water content in the brain. Because the amount of water is increased in the plaques of MS, these lesions can now be detected with a high degree of accuracy. The cause of MS is unknown. It has been suggested that exposure to infectious agents such as viruses could be involved, possibly setting off auto-immune disease directed against myelin. This could occur via a process known as molecular mimicry. This occurs when there is a similarity between proteins expressed by infectious agents, against which an immune attack is appropriately directed, and myelin proteins, against which the immune attack is mistakenly continued. Much research has attempted to find unique features in the immune systems of patients with MS that makes them more likely to have ongoing disease. To date, no clear cut difference has been found, apart from some possible differences in the way that the various proteins might be presented to the immune cells via molecules known as human leucocyte antigens (HLA). Furthermore, despite intensive investigation, no single infectious cause has been identified and it is possible that exposure to a variety of environmental factors can trigger the disease. In both northern and southern hemispheres, a latitudinal gradient exists in the prevalence of MS, with more cases identified in colder regions. In Australia, the prevalence of MS in Tasmania is several times greater than that of northern Queensland, providing some of the strongest evidence for an environmental influence on the development of MS. Nevertheless, MS also has an obvious hereditary component, as indicated by the observation that if one identical twin has MS there is a 25–30 per cent chance that the other twin will also get the disease, whereas the risk is only 3–5 per cent amongst non-identical twins. Consequently, there is active research attempting to identify genes that alter the risk of the disease. The auto-immune hypothesis has led to attempts to treat MS with medications that change the immune response. Cortisone (a steroid) speeds the rate of recovery from acute attacks of demyelination. A new drug called beta-interferon (which is a substance normally produced by the body as part of the defence mechanism against virus infection) reduces the frequency of attacks in patients with mild disease and reduces the rate of progressive MS, on average, by about 20 per cent. These recent advances are useful, but more effective treatments are required. In order to design such therapies we will almost certainly need to understand more about the cause of the disease. Rejection of transplanted organs Perfect matching of tissues occurs only if identical twins are involved in organ donation. In most cases, transplanted donor tissue will not match that of the 274 NATURE OF BIOLOGY BOOK 2 recipient perfectly and the immune system of the recipient will react against the non-self material. T cells are particularly important in tissue transplants. Helper T cells identify unmatched tissue and attack the grafted organ. Before an organ is transplanted from one person into another, the donor and potential recipient have their tissues ‘typed’ to find out the major antigens that are present in each. The amount of foreign or non-self material introduced into a recipient is minimised by matching the tissues as closely as possible. The better the match of MHC markers between donor and recipient, then the higher the chance that the transplant will be successful. Drugs are available that inhibit the immune response. Recipients of foreign tissue transplants must take the chemical cyclosporin for the rest of their lives to prevent rejection of the transplanted tissue. The beauty of cyclosporin is that it acts specifically against T cells and so the remainder of the immune system is available to act against disease-causing organisms. A range of other drugs are also used in association with cyclosporin. Immune deficency diseases ODD FACT The longest a child has lived without an immune system is 12 years. David lived in the USA in a sterile plastic enclosure and was known as ‘the boy in the bubble’. In 1997, 947 Australians received a bone marrow transplant. The immune system at birth is relatively immature (see figure 8.34). If maturation fails to occur then a baby has no protection against infection. Once the antibodies obtained from the mother via the placenta and milk are no longer active, a baby with an inactive immune system develops a range of infections as the baby encounters various micro-organisms. A baby with such a deficiency generally dies at a young age. Immune deficiency is a malfunction or a deficiency in one or more components of the immune system. Immune deficiency disorders can be inherited or may develop as a result of some other disease. Remember that bone marrow plays an important role in producing cells for the immune system. Bone marrow is a tissue that can be transplanted from person to person. Unlike heart