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SCHOLAR Study Guide CfE Higher Human Biology Unit 4: Immunology and Public Health Authored by: Eoin McIntyre (Previously Auchmuty High School) Reviewed by: Sheena Haddow (Perth College) Previously authored by: Mike Cheung Eileen Humphrey Eoin McIntyre Jim McIntyre Heriot-Watt University Edinburgh EH14 4AS, United Kingdom. First published 2014 by Heriot-Watt University. This edition published in 2016 by Heriot-Watt University SCHOLAR. Copyright © 2016 SCHOLAR Forum. Members of the SCHOLAR Forum may reproduce this publication in whole or in part for educational purposes within their establishment providing that no profit accrues at any stage, Any other use of the materials is governed by the general copyright statement that follows. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without written permission from the publisher. Heriot-Watt University accepts no responsibility or liability whatsoever with regard to the information contained in this study guide. Distributed by the SCHOLAR Forum. SCHOLAR Study Guide Unit 4: CfE Higher Human Biology 1. CfE Higher Human Biology Course Code: C740 76 ISBN 978-1-909633-19-3 Print Production and Fulfilment in UK by Print Trail www.printtrail.com Acknowledgements Thanks are due to the members of Heriot-Watt University’s SCHOLAR team who planned and created these materials, and to the many colleagues who reviewed the content. We would like to acknowledge the assistance of the education authorities, colleges, teachers and students who contributed to the SCHOLAR programme and who evaluated these materials. Grateful acknowledgement is made for permission to use the following material in the SCHOLAR programme: The Scottish Qualifications Authority for permission to use Past Papers assessments. The Scottish Government for financial support. The content of this Study Guide is aligned to the Scottish Qualifications Authority (SQA) curriculum. All brand names, product names, logos and related devices are used for identification purposes only and are trademarks, registered trademarks or service marks of their respective holders. i Contents 1 Non-specific defences 1.1 Introduction . . . . . . . . . . . . . . . . . . . 1.2 The immune system . . . . . . . . . . . . . . 1.3 Non-specific defences - physical and chemical 1.4 The inflammatory response . . . . . . . . . . 1.5 Non-specific cellular responses . . . . . . . . 1.6 Learning points . . . . . . . . . . . . . . . . . 1.7 Extended response question . . . . . . . . . . 1.8 End of topic test . . . . . . . . . . . . . . . . . 2 Specific cellular defences 2.1 Immune surveillance . . . . 2.2 Clonal selection theory . . . 2.3 T- and B-lymphocytes . . . . 2.4 The action of T-lymphocytes 2.5 The action of B-lymphocytes 2.6 Immunological memory . . . 2.7 Learning points . . . . . . . 2.8 Extended response question 2.9 End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 2 4 6 10 14 15 15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 18 20 23 26 27 30 32 33 34 3 The transmission and control of infectious diseases 3.1 Infectious diseases caused by pathogens . . . . . 3.2 Methods of transmission of pathogens . . . . . . 3.3 Control of spread of pathogens . . . . . . . . . . 3.4 Epidemiological studies of infectious diseases . . 3.5 Learning points . . . . . . . . . . . . . . . . . . . 3.6 Extended response question . . . . . . . . . . . . 3.7 End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 36 42 44 49 53 53 54 4 Active immunisation 4.1 Active immunisation and vaccination . . . . . . . . . . . 4.2 Herd Immunity . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Immunisation programmes . . . . . . . . . . . . . . . . . 4.4 The evasion of specific immune responses by pathogens 4.5 Learning points . . . . . . . . . . . . . . . . . . . . . . . 4.6 Extended response question . . . . . . . . . . . . . . . . 4.7 End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 56 63 67 70 78 79 80 5 End of unit test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 ii CONTENTS Glossary 85 Answers to questions and activities 1 Non-specific defences . . . . . . . . . . . . . . . . . 2 Specific cellular defences . . . . . . . . . . . . . . . 3 The transmission and control of infectious diseases . 4 Active immunisation . . . . . . . . . . . . . . . . . . 5 End of unit test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 87 91 95 98 102 © H ERIOT-WATT U NIVERSITY 1 Topic 1 Non-specific defences Contents 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Introduction . . . . . . . . . . . . . . . . . . . The immune system . . . . . . . . . . . . . . Non-specific defences - physical and chemical The inflammatory response . . . . . . . . . . 1.4.1 Inflammation . . . . . . . . . . . . . . . 1.4.2 The cellular basis of inflammation . . . Non-specific cellular responses . . . . . . . . 1.5.1 Phagocytes . . . . . . . . . . . . . . . . 1.5.2 Natural killer (NK) cells . . . . . . . . . Learning points . . . . . . . . . . . . . . . . . Extended response question . . . . . . . . . . End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2 4 6 6 7 10 10 12 14 15 15 Prerequisite knowledge You should already know about: • defences against disease (phagocytosis, antibodies, vaccination); • diseases (viruses, bacteria, fungi, parasites); • hygiene (personal, sexual, food, water). Learning objectives By the end of this topic, you should be able to: • state that the body’s capacity to protect itself against pathogens, some toxins and cancer cells is achieved by means of the immune system; • describe the nature of the body’s chemical and physical defences against pathogens; • describe the inflammatory response; • describe the non-specific cellular responses. 2 TOPIC 1. NON-SPECIFIC DEFENCES 1.1 Introduction If it were possible that an intelligent life-form from another planet in our galaxy could visit Earth, and that we could communicate with it, we might ask what it thought of the place. If we enquired about what it considered to be the dominant life-form, we might be surprised at the answer because it has been estimated that 90% of the energy processed by organisms on the planet is done so by bacteria. Likewise, the total biomass of bacteria on the planet is thought to exceed that of all other living things put together. With an average size of 1µm, they have found niches virtually everywhere, from the bedrock, to the clouds, the deep sea floor, and hot springs. And, of course, nine tenths of the cells within our bodies are bacteria. It may be a bit disconcerting to conceive of ourselves as habitats, but we are just that (and a very attractive one!) to bacteria and other microbes. Our tissues are warm and constantly bathed in nutrient- and oxygen-rich fluid, conditions which are perfect for microbes to thrive in. Much of this is true of all multicellular organisms, and so, to exist at all, they have had to evolve methods of countering colonisation by microbes. A common misconception is that all microbes are potential pathogens, but that is far from true. We could not live a healthy life without our varied and complex gut flora of bacteria, and trees could not absorb nutrients from the soil without the aid of the fungal threads attached to their roots. It should also be remembered that although we tend to think of bacteria in relation to infection, the heterotrophic organisms that test our defences come from all categories, so we have to be able to defend ourselves against viruses (e.g. flu), bacteria (e.g. pneumonia), fungi (e.g. athlete’s foot), protozoans (e.g. malaria), and even quite large animals (e.g. tapeworms). We will leave the discussion about whether viruses are alive to another time. This unit addresses the natural defences that our bodies have against microbial attack in the form of our immune system, and the precautions that human societies put in place to counter the spread of disease in the shape of public health measures. 1.2 The immune system Learning objective By the end of this section, you should be able to: • state that the function of the immune system is to protect the body against pathogens, some toxins and cancer cells. The body’s capacity to protect itself against pathogens, some toxins and cancer cells is achieved by means of the immune system. We have three lines of defence against attack by pathogens. 1. The first line of defence is non-specific - an external barrier of skin and mucous membranes and the secretions that they produce. The skin provides a physical barrier of dry, dead cells and mildly acidic conditions. Areas of the body which © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 3 are not protected by this barrier, such as the eyes and mouth, have secretions in the form of tears and saliva, which contain a variety of antimicrobial enzymes, e.g. lysozyme which degrades bacterial cell walls. 2. The second line of defence is also non-specific, and comes into play when the first line of defence is breached and an intruder, such as a bacterium, gets into the body tissues. The intruder produces chemical signals that are detected by a variety of white blood cells which will attack it in a number of ways, e.g. neutrophils and macrophages which engulf the invading cells, and natural killer cells (NK cells) which release chemicals that cause their death. An area of inflammation indicates that the second line of defence has been deployed. 3. The third line of defence, the specific immune response (to be covered in Topic 2) comes into play at the same time as the second line of defence. Here, the immune system directly targets the invader, which can be any organism or substance that carries foreign molecules. Immunity is the ability of the body to resist or overcome an infection by a pathogen and can be either innate or acquired. Innate immunity is inborn, non-specific, and does not change over time. Examples include: • phagocytosis by phagocytes; • skin epithelial cells; • mucus membranes of the lungs and gut; • ciliated cells of the respiratory tract; • lysozyme in tears. Acquired immunity develops throughout a person’s life time and can be induced either naturally or artificially. It involves another group of white blood cells, lymphocytes, which respond to marker chemicals on the surface of the foreign cells called antigens, producing antibodies against them. A second response is the production of memory cells, which enable the immune system to react more quickly and vigorously to reinfection by pathogens. The immune system: Questions Q1: What is the function of the immune system? .......................................... Q2: List two examples of non-specific first line of defence against diseases. .......................................... Q3: What is the function of the lysozyme in tears? .......................................... Q4: Explain the term ’innate immunity’ and list two examples. .......................................... Q5: What is a phagocyte? .......................................... © H ERIOT-WATT U NIVERSITY Go online 4 TOPIC 1. NON-SPECIFIC DEFENCES 1.3 Non-specific defences - physical and chemical Learning objective By the end of this section, you should be able to: • give examples of the body’s chemical and physical defences against pathogens; • explain that epithelial cells form a physical barrier and produce secretions