and liver transplants that require the death of a donor, bone marrow is taken from a living donor without long-term ill effects. An Australian Bone Marrow Donor Registry was established in 1989. The registry exists in a number of States and is coordinated from Sydney. The Australian registry is also linked with registries in other countries. Just as tissues have to be typed for organ transplants, bone marrow also has to be typed so that donor and recipient tissues can be matched as closely as possible and the chance of rejection of the transplant by the recipient is reduced. Even if the potential donor and recipient have matched class 1 and class 2 markers, additional tests may reveal other incompatibilities. Mismatched transplants are rarely done in Australia. Acquired immune deficiency syndrome (AIDS) It is generally accepted that acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV) (see figure 8.41). This virus infects only cells carrying a particular protein marker. The marker is found mainly on mature helper T cells and to a lesser extent on macrophages. Because HIV destroys a key component of the immune system, T helper cells, AIDS patients have greatly reduced defence against other invading organisms and develop a number of opportunistic diseases. They are also susceptible to Kaposi cancer, a rare cancer of blood vessel tissue. The development of disease after infection with HIV is variable. In some people the virus remains in infected cells for years with few or no apparent problems. In other people, the virus becomes active in a relatively short time and all the serious symptoms of AIDS appear. Once these occur, death usually follows within about two years. Some drugs delay the onset of the symptoms of ‘full blown’ AIDS. IMMUNITY: DEFENCE AGAINST DISEASE 275 PERSONAL STORY Rachel’s story — a case of systemic lupus erythematosus (sle) ‘Hey, Rachel. How come your face is so fat but the rest of your body is normal?’ Another comment about my weight — my somewhat ‘bloated’ appearance. I could cope with people’s interest and concern but not my physical changes. Why did everyone have to comment? Why couldn’t they be happy that I was getting well? Why hadn’t anyone heard of lupus? A small chilblain on my left middle finger initiated a series of strange, painful and ultimately debilitating symptoms that would eventually transform the normality of my adolescent world into a time of absolute confusion and despair. Systemic lupus erythematosus (SLE), or simply lupus, is a chronic autoimmune disease caused by inflammation in different parts of the body. Lupus commonly affects the skin and joints, and possibly organs such as the kidneys, heart, brain and other internal organs. Symptoms I suffered included joint and muscle pain, skin rashes, extreme fatigue, weakness, fever, headaches, hair and weight loss, and sensitivity to sunlight. Those who develop lupus are usually women in their childbearing years. I was only 14. From age 14 to 16, doctors couldn’t diagnose my peculiar symptoms. Blood tests indicated no signs of disease activity. I visited every specialist imaginable but to no avail. At times I was too sick to attend school in years 8 and 9, but, in year 10, I didn’t make it to school at all. Bedridden, in constant joint pain and overwhelmingly fatigued, I felt my dreams and aspirations crashing down around me. My dreams of completing VCE, attending university and becoming a teacher were in doubt. I just wanted to be my old, normal self again. While all of my friends were at school, working part-time jobs, socialising at parties and having boyfriends, I spent each day lying in my bed and trying to find the strength to walk with the aid of a walking stick throughout my house. I would watch from my window, waiting each day for friends to visit me. No one came. Teachers didn’t call. Life went on for those around me, while my body succumbed to the pain. I had never felt so alone. At the beginning of year 11, aged 16, I was finally diagnosed with lupus. Great joy — my symptoms had a name. I could now inform people about my illness and explain what was wrong with me. I could actually take drugs, corticosteroids, that would help relieve my pain. I would soon discover that they were to be both my best friend and worst enemy. With time, effort and determination, I was well enough to attend the last few weeks of year 10 prior to my diagnosis. My mother, 276 NATURE OF BIOLOGY BOOK 2 who didn’t drive, would push me to school in a wheelchair for half-day visits when I was well enough. So, you could imagine how happy I was at the prospect of taking medication that would give me enough energy to walk to and from school, to survive a full school day and to concentrate and attend to my numerous work requirements as a VCE student, just like everyone else. Although my hope for a promising future had been renewed, it wasn’t easy. Steroids had a range of side effects. I gained weight, particularly in my face which created a bloated appearance, and suffered severe acne, hair loss (not very attractive features to have in year 11!!) and regular infections ranging from colds to urinary tract and candida infections. However, I managed to cope positively with these side effects with support from my teachers, who extended time for my work requirements when necessary. Socially, my return to school wasn’t easy. One student lamented, ‘We heard you were dying,’ to which I replied, ‘Gee, thanks for coming to say good-bye.’ Re-establishing friendship groups was very hard. I felt like a new student but I guess in many ways, I was. With time, I had a support group of friends who helped me enjoy each day at school. Figure 8.39 Rachel fulfils her dream of graduating and becoming a teacher. Returning to school was a challenging time but I never doubted my will and ability to succeed. I sacrificed the social life of a VCE student in exchange for the life of a lupus student striving to achieve her dreams. I was successful in many ways. At the completion of year 12, I received the student award for Best All-Rounder. I was accepted in my chosen university course and studied a double degree of Teaching and Applied Science for four years. I was honoured as ‘Most Outstanding Home Economics Student Teacher of the Year’ and became a member of an honours society for students who were in the top 15% of their course. I am extremely proud of these achievements, which symbolise a time in my life when I felt destined to fulfil my dream of teaching. At the time I first wrote this piece [for Nature of Biology Book 2, Second Edition], I was a graduate secondary teacher of VCE and junior classes in Food Technology and Human Development. I was battling daily joint pain, fatigue and sensitivity to sunlight. Today, I am concluding my eighth year of secondary teaching and continue to suffer these symptoms in varying degrees. There has been no significant breakthrough in medical treatment for lupus patients, and I am still taking the course of medication I began almost 14 years ago. I have taken greater amounts of corticosteroids and immunosuppressant medication, which have made serious changes to my pain management. Their side effects have been extremely strong and I have had to cope with much discomfort. I seem to relapse into flares of the disease when under stress and cannot reach a state of complete remission. Whilst achieving great academic success in my younger years, beginning my career as a secondary teacher was where the real learning began. As a student, I could seek support from teaching staff who would extend time for me to complete important tasks. As a full-time secondary teacher in the workplace, I cannot always be awarded such leniency. Thus, adjusting to life in the workplace as a chronically ill person with a disease that is not well known is an ongoing challenge for me. Disclosure of my illness to teaching colleagues has at times proved frustrating yet, ultimately, integral to my survival in the workplace; without the understanding, compassion and patience I have received, I would find it extremely difficult to achieve the standard of professionalism as a teacher to which I aspire. I will be honest; teaching is not exactly the type of profession my doctors would wish me to pursue! Teaching requires much energy, commitment and resilience in responding to its many changing demands. I have experienced the challenge of aspiring to reach my goal of becoming a teacher, and the ongoing challenge of learning how to sustain my teaching life. Learning how to grow and extend my skills and knowledge as a teacher without exacerbating my lupus is extremely difficult and there are some aspects of my job that I know I will not completely fulfil. However, it is also important that I remember not to rule anything out completely, to focus on what I can do, not what I can’t do. This is paramount to my true success as a person suffering a chronic illness. Yes, I still have lupus, for which there is still no known cure. Yes, I still battle daily with a myriad of symptoms. Years of treatment are starting to show effects on my body as I am in the early stages of osteoporosis and I find that my symptoms have slightly changed over the years. I don’t seem to pull up from severe bouts of lupus as well as I used to when I was younger! Yes, I am still a secondary teacher, one who has progressed with more experience, and I so enjoy the many rewards of making a difference in the lives of my students. I believe I am living a happy, fulfilled life, but I do not always find it easy to get that balance of working and looking after myself — such is the life of a chronically ill person. What I do have is the strength to keep looking forward and I know I will keep doing so with love and support from family, friends and work colleagues … and having a greater acceptance of my complete self, whatever