against infection. You should remember from Unit 1 that epithelial cells provide the inner and outer linings of body cavities, for example the stomach and the urinary tract. They act as the barrier between the external environment and the body tissues. The skin is considered to be the first line of defence for the human body. Its structure ensures that very few microorganisms can penetrate unless it is damaged. In addition, the secretion of antimicrobial chemicals by the skin and tear glands offers additional protection. The outermost part of the skin, or epidermis, is a multilayered tissue. At its base are stem cells which divide to continually replace the layers above it. As they move from the base towards the surface, the cells gradually change their structure to give the epidermis its tough elastic properties. The outer layer consists of dead cells, which are regularly sloughed off as a result of friction with the environment. These are dry and provide an environment which is inhospitable to microbes. Associated with the hair follicles on the skin are the sebaceous glands, which secrete the waxy sebum that keeps the skin supple and contains fatty acids which have antimicrobial properties. Similarly, earwax contains chemicals which inhibit the growth of pathogenic bacteria and fungi. Certain types of epithelial cells secrete fluids that are necessary for processes such as digestion, protection, excretion of waste products and the regulation of the metabolic processes of the body, e.g. the goblet cells which secrete mucus. Epithelial tissues containing goblet cells © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 5 Some epithelial tissues are specialised to secrete specific substances, such as enzymes, hormones and lubricating fluids, to defend against infections. The goblet cells in the trachea secrete mucus which, being a sticky substance, is able to adhere to foreign particles, thus holding them on the surface. This adhesion allows the cilia which line the bronchi to sweep the mucus, with its entrapped particles, up into the pharynx where it is swallowed. Antimicrobial chemicals are also found in the mucus, secreted by the epithelial linings of the respiratory and upper gastrointestinal tracts. The body can also provide other physical and chemical defences: • tiny hairs at the entrance to the nose; • cough and sneeze reflexes; • acid secretions which kill microbes, e.g. stomach; • the so-called ’friendly’ bacteria which are the many harmless microbes normally found on the skin and epithelial linings that are exposed to the external environment - by means of a variety of mechanisms, these microbes can suppress the growth of other potentially more dangerous and harmful ones. Non-specific defences - physical and chemical: Questions Q6: State two ways in which the skin is a physical barrier to microbes. .......................................... Q7: State two ways in which the epithelium presents a chemical barrier to microbes. .......................................... © H ERIOT-WATT U NIVERSITY Go online 6 TOPIC 1. NON-SPECIFIC DEFENCES 1.4 The inflammatory response Learning objective By the end of this section, you should be able to: • state that mast cells release histamine; • explain that histamine causes vasodilation and increases capillary permeability; • state that mast cells also secrete cytokines which act as signalling molecules; • explain that the increased blood flow and the secretion of cytokines lead to: 1.4.1 ◦ accumulation of phagocytes such as macrophages and neutrophils; ◦ delivery of antimicrobial proteins and clotting elements to the site of infection/damage. Inflammation We are all familiar with the reddening which follows the infection of a scratch, bite or sting. However, in medical terms, inflammation is a more complex issue. It is a response of the immune system to an infection or irritation. Some 2000 years ago, inflammation was characterised into: • rubor - redness; • calor - heat; • tumour - swelling; • dolo - pain; • functio laesa, the fifth sign of inflammation, which results in the dysfunction of the organs involved. © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 7 Main events in the inflammatory response Go online 10 min .......................................... 1.4.2 The cellular basis of inflammation The main purpose of the complex inflammatory process is to bring fluids, proteins and cells from the blood to the damaged tissues. It should be remembered that the fluid that bathes the cells of the body’s tissues and organs lacks most of the proteins and cells that are found in the blood because they are not able to pass through the capillary walls. Thus, to combat damage and infections, there must be mechanisms which allow these proteins and cells to move out of the blood circulation and into the surrounding tissue fluid. This process can be broken down into six stages. Stage 1: The action of mast cells Mast cells are found in connective tissue, where they cluster around blood vessels and nerves. They are most common where our tissues meet the outside world, e.g. skin, gut, mouth, eyes and nose. Although they resemble certain white blood cells and, like them, are produced by stem cells in the bone marrow, they are derived from a different cell line. Perhaps best known for mediating allergies, they also play a key role in protection against infection. They are activated by chemicals that are released during an infection or from damaged cells, as a result of which they release histamine in large quantities. © H ERIOT-WATT U NIVERSITY 8 TOPIC 1. NON-SPECIFIC DEFENCES A mast cell Stage 2: Vasodilation and increased capillary permeability Histamine is a small, organic, nitrogenous molecule which has many roles in the body. In the inflammatory response, it stimulates the arterioles of the affected area to dilate, increasing blood flow into the capillary beds, and the walls of the capillaries to become more permeable, allowing plasma, proteins and white blood cells (neutrophils) to pass through. Within minutes of an injury, this is noticeable as a swelling and reddening of the area, and a feeling of heat. Stage 3: Secretion of cytokines The mast cells and the neutrophils also release a type of signalling compound called cytokines. Like histamine, these have a wide range of roles in the body, but in this case they act to attract another type of white blood cell, monocytes, to the area. Stage 4: Phagocytosis Once in the tissue, the neutrophils begin the removal of invading bacteria by phagocytosis. They are soon joined by the monocytes, which mature into macrophages and then clean up the damaged area by engulfing cell debris and bacteria by phagocytosis. After digestion is complete, the identifying surface molecules (antigens) of invading cells are transported to the surface of the macrophages where they assist the other cells of the immune system to develop protection against the invader. The term ’phagocyte’ is used to refer to a general grouping which includes macrophages, neutrophils and mast cells, all of which are capable of phagocytosis, but which differ in other respects. Stage 5: The complement system The complement system is so-called because it helps, and indeed amplifies, the action of the phagocytes in combating infection. It comprises over 25 small proteins found in the blood, which are synthesised by the liver. These remain in an inactive form until stimulated by one of several triggers; in particular the cascade is triggered if cells which lack the surface proteins typical of the body are encountered. © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 9 Activation of the first complement protein leads to activation of the second, which activates the third, and so on, resulting in a cascade effect. These substances have several basic functions, including enhancing phagocytosis, attracting macrophages and neutrophils, and rupturing the membranes of microbes. Stage 6: Clotting elements and the coagulation system The increased permeability of the capillary walls leads to an increased flow of proteins (’clotting elements’) as well as white blood cells into the tissues, and a second cascade system (the ’coagulation system’) becomes active. In the infected tissue, a chemical ’tissue factor’ is released that initiates the cascade which results in the conversion of the soluble protein fibrinogen to insoluble fibrin. The fibrin strands form a web which helps to contain the infection and inflammation. The cellular basis of inflammation: Questions Q8: Where are mast cells found? .......................................... Q9: State two effects of the histamine released by mast cells. .......................................... Q10: Name the chemical signalling molecule which is released by mast cells and neutrophils. .......................................... Q11: Which type of white blood cells are attracted by this chemical? .......................................... Q12: By what process do these cells remove bacteria from the site of infection? .......................................... Q13: Name the cascade system which delivers antimicrobial proteins to the infected site. .......................................... Q14: Name the soluble and insoluble proteins at the end of the coagulation system. .......................................... © H ERIOT-WATT U NIVERSITY Go online 10 TOPIC 1. NON-SPECIFIC DEFENCES 1.5 Non-specific cellular responses Learning objective By the end of this section, you should be able to: • state that the white blood cells involved in the non-specific response are phagocytes and natural killer (NK) cells; • state that phagocytes and NK cells release cytokines; • explain that cytokines stimulate the specific immune response; • state that phagocytes recognise surface antigen molecules on pathogens; • state that phagocytes destroy pathogens by phagocytosis; • explain that phagocytosis is engulfing and digesting solid particles; • state that NK cells induce pathogens to produce self-destructive enzymes; • state that this process of induced self-destruction by enzymes is called apoptosis. The business of defending the body against foreign cells and molecules which have penetrated the first line of defence falls to certain types of white blood cell. In this section, we will consider the non-specific role of two groups: the phagocytes (monocytes and neutrophils) and natural killer (NK) cells. 