its shape or form. Figure 8.40 Rachel preparing for class IMMUNITY: DEFENCE AGAINST DISEASE 277 Core Capsid RNA molecules carrying virion’s genetic code Enzymes Figure 8.41 Drawing of a model Envelope of fat molecules of the human immunodeficiency virus (HIV) that causes acquired immune deficiency syndrome (AIDS) Glycoprotein molecules embedded in the envelope It is now known that lipids make up about 30 per cent by weight of the HIV-1 virus (figure 8.42a). Disruption of the HIV-1 lipid surface by certain chemical agents reduces the infectivity of the virus. Researchers at the Macfarlane Burnet Institute for Medical Research and Public Health are investigating ways of developing new antiviral strategies with drugs that would prevent the spread of HIV-1 (figure 8.42b). (a) lipid bilayer membrane HIV Figure 8.42 (a) Disruption of the HIV lipid surface by certain chemical agents reduces the infectivity of the virus. (b) Electron micrograph of HIV-1 being released from an infected host surface proteins disrupt the lipid bilayer (b) Do plants have an immune system? unsuccessful infection 278 NATURE OF BIOLOGY BOOK 2 Plants have no distinct immune system of the kind found in humans and many other animals. However, most plants are resistant to pathogens. Plants have evolved over years in situations in which they were exposed to pathogens. Only those plants which had appropriate structural and physiological characteristics to resist infection survived, and their genetic material was transmitted to future generations. ODD FACT Many antibiotics used with animals, including humans, are extracted from plants and fungi. Mechanical barriers The cuticle and epidermal cells form an outer barrier for plants in much the same way as skin does in humans. The silicon content of some leaves makes them particularly resistant to the degrading enzymes of pathogens. If a disease-causing organism penetrates the outer layers, and the stomata in particular can be a point of entry, layers of thickened cells (called cork) form in many cases. This gives rise to abnormal swellings at the infection site. These swellings are called galls and limit the distribution of the parasite in the plant. Galls are caused by pathogenic organisms, including insects and nematode worms. Chemical barriers Figure 8.43 Some plants resist disease by producing chemicals that act as antibiotics. Lemon trees, Citrus limonia (figure 8.43), and mint plants, Mentha spp., produce oils that repel some insect pests. Stone fruit trees, such as plum and peach, secrete gum around an infected area to ‘seal it off’ from the rest of the plant. Other chemicals that have a defence role in plants include resins, tannins and phenolic substances. New methods of plant breeding are being developed to produce plants that are resistant to specific diseases. These include cell and tissue culture and recombinant DNA technology (see chapter 12). KEY IDEAS • Any part of the immune response can be faulty. • Cells of the immune system are involved in allergic reactions. • An immune system can lose the ability to distinguish ‘self’ from ‘nonself’. • The action of the immune system can be reduced by treatment with certain drugs. • Antibodies are sometimes injected to inhibit an immune response. • Most plants resist infection by mechanical and chemical means. QUICK-CHECK 24 Explain why treatment of transplant patients with the drug cyclosporin reduces the chance of transplant rejection. 25 Explain why a person suffering from an allergy may be treated with an antihistamine. 26 Explain what is meant by an auto-immune disease. 27 Explain why some women are given an injection of immunoglobulin shortly after the birth of a baby. 28 Explain why a person with AIDS is particularly susceptible to a range of infections. 29 A baby is born with a defective thymus. Comment on the baby’s ability to resist infection — immediately after birth and at six months of age. 30 Why are galls effective in reducing the spread of infection in some plants? IMMUNITY: DEFENCE AGAINST DISEASE 279 BIOCHALLENGE Autocrine 1 Cytokines are protein molecules that act as messengers between cells of the immune system. An immune cell may communicate with itself, an autocrine effect, with a cell nearby, a paracrine effect; or with a cell some distance away, an endocrine effect. You will recall from chapter 5 that this is similar to communication by hormones. One difference is that hormones are more likely to act on distant cells than close ones while Paracrine cytokines are more likely to act on close cells than on distant ones. Explain why this difference is biologically logical, given the organs and cells involved in the immune and hormonal systems of the body. Endocrine Ovary 2 IgY from blood Oviduct IgA locally secreted Immunoglobulins pass from a mother hen into a developing egg. IgY immunoglobulins are found in the yolk of an egg, and IgM and IgA are found in the white. The white forms a watery liquid, the amniotic fluid, in which a chick develops, and the yolk becomes nutrient for the developing embryo. In a newly hatched chick, IgY is found in its serum and IgM and IgA in its intestine. a Why would it be important for a chick to have some immunity immediately after hatching? b Suggest an explanation for the different positions of the immunoglobulins in a newly hatched chick. c Given that immunoglobulins are present in the chick, explain whether any immunity they give would be passive or active immunity. d Explain whether the immunity in a chick is likely to be long lasting or temporary. IgA in albumin IgY in the yolk 3 Non-identical twin calves are genetically equivalent to non-twin siblings. They share some proteins but many are different. Sometimes, the two placentas of twin calves fuse and chimeric calves develop. A chimera is an animal that contains cells from two or more genetically different individuals. Stem cells from each calf travel in the bloodstream, enter the body of the other calf and colonise the bone marrow of the other calf. In effect, the result is that both calves have their own cells as well as cells identical to those of their non-identical twin. a What conclusion could you reasonably make about the ability of fetal cells to distinguish between self and non-self cells? b Skin from calf A was grafted onto calf B. Explain whether you would expect rejection of the skin graft or not. c Explain whether you would expect the same result if skin from calf B was grafted onto calf A. d Tests were carried out on the calves when they were six months old. Would you expect the antibodies in each calf to be identical to those in the other calf? Explain your answer. 280 NATURE OF BIOLOGY BOOK 2 Fused placentas A B Chimeric calves CHAPTER REVIEW Key words acquired immune deficiency syndrome (AIDS) acquired immunity active immunity acute myeloid leukaemia agglutination allergic responses antibodies antigen attenuated auto-immune diseases B cells B-memory cells bone marrow cellular immunity class 1 markers class 2 markers clone colony stimulating factor (CSF) complement proteins cytokines CROSSWORD cytotoxic T cells (Tc) galls helper T cells (Th) histamine humoral immunity immune deficiency immune system immunoglobulins inflammation interferons lymph lymphocytes macrophages major histocompatibility complex (MHC) mast cells monocytes natural killer (NK) cells neutrophils Nobel Prize non-self receptors non-specific immunity opportunistic infection passive immunity phagocytes plasma cells primary antibody response pus secondary antibody response self antigens self receptors specific immunity sub-clinical infection T cells toxoids vaccination vaccines Questions ▲ ▲ ▲ ▲ Figure 8.44 1 Making connections between concepts ➧ Make a concept map using at least eight key words from the list at the end of this chapter. In making your map, you may add other concept labels. 2 Analysing information and applying understanding ➧ Bacteria of the kind shown in figure 8.44 infect a skin wound. a Explain the immune response that takes place at the wound site. b Explain how many different kinds of B cells would react to the bacteria. Draw one of them. c Explain how many different kinds of antibodies would be produced in response to the bacteria. d Draw a macrophage cell that has ingested a bacterium of this kind. e How will T cells respond to the infection by these bacteria? 3 Analysing information and drawing conclusions ➧ Di George’s syndrome is a disease of the immune system in which B cells are produced but not T cells. a Explain whether a person with Di George’s syndrome would be able to produce antibodies. b Explain to what extent you think a person with Di George’s syndrome is likely to accept or reject a tissue transplant. 4 Analysing information and applying understanding ➧ The ‘Mantoux’ test is designed to determine whether a person has antibodies against the bacillus IMMUNITY: DEFENCE AGAINST DISEASE 281 responsible for tuberculosis. When the test is carried out a small amount of ‘test’ solution is injected under the skin on the arm. If the test is positive, a red area appears around the site of injection. a What material must be in the ‘test’ solution to react with antibodies in the blood? b What do you think causes the redness around the injection site? c Explain the various ways in which a person might have obtained antibodies against tuberculosis. 5 Analysing information and applying understanding ➧ Look at table 8.3 on page 268. The injections of triple antigen ‘DTP’ and Sabin vaccine ‘OPV’ that are given to babies at four and six months are called ‘booster shots’. Given that the baby has been immunised at two months, explain why booster shots are given. 