1.5.1 Phagocytes The name ’phagocyte’ is an umbrella term encompassing several types of white blood cell and mast cells; their common features include their origin in the bone marrow, their ability to move about (motility) and their ability to carry out phagocytosis. © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 11 Phagocytosis: Steps Go online 10 min .......................................... The two most important phagocytes are the white blood cells: neutrophils and monocytes. A question to be asked is how do the phagocytes (and the complement system mentioned earlier) identify bacteria; what makes them stand out from the cells of the body itself? The answer lies in proteins located on the surface of the cell membrane. If a phagocyte encounters a cell which is lacking the protein markers typical of cells belonging to the body, then a response is triggered. Neutrophils Neutrophils make up two thirds of the white blood cells in the blood and are the main cells found in pus. They are attracted to the site of infection by the cytokines released by the damaged cells, arriving in large numbers within minutes. The neutrophils also release cytokines themselves, but their immediate effect is the engulfing of bacteria. Their lifespan is short, being only 5-7 days in the circulation, and 1-2 days at an infection site. This reflects the fact that they cannot replenish the digestive enzymes with which they break down ingested bacteria. © H ERIOT-WATT U NIVERSITY 12 TOPIC 1. NON-SPECIFIC DEFENCES Once they have engulfed bacteria, the neutrophils express signal molecules on their cell membranes which identify them to the larger macrophages, which then consume them in turn. In addition, they secrete antimicrobial chemicals which kill bacteria by disrupting their cell walls. Monocytes Monocytes are the largest of the white blood cells; at up to 20µm they are nearly twice the size of neutrophils. They are much less common than neutrophils, making up only some 5% of the total white blood count. About half of the body’s complement of monocytes is held in reserve in the spleen, the other half circulating in the blood and migrating into the tissues where they mature into macrophages capable of phagocytosis. Attracted by cytokines that are released by neutrophils and damaged cells, additional monocytes migrate from the blood to an infection site and turn into macrophages. They then begin to engulf damaged cells, bacteria and ’old’ neutrophils. Unlike neutrophils, macrophages can live for several months. Also, they express the antigens of ingested bacteria on their outer membranes to help the other white blood cells of the immune system (lymphocytes) identify the invaders and produce specific antibodies to combat them. Phagocytes: Questions Q15: Name the chemical produced by phagocytes and NK cells. Go online .......................................... Q16: What is the function of this chemical? .......................................... Q17: By what do phagocytes recognise pathogens? .......................................... Q18: What is phagocytosis? .......................................... 1.5.2 Natural killer (NK) cells NK cells are attracted to the site of an infection (or a tumour) after about three days by the cytokines released by the damaged cells. They identify infected cells and tumour cells by the presence of certain key surface chemicals and then release two types of enzymes: perforin and a type of protease known as granzyme. The perforin causes pores to develop in the cell membrane of the target cell so that the granzyme can enter the cell and induce programmed cell death (apoptosis). The cell contains apoptosis pathways which allow it to self-destruct by enzyme action and thus be recycled in a controlled way; these pathways are activated by the granzymes and, critically, they also cause the destruction of the viruses in the cell. Like neutrophils, NK cells also secrete antimicrobial chemicals. © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 13 Action of a natural killer cell Apoptosis: Steps Go online 5 min .......................................... Apart from their role in non-specific response, phagocytes and NK cells are also involved in the specific immune response (described later). After their action against invading pathogens, they then secrete interleukin, a cytokine that stimulates the specific immune response by activating T lymphocytes. © H ERIOT-WATT U NIVERSITY 14 TOPIC 1. NON-SPECIFIC DEFENCES Natural killer (NK) cells: Questions Q19: What do the NK cells induce target cells to produce? Go online .......................................... Q20: What is the process of programmed self-destruction in cells called? .......................................... 1.6 Learning points Summary Physical and chemical defences • The function of the immune system is to protect the body against pathogens, some toxins and cancer cells. • Give examples of the body’s chemical and physical defences against pathogens, e.g. sebum secreted onto the skin contains fatty acids with antimicrobial properties; the dry outer layers of the epidermis create an environment hostile to pathogens. The inflammatory response • Mast cells release histamine. • Histamine causes vasodilation and increases capillary permeability. • Mast cells also secrete cytokines which act as signalling molecules. • The increased blood flow and the secretion of cytokines lead to: ◦ ◦ accumulation of phagocytes such as macrophages and neutrophils; delivery of antimicrobial proteins and clotting elements to the site of infection/damage. Non-specific cellular responses • The white blood cells involved in the non-specific response are phagocytes and natural killer (NK) cells. • Phagocytes and NK cells release cytokines. • Cytokines stimulate the specific immune response. • Phagocytes recognise surface antigen molecules on pathogens. • Phagocytes destroy pathogens by phagocytosis. • Phagocytosis is engulfing and digesting solid particles. • NK cells induce pathogens to produce self-destructive enzymes. • The process of induced self-destruction by enzymes is called apoptosis. © H ERIOT-WATT U NIVERSITY TOPIC 1. NON-SPECIFIC DEFENCES 1.7 15 Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of the inflammatory response before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: The inflammatory response Give an account of the inflammatory response. (8 marks) .......................................... 1.8 End of topic test End of Topic 1 test Q21: Complete the sentences by matching the parts on the left and the right. (8 marks) Go online The immune system protects the body against cytokines. Sebum on the skin contains fatty acids with a hostile environment. Pathogens find the dry outer layers of the skin to be histamine. Mast cells release clotting elements. Histamine causes antimicrobial properties. Cytokines act as pathogens. Increased blood flow leads to delivery of signalling molecules. Phagocytes are attracted by vasodilation. .......................................... Q22: Complete the paragraphs by selecting words from the list. (10 marks) response are The white blood cells involved in the ) cells. Both phagocytes and NK cells release killer ( stimulate the specific immune response. and natural which molecules on their Phagocytes target pathogens which they recognise by the and digesting them in a process cell surface. They then destroy them by . called The NK cells release enzymes of the which induce infected cells and pathogens to produce pathways. Word list: antigen, apoptosis, cytokines, engulfing, enzymes, NK, non-specific, phagocytes, phagocytosis, self-destructive. © H ERIOT-WATT U NIVERSITY 16 TOPIC 1. NON-SPECIFIC DEFENCES .......................................... Q23: What is the function of the immune system? (1 mark) .......................................... Q24: State two ways in which the skin prevents infection. (2 marks) .......................................... Q25: Name the cells which release histamine. (1 mark) .......................................... Q26: State the functions of histamine. (2 marks) .......................................... Q27: Name the signalling molecules released by these cells. (1 mark) .......................................... Q28: State the function of the signalling molecules. (1 mark) .......................................... Q29: What is delivered by the increased blood flow to the site of infection? (2 marks) .......................................... Q30: Name the two types of white blood cells involved in the non-specific response. (1 mark) .......................................... Q31: How do phagocytes recognise pathogens? (1 mark) .......................................... Q32: Describe the process of phagocytosis. (1 mark) .......................................... Q33: What do NK cells induce infected cells and pathogens to produce? (1 mark) .......................................... Q34: Name the process of programmed cell death. (1 mark) .......................................... © H ERIOT-WATT U NIVERSITY 17 Topic 2 Specific cellular defences Contents 2.1 Immune surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.2 2.3 Clonal selection theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T- and B-lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 23 2.4 2.5 The action of T-lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . The action of B-lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 27 2.6 2.7 Immunological memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 32 2.8 2.9 Extended response question . . . . . . . . . . . . . . . . . . . . . . . . . . . . End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 34 Learning objectives By the end of this topic, you should be able to: • describe the immune surveillance system in terms of the cells involved and their functions; • explain clonal selection theory and its role in the specific immune response; • describe the functions of T- and B-lymphocytes; • explain the role of immunological memory in the development of immunity. 18 TOPIC 2. SPECIFIC CELLULAR DEFENCES In the previous topic, the body’s general response to invasion by pathogens or other damage was described. This topic deals with the very sophisticated system which allows the body, once it has met a particular pathogen, to respond very promptly and efficiently to a second (or later) invasion by that organism. 2.1 Immune surveillance Learning objective By the end of this section, you should be able to: • describe the role of white blood cells as constantly monitoring the tissues; • explain that pathogens, and other foreign cells or materials, are recognised by their antigens, which are molecules on their surfaces that activate the immune system; • state that cytokines are released when tissues are damaged or invaded; • explain that cytokines attract specific white blood cells (monocytes) to the infected/damaged tissue; • explain that some of these cells absorb pathogens and display fragments of their cell membranes on their surface. The immune system operates by means of the activities of several different types of cell. It responds to the presence of pathogens, and other foreign cells or materials which are recognised by their antigens; that is molecules on their surfaces which activate the immune system. The cells of the non-specific immune response are the mast cells, phagocytes and natural killer (NK) cells, whereas the specific immune response operates by means of the B- and T-lymphocytes. These cells, along with red blood cells (erythrocytes) and platelets (thrombocytes), are all produced by division of the multipotent stem cells in the red bone marrow (the haematopoietic stem cells). A simplified diagram of this family tree is shown below. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES Haematopoiesis The haematopoietic stem cells give rise to two families of cells, namely those formed from the common myeloid progenitor, and those from the common lymphoid progenitor. The myeloid group includes red blood cells (erythrocytes), thrombocytes (platelets), mast cells and the various white blood cells involved in the non-specific response. Cells of the surveillance system The cells involved in the specific immune response, namely the T- and B-lymphocytes, belong to the lymphoid family. An exception is the natural killer (NK) cell which, though belonging to the lymphoid group, acts as part of the non-specific response. The cells associated with the non-specific response provide a surveillance system in the following ways: 1. mast cells are found within the tissues and respond within seconds to damage or infection by releasing histamine; 2. neutrophils, which circulate in the blood, enter the tissues when the histamine released by the mast cells causes increased blood flow to the affected tissue, increasing permeability of the capillary walls - they are attracted to the damaged area by chemical signals released by damaged cells; 3. the mast cells and neutrophils, as well as mopping up damaged cells and invading pathogens by phagocytosis, also release cytokines which attract monocytes to the tissue - these mature into macrophages which engulf damaged cells, pathogens, and any neutrophils which are signalling that they have themselves engulfed pathogens; © H ERIOT-WATT U NIVERSITY 19 20 TOPIC 2. SPECIFIC CELLULAR DEFENCES 4. some of the macrophages present fragments of the cell membrane of engulfed pathogens on their own cell surface - these cells migrate to the lymph nodes where the pathogen fragments, carrying their unique antigens, activate the B- and Tlymphocytes which are stored there. Immune surveillance: Questions Go online Q1: Name the cells of the nonspecific immune system which first respond to infection and are located within the tissues. .......................................... Q2: Name the cells of the nonspecific immune system which first respond to infection and are located in the blood. .......................................... Q3: Name the chemicals which attract monocytes to the damaged tissue. .......................................... Q4: Where are the B- and T-lymphocytes stored? .......................................... Q5: How do some of the cells that monocytes develop into identify pathogens to the specific immune system? .......................................... .......................................... 2.2 Clonal selection theory Learning objective By the end of this section, you should be able to: • state that clonal selection theory explains the way in which lymphocytes are developed to respond to specific antigens which invade the body; • state that lymphocytes have a single type of receptor on the cell membrane which is specific to one antigen; • explain how antigen binding leads to repeated lymphocyte division, which results in a clonal population of lymphocytes. The Theory Clonal Selection Theory was proposed in 1957 by an Australian medical researcher, Frank Macfarlane Burnet, as an answer to the question: how do we account for the immune system’s ability to produce antibodies in response to new antigens? A radical feature of the theory was that the body actually has lymphocytes carrying antibodies for antigens which it has never encountered. Given the vast range of potential © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES 21 antigens that exists, this seems highly improbable. However, subsequent research, most recently into the genes controlling the production of antibodies, has confirmed the validity of Burnet’s concept and, indeed, it underpins our whole understanding of the operation of the adaptive immune system. Several Nobel Prizes have been awarded for research in this field. The steps in the development of lymphocytes which carry receptors specific to one antigen is summarised below. As the process is similar in the B- and T-lymphocytes (covered in the next section), they have not been dealt with separately here. Clonal selection theory: Steps Go online 1. In the red bone marrow, haematopoietic stem cells divide to produce daughter cells. 2. As a result of genetic rearrangement, during differentiation these immature lymphocytes each develop a different antigen receptor on their cell membranes. 3. Those immature lymphocytes which carry a receptor that will bind with an antigen from the body’s own tissues are destroyed in the bone marrow. 4. The lymphocytes carrying other antigen receptors are released from the bone marrow and move through the circulatory system to the lymph glands or thymus gland where they mature into inactive lymphocytes. 5. Most of these inactive lymphocytes will never encounter an antigen to match their receptor. 6. Inactive lymphocytes which do meet an antigen matching their receptor become activated and divide to produce many clones of themselves. .......................................... © H ERIOT-WATT U NIVERSITY 22 TOPIC 2. SPECIFIC CELLULAR DEFENCES Genetic background to antibody variability To understand better how the variability of the receptors (and the antibodies to which they are related) arises, it is necessary to delve a little into the genetic control of antibody production. Antibodies (also known as immunoglobulins) exist in two forms, one which is bound to the outer surface of the cell membrane of lymphocytes, and another which is secreted by these cells and exists as soluble protein in the blood plasma, tissue fluid and lymph. These antibody molecules are made up of four basic polypeptide chains that are coded for by three genes which are located on three different chromosomes. Each of these genes is composed of many segments. In the course of differentiation, these segments are subject to such a degree of alternative splicing during DNA transcription that there are approximately 3 × 10 11 unique potential antibody molecules that could be expressed on the cell membrane. Only one of these would be found on any particular lymphocyte. The development of immunity The receptors on the inactive lymphocytes act like antibodies in that they specifically bind to a single antigen molecule. If this happens, then a series of changes are triggered in the lymphocyte. The combination of gene segments becomes fixed, and only that combination will be used to produce antibodies by that cell and its clones. The activated lymphocyte begins to divide to produce two types of cloned daughter cell: 1. plasma cells, which have extensive folded membrane layers in the cytoplasm that are covered with ribosomes to produce large quantities of the polypeptides which will be formed into antibodies in the Golgi apparatus; 2. memory cells, which remain in the lymph glands ready to be activated by subsequent encounters with the same antigen - during the first exposure to the antigen, e.g. during an infection, these cells undergo a considerable degree of minor mutations and the mutants with the best match of receptor to antigen are maintained, the being remainder destroyed - during a second infection, these cells produce a much more rapid and effective response. Clonal selection theory: Questions Q6: Go online Put the steps from clonal selection theory into the correct order. • Those immature lymphocytes, which carry a receptor that will bind with an antigen from the body’s own tissues, are destroyed in the bone marrow. • As a result of genetic rearrangement, during differentiation these immature lymphocytes each develop a different antigen receptor on their cell membranes. • Inactive lymphocytes, which do meet an antigen matching their receptor, become activated and divide to produce many clones of themselves. • Most of these inactive lymphocytes will never encounter an antigen to match their receptor. • In the red bone marrow, haematopoietic stem cells divide to produce daughter cells. • The lymphocytes that carry other antigen receptors are released from the bone marrow and move through the circulatory system to the lymph glands or thymus gland where they mature into inactive lymphocytes. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES 23 .......................................... Q7: What does clonal selection theory explain? .......................................... Q8: To how many different types of antigen do the receptors on each lymphocyte respond? .......................................... .......................................... 2.3 T- and B-lymphocytes Learning objective By the end of this section, you should be able to: • state that lymphocytes respond specifically to antigens on foreign cells, cells infected by pathogens and toxins released by pathogens; • state that T-lymphocytes have specific surface proteins that allow them to distinguish between the surface molecules of the body’s own cells and cells with foreign molecules on their surface; • explain that autoimmune diseases arise as a result of a failure of immune system regulation, leading to a response by T-lymphocytes to self antigens; • state that activated B-lymphocytes secrete antibodies into the blood and lymph; • explain that allergies are a hypersensitive B-lymphocyte response to an antigen that is normally harmless. Distinguishing ’self-’ from ’non-self’ antigens As was described in Section 2.1, T- and B-lymphocytes are produced by the haematopoietic stem cells in the red bone marrow and they belong to the lymphoid group of cells. Both have the ability to respond to specific antigens, which may be: part of foreign cells; attached to the surface of cells which are infected by pathogens; or toxins (biologically produced poisons). This response to specific antigens is achieved by the cells having receptor proteins on their cell membranes which are only capable of binding with that antigen. Given that lymphocytes which carry receptors for the body’s own (’self’) antigens are eliminated before they can leave the bone marrow, this enables the lymphocytes collectively to distinguish between the foreign (’non-self’) antigens and those of the body’s own cells. The mechanism of antigen binding and the subsequent response of the cell are the main differences between actions of the T- and B-lymphocytes. Once released from the bone marrow, T- and B-lymphocytes differ in the locations where they mature. For T-lymphocytes it is the thymus gland which is found in front of the heart underneath the sternum (breast bone); for B-lymphocytes it is small patches of cells in © H ERIOT-WATT U NIVERSITY 24 TOPIC 2. SPECIFIC CELLULAR DEFENCES the extensive network of lymph glands associated with the intestine. Once mature, the lymphocytes may be found throughout the body, but in particular they locate in the lymph glands and the spleen, where they can readily detect foreign antigens in the lymph and blood which are filtered through these organs. Autoimmune disease An autoimmune disease is a disorder in which the immune system is triggered by one or more of the body’s own self antigens. What causes the immune system to no longer distinguish between self and non-self antigens is unknown. One suggestion is that some microorganisms (such as bacteria or viruses) or drugs may induce some of these changes, especially in people who are genetically predisposed to develop autoimmune disorders. More than eighty such diseases have been identified and T-lymphocytes are principally involved, although some disorders are caused by B-lymphocytes. Examples include Celiac disease, Multiple sclerosis, Rheumatoid arthritis, and Type-1 diabetes. Treatment is dependent on the nature of the disease: Type-1 diabetes is addressed by the injection of the missing hormone (insulin); others may be controlled by reducing the immune system’s response with immunosuppressive drugs. Allergy Allergies are very common. According to Allergy UK, one in four people in the UK suffers from an allergy at some point in their lives. The numbers are increasing every year and up to half of those affected are children. Common allergies include hay fever and eczema although, strictly, these are symptoms of an allergy to grass pollen and a substance such as latex. The most severe allergies cause anaphylactic shock, which can be rapidly fatal; although most often associated with foods, such as peanuts, or insect stings, anaphylaxis can be caused in those who are susceptible by almost any foreign substance. An allergy is an immune response to substances in the environment that are usually not harmful. The causes of allergies are both genetic and environmental. Not only has the immune system to separate self from non-self antigens, but it must not initiate a response to antigens from harmless sources such as food or pollen. For most substances this works perfectly, but, occasionally, instead of ignoring a harmless antigen, the B-lymphocytes respond to an otherwise harmless antigen and set the immune response in motion. When a person first encounters an antigen to which they are genetically susceptible, the cells that react in this sensitising exposure are B-lymphocytes. These secrete the antibody IgE (immunoglobulin E) which attaches to mast cells and activates them. A second exposure to this antigen causes the mast cells to release large quantities of histamine and cytokines which, in turn, cause symptoms such the swelling of the tissues, irritation of the eyes and nose, and, in the most severe cases, the loss of blood pressure which is known as shock. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES 25 Mast cells: Steps Go online 1. The first time an allergy-prone person encounters an allergen such as ragweed. . . 2. . . .he or she makes large amounts of ragweed IgE antibody. 3. These IgE molecules attach themselves to mast cells. 4. The second time that person has a brush with ragweed the IgE-primed mast cells release granules and powerful chemical mediators, such as histamine and cytokines. 5. These chemical mediators cause the characteristic symptoms of allergy. .......................................... T- and B-lymphocytes: Questions Q9: What substances trigger the immune response? .......................................... Q10: How do T-lymphocytes distinguish between self and non-self antigens? .......................................... Q11: What causes an autoimmune disease? .......................................... © H ERIOT-WATT U NIVERSITY Go online 26 TOPIC 2. SPECIFIC CELLULAR DEFENCES Q12: State the reaction of B-lymphocytes to being activated. .......................................... Q13: What causes an allergy? .......................................... 2.4 The action of T-lymphocytes Learning objective By the end of this section, you should be able to: • state that one group of T-lymphocytes destroys infected cells by inducing apoptosis; • state that another group of T-lymphocytes secrete cytokines that activate Blymphocytes and phagocytes; • explain that, when pathogens infect tissue, some phagocytes capture the pathogen and display fragments of its antigens on their surface; • explain that these antigen-presenting cells activate the production of a clone of T-lymphocytes that move to the site of infection under the direction of cytokines. T-lymphocytes, of which there are several types, are so-called because they mature in the thymus gland (and the tonsils). T-lymphocytes (along with phagocytes) are responsible for the cell-mediated response of the adaptive immune system. Two of these types are described here. Cytotoxic T cells Also known as Killer T cells, Cytotoxic T cells carry protein receptors on their cell membrane like all T cells. This allows them to recognise specific antigens when they come into contact with them on the surface of pathogens or cancer cells. Once attached to the target cell, they use an enzyme to perforate the wall of the cell and then inject other enzymes which induce the cell to undergo apoptosis (programmed cell death). Helper T cells As their name implies, these cells assist other white blood cells, e.g. by inducing the maturation of B-lymphocytes into plasma cells and memory B cells, and the activation of cytotoxic T cells and macrophages. Their receptors only detect antigens when they are expressed on the surface of antigen-presenting cells (APCs) such as macrophages, certain B-lymphocytes, and dendritic cells (another white blood cell type formed in haematopoietic stem cells of the red bone marrow). These APCs either engulf and digest pathogens, or they absorb the antigens which are attached to their receptors, and then display the antigens on their cell surface. Once activated, the Helper T cells divide rapidly, and then secrete the cytokines which activate B-lymphocytes and direct them along with macrophages to the site of the infection. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES 27 The action of T-lymphocytes: Questions Q14: What do Cytotoxic T Cells induce to destroy pathogens? .......................................... Go online Q15: How do antigen-presenting cells acquire the antigens which they present? .......................................... Q16: What do Helper T Cells secrete to activate B-lymphocytes? .......................................... Q17: What activates Helper T cells? .......................................... 2.5 The action of B-lymphocytes Learning objective By the end of this section, you should be able to: • explain that B-lymphocytes are activated by antigen-presenting cells or Tlymphocytes; • explain that these activated cells divide repeatedly to produce a clone of Blymphocytes that secrete antibodies into the lymph and blood, through which they make their way to the infected area; • state that each B-lymphocyte clone produces a specific antibody molecule that will recognise a specific antigen surface molecule on a pathogen or a toxin; • explain that antigen-antibody complexes may inactivate a pathogen or toxin, or render it more susceptible to phagocytosis; • state that in other cases the antigen-antibody complex stimulates a response which results in cell lysis. The activation of B-lymphocytes B-lymphocytes may be activated in two ways. Antigen-presenting cells, such as macrophages which have engulfed pathogens, migrate from the site of infection to the lymph nodes, where they display the antigens of the pathogen on their cell membrane. These are transferred directly to the B-lymphocytes there which carry the receptor for that antigen, so activating them. Alternatively (and more frequently), T-lymphocytes which have come into contact with the pathogens carry the foreign antigens, in combination with carrier molecules on their cell surface, to the B-lymphocytes in the lymph nodes. These antigens are likewise transferred to the receptors of the B-cells and activate them. © H ERIOT-WATT U NIVERSITY 28 TOPIC 2. SPECIFIC CELLULAR DEFENCES The production of antibodies B-lymphocytes are responsible for the humoral response of the adaptive immune system. Their principal function is to produce antibodies specific to particular antigens, although some also act as antigen-presenting cells and develop into memory B cells. Antigens may either be proteins on the surface of pathogens or toxins. When activated by an antigen binding to their specific receptors, B-lymphocytes divide repeatedly by mitosis to form a clone of plasma cells. These clones are identical to the parent cells, and so all produce and release large quantities of the antibody which is specific to the antigen responsible for the initial activation. The action of antibodies Antibodies (also known as immunoglobulins) are large Y-shaped protein molecules which are released into the blood, tissue fluid or lymph. If they encounter their target antigen, they bind to it, forming an antigen-antibody complex. What follows depends on the actual antigens and pathogens involved: 1. the antibodies cluster around viruses, blocking the sites at which they bind to their host cells - in a similar fashion, antibodies may bind with bacterial toxins so rendering them harmless and identifying them to macrophages; 2. antibodies binding to the surface of bacteria may also cause them to cluster together (agglutinate); 3. some antigens are soluble and circulate in the plasma and lymph - antibodies cause these to precipitate; 4. macrophages patrolling the tissues will be attracted to pathogens and antigens which are identified by the antibodies attached to their surfaces, and remove them by phagocytosis; 5. as mentioned in an earlier section, the complement system involves over twenty plasma proteins which act in a cascade to bring about several actions as part of the innate immune system. However, the complement systems is also activated by the binding of antibodies to the antigens of pathogens and other foreign cells (e.g. red blood cells of a different blood group to the host). In this case, their effect is to create pores lined with complement proteins in the pathogen’s cell membrane (known as the ’membrane attack complex’), through which fluid floods into the cell causing its lysis. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES 29 Inflammatory response The action of B-lymphocytes: Questions Q18: Which cells activate B-lymphocytes? .......................................... Q19: Explain what a clone is. .......................................... Q20: When activated, what do B-lymphocytes release? .......................................... Q21: Explain what is meant by the term ’specific’ in relation to antibodies. .......................................... Q22: When an antibody attaches to an antigen, what is formed? .......................................... Q23: How do antibodies de-activate viruses? .......................................... Q24: How do antibodies prepare bacteria for phagocytosis? .......................................... Q25: Explain how antibodies cause the lysis of pathogen cells. .......................................... © H ERIOT-WATT U NIVERSITY Go online 30 TOPIC 2. SPECIFIC CELLULAR DEFENCES 2.6 Immunological memory Learning objective By the end of this section, you should be able to: • state the some of the cells produced when lymphocytes are activated survive long-term as memory cells; • explain that a second exposure to the same antigen stimulates these memory cells rapidly to divide and produce a new clone of lymphocytes; • state that these new cloned lymphocytes produce a secondary response which is much more rapid and greater in terms of antibody production. So far, this topic has described the very efficient way in which the body reacts to invasion by pathogens and foreign antigens. However, the cleverest part of the story remains to be told: once it has met a particular pathogen or antigen, the immune system is able to remember the foreign antigen signature so that, in any future exposure to that antigen, it can respond so quickly and effectively that the infection is stopped before it can begin. The formation of memory cells When an inactive lymphocyte meets the antigen which matches its receptors, it is activated into rapid cell division. Most of these cloned cells will move to another part of the lymph glands (as plasma cells in the case of B-lymphocytes) or to the site of the infection (in the case of T-lymphocytes). A proportion remain behind in the original areas of the lymph nodes where they undergo a selection process which weeds out the cells with the least effective antibodies in terms of fitting the antigen. As a result, by the time the initial infection is brought under control, the antibodies being produced are much more effective than those first released. These memory cells are long-lived, and their numbers increase at each re-exposure to the antigen until an optimum level is reached. Both B- and T-lymphocyte memory cells are found not only in the lymph nodes, but in the spleen as well where blood is filtered and so can be monitored. In addition, there are T-lymphocyte memory cells which circulate in the blood and so are in constant contact with the tissues. The secondary response When a particular antigen invades the body a second time, the memory cells are activated very quickly, dividing to form plasma cells and more memory cells, which are again subject to selection for most effective antibody production. In consequence, the secondary response is much quicker than the primary response and involves much higher concentrations of (more effective) antibodies. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES 31 Primary and secondary immune responses A concurrent infection involving a different antigen will not be met with this rapid and massive production of antibodies. This is because of the specific nature of the antibody response; it only responds to the antigen which activated it. Other antigens have to start at the beginning of the process. Immunological memory: Questions Q26: What is the source of lymphocyte memory cells? .......................................... Q27: State the effect that a second exposure to an antigen has on lymphocyte memory cells. .......................................... Q28: How does the secondary immune response differ from the primary response? .......................................... © H ERIOT-WATT U NIVERSITY Go online 32 TOPIC 2. SPECIFIC CELLULAR DEFENCES 2.7 Learning points Summary Immune surveillance • The role of white blood cells as constantly monitoring the tissues. • Pathogens, and other foreign cells or materials, are recognised by their antigens - molecules on their surfaces that activate the immune system. • Cytokines are released when tissues are damaged or invaded. • Cytokines attract specific infected/damaged tissue. • Some of these cells absorb pathogens and display fragments of their cell membranes on their surface. white blood cells (monocytes) to the Clonal selection theory • Clonal selection theory explains the way in which lymphocytes are developed to respond to specific antigens which invade the body. • Lymphocytes have a single type of receptor on the cell membrane which is specific to one antigen. • Antigen binding leads to repeated lymphocyte division, which results in a clonal population of lymphocytes. T- and B-lymphocytes • Lymphocytes respond specifically to antigens on foreign cells, cells infected by pathogens and toxins released by pathogens. • T-lymphocytes have specific surface proteins that allow them to distinguish between the surface molecules of the body’s own cells and cells with foreign molecules on their surface. • Autoimmune diseases arise as a result of a failure of immune system regulation, leading to a response by T-lymphocytes to self antigens. • Activated B-lymphocytes secrete antibodies into the blood and lymph. • Allergies are a hypersensitive B-lymphocyte response to an antigen that is normally harmless. T-lymphocytes • One group of T-lymphocytes destroys infected cells by inducing apoptosis. • Another group of T-lymphocytes secrete cytokines that activate Blymphocytes and phagocytes. • When pathogens infect tissue, some phagocytes capture the pathogen and display fragments of its antigens on their surface. © H ERIOT-WATT U NIVERSITY TOPIC 2. SPECIFIC CELLULAR DEFENCES Summary continued • These antigen-presenting cells activate the production of a clone of Tlymphocytes that move to the site of infection under the direction of cytokines. B-lymphocytes • B-lymphocytes are activated by antigen-presenting cells or T-lymphocytes. • These activated cells divide repeatedly to produce a clone of B-lymphocytes that secrete antibodies into the lymph and blood, through which they make their way to the infected area. • Each B-lymphocyte clone produces a specific antibody molecule that will recognise a specific antigen surface molecule on a pathogen or a toxin. • Antigen-antibody complexes may inactivate a pathogen or toxin, or render it more susceptible to phagocytosis. • In other cases the antigen-antibody complex stimulates a response which results in cell lysis. Immunological memory 2.8 • Some of the cells produced when lymphocytes are activated survive longterm as memory cells. • A second exposure to the same antigen stimulates these memory cells rapidly to divide and produce a new clone of lymphocytes. • These new cloned lymphocytes produce a secondary response which is much more rapid and greater in terms of antibody production. Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of clonal selection theory before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Clonal selection theory Give an account of clonal selection theory. (6 marks) .......................................... © H ERIOT-WATT U NIVERSITY 33 34 TOPIC 2. SPECIFIC CELLULAR DEFENCES 2.9 End of topic test End of Topic 2 test Q29: Match the phrases on the left with the words and phrases on the right. (8 marks) Go online Constantly monitoring the tissues: autoimmune. Identify pathogens to the immune system: monocytes. Released by damaged cells: receptors. Attracted to infected tissues: specific. Located on the cell membrane of lymphocytes: allergic. Receptor only binds to one antigen: white blood cells. A response by T-lymphocytes to the body’s own antigens: cytokines. antigens. A hypersensitive response by B-lymphocytes: .......................................... Q30: Complete the sentences by matching the parts on the left and the right. (7 marks) T-lymphocytes destroy infected cells by inducing T-lymphocytes. T-lymphocytes secrete cytokines that activate a clone of T-lymphocytes. Antigen-presenting cells activate the production of an antigen-antibody complex. B-lymphocytes are activated by antigen-presenting phagocytosis. Each B-lymphocyte clone produces B-lymphocytes. Antigen-antibody complexes render pathogens susceptible to apoptosis. a specific antibody molecule. .......................................... Cell lysis is a response stimulated by Q31: Explain how T-lymphocytes identify pathogens. (2 marks) .......................................... Q32: Describe what happens after B-lymphocytes are activated. (2 marks) .......................................... Q33: Explain why the secondary response to a pathogen is more effective than the primary response. (2 marks) .......................................... © H ERIOT-WATT U NIVERSITY 35 Topic 3 The transmission and control of infectious diseases Contents 3.1 Infectious diseases caused by pathogens . . . . . . . . . . . . . . . . . . . . . 36 3.2 3.3 Methods of transmission of pathogens . . . . . . . . . . . . . . . . . . . . . . Control of spread of pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . 42 44 3.4 Epidemiological studies of infectious diseases . . . . . . . . . . . . . . . . . . 3.4.1 Epidemiology and the spread of disease . . . . . . . . . . . . . . . . . . 49 49 3.5 3.4.2 Control measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 53 3.6 3.7 Extended response question . . . . . . . . . . . . . . . . . . . . . . . . . . . . End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 54 Learning objectives By the end of this topic, you should be able to: • describe the nature of pathogens and disease; • describe the ways in which pathogens may be transmitted; • describe the methods by which the spread of pathogens may be controlled; • list the different degrees of spread of infectious diseases; • explain the measures which can be taken to control the spread of a disease within a population. 36 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES In the previous topics of this unit, the body’s immune defences, both specific and nonspecific, were described. In this topic, the focus is on the ways in which diseases spread through populations and the means by which they may be controlled. 3.1 Infectious diseases caused by pathogens Learning objective By the end of this section, you should be able to: • list the types of infectious agent that cause disease; • name an example of a disease caused by each type of pathogen. Pathogen is a very broad term which encompasses anything that can produce disease in its host. It is generally used to refer to some sort of micro-organism, and includes viruses, bacteria, fungi, protozoans, and even the misfolded proteins that are prions. Excluded are carcinogens, for example blue asbsestos (crocodilite), and neurotoxins, such as that produced by the bacterium Clostridium botulinum. Pathogens are, of course, just trying to make a living like any other organism; the problem lies in that they use us as their habitat and source of nutrition, causing our bodies damage in the process. It should be remembered that on our body surfaces, in our intestinal tract, and within our tissues we harbour huge numbers of micro-organisms which do us no harm or, indeed, are extremely beneficial to us. The term disease also needs definition as a condition in which the body malfunctions in some way; in this topic, we are concerned only with diseases which are caused by pathogens, rather than inherited, psychological or deficiency diseases. New diseases are discovered every year, with more than 30 being described in the last 20 years. Estimates of the total number of human diseases vary considerably, although something in excess of 30,000 is a common suggestion. © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Viruses Bird flu virus http://blog.patentology.com.au/2011/11/shades-of-gray-as-dispute-over.html (https://pl us.google.com/116299882295651429004/about) / http://creativecommons.org/licenses /by-nc-sa/3.0/au/ Most viruses have a diameter of between 20 and 300nm (nanometres, 10 -9 m). All consist of a protein coat containing a molecule of nucleic acid (RNA or, more rarely, DNA), but they lack any other cellular organelles and are consequently dependent on other cells for their reproduction. They are found in all other life-forms. Diseases caused by viruses range in severity from mild infections such as the common cold and herpes (cold-sores) to those with very high mortality rates such as smallpox and ebola. © H ERIOT-WATT U NIVERSITY 37 38 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Bacteria Escherichia coli A bacterium is typically between 0.5 and 5.0µm (micrometres, 10 -6 m) in length. They have a cell membrane inside a cell wall, but lack any membrane-enclosed organelles such as a nucleus. However, their cytoplasm is organised by a cytoskeleton of structural proteins and contains ribosomes. Their genes are carried on a single circular chromosome of DNA, and on smaller DNA plasmids. Diseases caused by bacteria include tetanus, typhoid