6 Analysing and interpreting data and communicating information and ideas effectively ➧ A person can be classified into one of four groups in the ABO blood group system on the basis of the antigen found on the red blood cells and the antibodies in the plasma. The four groups are: Blood group Antigen on red blood cell Antibody in plasma A A anti-B B B anti-A A and B neither anti-A nor anti-B neither A nor B anti-A and anti-B AB ODD FACT In 2004 in a Sydney hospital, a patient died after two nurses gave type A+ blood to a woman whose blood group type was O+. q Antibody preparations are made so that blood can be tested and typed. The first column in figure 8.45 contains a test sample of blood that has been tested with anti-A and anti-B antibodies. How would you ‘type’ or classify this blood? Because the test blood has reacted with anti-B, the cells must have antigen B. There is no reaction with anti-A. The unknown blood must be from a group B person. a Draw the test panels you would expect to obtain when testing blood of groups B, AB and O. Explain why you predict each result. b Fresh blood was found on a broken window at the scene of a crime. Blood from four suspects was compared with blood from the window. The results obtained are shown in figure 8.45. Test blood sample Blood + anti-A Blood + anti-B Figure 8.45 282 NATURE OF BIOLOGY BOOK 2 Control blood + saline Suspect 1 Suspect 2 Suspect 3 Suspect 4 Blood from broken window i What was the blood group of each of the samples tested? ii Explain which suspect could have been at the scene of the crime. iii What is the purpose of the control panels? c Write a short mystery story involving blood testing. See if other class members can solve the mystery. 7 Analysing information and applying understanding ➧ The red blood cells of a Rhesus positive (Rh +ve) person have Rhesus protein (antigen) on their surfaces. A person with Rhesus negative (Rh −ve) blood has neither Rhesus antigen on the cells nor Rhesus antibody in the plasma. Sometimes, when a blood bank runs short of Rh −ve blood, Rh +ve blood may be given to a male who has never before had a transfusion. a Why can such a transfusion be given without danger to the recipient? b Explain the immune response in a male who receives such a transfusion. c If the male required a transfusion two years later, what kind of Rhesus blood could he be given and why? d Explain why young women who are Rhesus negative are not given Rh +ve blood even though it would be a safe transfusion the first time it was given. Antigen Hinged region Light chain Heavy chain Figure 8.46 8 Analysing and synthesising data and communicating ideas effectively ➧ a Briefly explain the role of antibodies. b Briefly explain the role of antigens. c Explain why the two ‘arms’ of an antibody are shown with identical antigens (see figure 8.46). Would you ever expect the two antigens to be different? d What is the function of the hinged region of an antibody? e By what means do cells of the immune system communicate with other cells of the body? 9 Interpreting data and communicating ideas effectively ➧ Thymocytes are developing T lymphocytes in the thymus. At different stages of development they have different amounts of surface molecules called CD4 and CD8. Thymocytes can be separated into four different groups on the basis of their surface molecules: Group 1 low CD4 and low CD8 Group 2 low CD4 and high CD8 Group 3 high CD4 and low CD8 Group 4 high CD4 and high CD8 IMMUNITY: DEFENCE AGAINST DISEASE 283 (a) (b) Figure 8.47 To separate the groups, different coloured fluorescent markers are attached to molecules that will bind specifically with either CD4 or CD8 surface molecules. The cells are then passed through a machine that can sort and count cells with different fluorescent markers. The number of cells separated into each group is shown in a form similar to a contour map (see figure 8.47a), where each height above the baseline is shown in a different colour. These data can also be used to produce a three-dimensional image (see figure 8.47b). a What general term is used to describe molecules on cell membranes? b To what kind of molecules would the fluorescent markers be attached? Explain your choice. c Note the four coloured spots in figure 8.47a. To which group of thymocytes does each coloured spot correspond? d Examine figure 8.47b. Which group of thymocytes contained the greatest number of cells? Which group contained the least cells? 10 Using the web ➧ Go to www.jaconline.com.au/natureofbiology/natbiol2-3e and click on the ‘Avian influenza’ weblink for this chapter. Select ‘Avian influenza’ and then ‘Frequently asked questions — Avian influenza’, and answer the following questions. a Why is a name such as A H5N1 given as well as the more general name of avian influenza? b What prohibitions on imports exist that reduce the chance of avian flu being introduced into Australia? c What is the latest information about infections and deaths attributable to avian flu? d How do symptoms of avian influenza compare with normal influenza? e Are vaccines against avian flu being developed? 284 NATURE OF BIOLOGY BOOK 2