fever, diphtheria, syphilis, cholera, salmonella, pneumonia, meningitis and tuberculosis. © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Fungi Athlete’s foot fungus in lab culture (http://commons.wikimedia.org/wiki/Category:Athlete%27s_foot#mediaviewer/File:Athl ete%27s_Foot_Fungus_microscope.jpg by Ecorahul, licensed under http://creativecom mons.org/licenses/by-sa/3.0 via http://commons.wikimedia.org/) Comprised of a cell wall made of chitin (the same protein as makes up insect exoskeletons), cytoplasm with organelles, and a nucleus with chromosomes, most fungi exist as long filaments of cells called hyphae which are typically 5µm wide; some are found as single cells (e.g. yeast). Relatively few fungi cause diseases in humans, but they can lead to serious complications in certain situations. Those that people are most likely to be familiar with are the mild, if annoying, infections such as athlete’s foot and thrush. However, the latter shows just how these microbes can cause serious problems if they gain entry to the deeper body tissues. If the Candida yeast (which causes thrush) invades the tissues after a transplant operation for which the patient’s immune system has been suppressed, the result can be systemic candidiasis, which has a mortality rate of up to 50%. © H ERIOT-WATT U NIVERSITY 39 40 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Protozoans Plasmodium, (about 12µm long) the protozoan causing malaria, among host’s red blood cells In many ways, the members of this very diverse group of organisms resemble free-living animal cells, in that they have a cell membrane, nucleus and organelles. Diseases caused by protozoans include: several involving insect vectors as alternate hosts, e.g. malaria, Chagas disease, sleeping sickness; toxoplasmosis, with cats as an alternate host; and amoebic dysentery, which is spread through faecal contamination of food or water. © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 41 Prions Cow brain tissue, showing the microscopic holes typical of bovine spongiform encephalopathy (BSE) Prions are not organisms but a type of misfolded protein which appear to be passed from host to host by consumption of infected tissue. They are thought to cause protein to alter and accumulate in the host’s brain and other neural tissue, a change which is untreatable and ultimately fatal. Examples are kuru and Creuztfeldt-Jakob Disease (CJD). Their size is a matter of speculation, but one estimate is about 10nm. Infectious diseases caused by pathogens: Question Q1: Complete the following table to show the types of organism that are pathogens and examples of the infectious diseases which they cause. Type of pathogen Example of disease Pathogens and diseases: bacteria, candidiasis, CJD, fungi, herpes, malaria, pneumonia, prion, protozoa, virus. .......................................... © H ERIOT-WATT U NIVERSITY Go online 42 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 3.2 Methods of transmission of pathogens Learning objective By the end of this section, you should be able to: • explain that pathogens may be transmitted by direct physical contact, water, food, body fluids, inhaled air or vector organisms. Pathogens which cause infectious diseases are very sensitive to their environments. They only have the ability to survive and multiply if there is the availability of correct nutrients and the right environmental conditions. Some microbes such as bacteria, for example, require an optimum temperature range (20 to 40 ◦ C), sufficient moisture, correct pH and oxygen levels. However, some bacterial spores can survive extreme environmental conditions. The transmission of an infectious disease is the passing on of a pathogen from an infected host individual to another individual by one or more of the following methods: • physical contact (contagious diseases) ◦ direct physical contact takes place by touch, like a handshake or sexual contact - even though the skin is host to many microbes, the majority of these are benign unless they gain access to the internal organs; the most common bacteria found on the skin that can cause infection are Staphalococcus and Streptococcus, and the most notorious is methycillinresistant Staphalococcus aureus (MRSA); ◦ indirect physical contact usually takes place by touching contaminated surfaces, like a door handle or floor - free living microbes, such as bacteria and fungi, can survive on non-living objects longer than viruses; Rhinoviruses (cold) and gastroenteritis can be spread in this manner, as can some pathogenic fungi such as the Trychophyton species which cause athlete’s foot • water-borne diseases are most often spread via drinking water that has been contaminated with human or animal faeces; this is the faecal-oral infection route - in Economically Less Developed Countries, four-fifths of all the illnesses are caused by water-borne pathogens, with diarrhoea caused by cholera or dysentery being the leading cause of child mortality; • food-borne diseases, of which there are over 250, are caused by a variety of bacteria, viruses, and parasites - they usually result from poor personal hygiene, poor hygiene in food preparation, or in the food material supply chain; diseases caused by food-borne organisms include: cholera, rotavirus, shigellosis (bacillary dysentery), typhoid fever, hepatitis A and hepatitis E; • body fluids - a healthy person who gets infected mucus into their eyes, nose, or mouth can become infected with certain diseases that are spread in the blood or which grow in the flesh around a wound where the body may produce pus (a viscous, yellowish-white fluid that is formed in infected tissues mainly from white blood cells), e.g. hepatitis (in its several forms); some diseases are caused by microbes which are carried in the fluids exchanged during sexual © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 43 relations, e.g. HIV (human immunodeficiency virus) which causes AIDS (acquired immunodeficiency syndrome); • air-borne transmission occurs when microbes are attached to droplets of moisture in the air (e.g. from a sneeze) or to dust particles that are inhaled - such microbes can travel long distances before they are inhaled by other people, e.g. the measles virus, bacteria such as Mycobacterium tuberculosis (TB), and Bacillus anthracis (anthrax); • vector organisms provide a pathway for a pathogen to be transmitted between animals and humans or other animals, with some vector organisms providing this transport by blood-sucking - the vectors are largely unaffected by the pathogen, thus allowing for the successful transport of the disease. According to WHO, the most deadly vector-borne disease is Malaria, killing over 1.2 million people annually, mostly African children under the age of five. Another vector-borne disease is dengue fever (DF), a viral disease also spread by mosquitoes. Together with associated dengue haemorrhagic fever (DHF), DF is the world’s fastest growing vector-borne disease. In Britain, Lyme disease is of increasing concern; it is caused by bacteria of the Borelia genus and is spread by ticks when they take a blood meal on a human, dog, or other mammals such as deer. Methods of transmission of pathogens: Question Q2: Complete the following table to show the types of organism that are pathogens and examples of the infectious diseases which they cause. Method of transmission Example of disease Methods of transmission and diseases: body fluids, dengue fever, direct physical contact, dysentery, food, gastroenteritis, HIV, indirect physical contact, inhaled air, measles, MRSA, typhoid, vectors, water. .......................................... © H ERIOT-WATT U NIVERSITY Go online 44 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 3.3 Control of spread of pathogens Learning objective By the end of this section, you should be able to: • state that the spread of pathogens can be controlled by quarantine and antisepsis; • explain the role of individual responsibility by means of good hygiene, care in sexual health, and appropriate storage/handling of food; • describe the role of community responsibility by means of quality of water supply, safe food webs, and appropriate waste disposal systems; • explain the role of vector control in reducing the spread of pathogens. Quarantine Quarantine controls the spread of an infectious disease by keeping potentially infected individuals, i.e. those who may have been exposed to the disease, apart from the remainder of the population. Persons who are known to be ill with a contagious disease are isolated from all others. The Apollo 11 astronauts are quarantined following their return to Earth © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES During the global outbreak of SARS (severe acute respiratory syndrome) in 2003, public health officials introduced measures aimed at controlling its spread in affected areas. Initially, this was done by alerting health-care providers and providing them with diagnostic protocols. Many of the SARS cases were quickly identified. However, it was soon recognised that the disease had spread at a much greater rate than was initially thought. As a result, several countries/regions introduced the use of mass quarantine for all individuals suspected of having had contact with a confirmed SARS case. These coordinated global efforts were remarkably effective in controlling the spread of SARS and, to date, the disease has not made a significant re-emergence. Modern quarantine lasts only as long as necessary to protect the public by providing health care, such as immunisation or drug treatment. Nowadays, quarantine is more likely to involve limited numbers of exposed persons in small areas rather large numbers in whole neighbourhoods or cities. Antisepsis Antiseptics are chemicals which are applied to skin or living tissue to reduce the possibility of transmission of pathogens, and to counter the infection of healthy tissue, or the decomposition of dead or damaged tissue. They act against microbes by disrupting cell structures including: cell wall/membrane, internal membranes, protein structures, DNA and RNA. In so doing, antiseptics also either kill the pathogens or inhibit their growth and reproduction. Hand washing is at once the simplest and yet one of the most effective techniques. Decontamination of the hands can be achieved either with plain soap and water, or by use of an antiseptic hand gel. The use of soap is important as it helps lipids dissolve and so dislodges bacteria held in natural skin oils. Although it does not counter the spread of droplet-borne infections, hand washing is very effective against pathogens spread by the faecal-oral route. Therefore, hand washing is very important after using the toilet, touching raw food, changing a baby’s nappies, cleaning up after a pet, or removing rubbish bins. Disinfectants are also antimicrobial agents which work by destroying the cell wall of pathogens or by interfering with their metabolism. They are used on non-living surfaces such as food preparation areas in the domestic kitchen or commercial premises such as butcher’s shops, restaurants, and of course in hospitals. Individual responsibility An individual’s personal behaviour can have a considerable impact on the control and prevention of the spread of disease. This applies not just to the health of their own immediate household, but collectively it contributes greatly to community health. Emphasis should be placed on an individual’s responsibility to: • provide good hygiene both personally and within the home; • be sensitive to oneself and to others in matters of sexual health; • take care over the appropriate handling and storage of food. © H ERIOT-WATT U NIVERSITY 45 46 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Community responsibility Once humans ceased to be hunter-gatherers and started to live in groups larger than a family, there had to be a division of labour, and we began to depend on the others in the community to carry out certain key tasks for us. Today, few of us kill and butcher our own meat, or have our own private water supply. In Britain we expect our rubbish to be collected and only country-dwellers rely on a septic tank to process their sewage. The most fundamental of community responsibilities is the provision of clean, safe (potable) drinking water. This can only be assured if contamination by sewage is prevented by ensuring that waste water and drinking water cannot mix. To achieve this, we have sewerage systems to remove waste water and our drinking water is taken from (relatively) uncontaminated sources, filtered, purified to remove dangerous chemicals, and disinfected to eliminate most bacteria. It is interesting that in Britain we wash our cars, water the garden and flush our toilets with water of drinking quality when potable water is a scarce and valuable resource to much of the world’s population. Waste water treatment works The other side of the coin to the provision of potable water is the provision of effective sanitation. This requires not just the clear separation of sewage from drinking water, but the disposal of sewage in such way that it cannot contaminate cooking, washing or bathing water, or indeed the water children swim in. We should remember that only fifty years ago, Scottish coastal towns were still pouring raw sewage straight into the sea, often close to bathing beaches. Over one-third of the world’s population, nearly 2.5 billion people, have inadequate access to sanitation, and over one billion people do not have access to enough safe water. These conditions, combined with poor hygiene, are largely responsible for the fact that there are globally between 1.7 and 5 billion cases of diarrhoea annually (e.g. typhoid, cholera, dysentery). Of those affected, about three million die each year. © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Community responsibility can reduce the number of cases of diseases, and actions may include: • access to safe drinking water; • improved sanitation; • supervision of food chains, by insisting on minimum standards of hygiene, e.g. in abattoirs, restaurants, fast-food outlets, supermarkets, market stalls; • health education of all age-groups, especially children, parents and the elderly. Control of vectors Most vector organisms are blood-sucking arthropods, particularly insects and arachnids (ticks). The relationship between the pathogen and its hosts is one that has evolved over a long time because the pathogens can often only complete their life cycle if they have access to a different host species at each stage. On a global scale, the Anopheles mosquitoes which spread malaria are the most important insect vectors. They carry the Plasmodium protozoan, which passes part of its life-cycle in the mosquito as its primary host, but must then be transferred to a mammal such as a human as a secondary host to complete its life cycle. For the disease to spread, the pathogen must be again taken into a mosquito in a blood meal. Female Anopheles mosquito feeding The most effective way to combat the disease is to limit the available habitat for the larval stages of the mosquito, which means removing the stagnant water in which the eggs are laid, for example that collected in old tyres. Other techniques include: the sterile male technique, in which large quantities of laboratory-bred sterile male mosquitoes are released, and the introduction of fish which eat the mosquito larvae. In Britain, five species of Anopheles are found (three in Scotland), but since most of the marshland in the country has long since been drained, malaria died out several centuries ago. © H ERIOT-WATT U NIVERSITY 47 48 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Insecticides have also been used, but as with antibiotics, over-use and misuse have led to the development of resistant varieties. In Scotland, Ixodes ricinus (sheep tick) spreads Borrelia bacteria which cause Lyme disease. The bacteria are passed between the tick and two types of mammal host. Unlike the mosquitoes, where only mature females take a blood meal, all ticks of all sizes feed on blood. Sheep ticks mating (the larger size of the female gives an idea of the size that a male would grow to after feeding) In the earliest stages of the life cycle, ticks prefer mice as their hosts (although they will attach to any available food source), and can only pick up Borrelia from them. In the final stage, ticks prefer large mammals, such as deer, foxes or sheep (or humans), to whom they can transfer the bacteria, but from whom none of the stages can get the bacteria. In the context of the increasing occurrence of large wild mammals in and around urban areas, and the growing use of forests for recreation, ticks pose a serious health risk which is not widely appreciated. The obvious vector control measure of severely reducing deer and fox populations is likely to be controversial. Control of spread of pathogens: Questions Q3: Go online Describe how the spread of pathogens is controlled by quarantine. .......................................... Q4: Describe how the spread of pathogens is controlled by antisepsis. .......................................... Q5: List the ways in which individuals should take responsibility for the control of the spread of pathogens. © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 49 .......................................... Q6: State the areas of control of pathogens that are the responsibility of communities in More Economically Developed Countries. .......................................... Q7: Explain the role of vector control in reducing the spread of pathogens. .......................................... 3.4 Epidemiological studies of infectious diseases Learning objective By the end of this section, you should be able to: • state that epidemiology is the study of the causes and patterns of spread of disease; • describe the patterns of disease spread as: • 3.4.1 ◦ sporadic (occasional occurrence); ◦ endemic (regular cases occurring in an area); ◦ epidemic (unusually high number of cases in an area); ◦ pandemic (a global epidemic). describe control measures to include preventing transmission, drug therapy, immunisation or a combination of these. Epidemiology and the spread of disease Epidemiology is the study of the causes and patterns of spread of disease. As such, it underpins public health decisions, provides the foundation for the development of policy and the direction of research. At different times and places, diseases show different patterns of spread. Sporadic In an age of global travel, it is inevitable that an infected person will arrive in a country and develop a disease which is not normally present in that area. If the local population are mostly vaccinated against that disease, or no vector species exists, then the pathogen will be unable to find an alternative host before the patient’s immune system eradicates it, and so it dies out in that area. An example would be malaria in Britain. Every year people arrive in the country carrying the Plasmodium protozoan in their blood, but as the Anopheles mosquitoes are restricted to very specific uncommon habitats, the disease is usually unable to spread before the patient is treated and the pathogen eliminated. © H ERIOT-WATT U NIVERSITY 50 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Endemic An infection is said to be endemic when that infection is maintained in the population without the need for external inputs. For example, rubella and the common cold rhinovirus are endemic in Britain, but malaria is not. To maintain this steady state, the pathogen must be able to find new hosts sufficiently frequently to avoid extinction, but not so often that the number of cases begins to increase significantly. This equilibrium depends on the relationship between the number of new cases that one infected person can generate before their infectious period is over (as their immune system controls the infection), and the number of susceptible people in the population. Epidemic An epidemic occurs when the number of cases of a disease increases significantly above that normally recorded. For this to happen, the equilibrium of the endemic state must be disturbed in some way. It might, of course, also be the result of some new pathogen arriving, against which the immune systems of the population give no immediate protection. Every winter in Scotland, susceptible individuals (over 65, pregnant women, those with particular health conditions, pre-school and primary school children) are offered an injection of the flu vaccine which counters the strains of Influenzavirus which are expected in the coming flu season. This is always something of a gamble, as the flu virus mutates frequently and the health authorities have to judge which strains will predominate in any winter. Pandemic When a disease reaches epidemic proportions in many different countries, it is classed as a pandemic. Modern air transport links make the potential for the global spread of a disease much greater, but this is countered by a much deeper understanding of the behaviour of diseases and more sophisticated methods of tracing potentially infected individuals. Thus, while the swine flu pandemic of 2009 killed roughly 18,000 people, the Spanish flu pandemic of 1918 is estimated to have killed between 20 and 100 million. Both of these outbreaks involved the H1N1 variant of the type A Influenzavirus. Epidemiology and the spread of disease: Question Q8: Match the phrases on the left with the words on the right. Go online The disease occurs occasionally in a population: endemic. Cases of the disease occur regularly in an area: pandemic. There are unusually high numbers of cases in an area: sporadic. Unusually high numbers of cases in many countries: .......................................... epidemic. © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 3.4.2 Control measures When an outbreak of disease is anticipated or has already begun, there are a number of strategies that health authorities can adopt to control the outbreak and reduce the possibility of it reaching epidemic or pandemic proportions. These may be applied singly or in combination. Preventing transmission If a disease outbreak has already begun, infected individuals can be isolated and known contacts quarantined. The media can be used to inform the public of symptoms, and information can be gathered by communication with travel companies, immigration officials, business contacts and others who might have knowledge of an infected person’s movements. Airport officials can be alerted so that passengers on flights from particular countries can be screened and alerted to the symptoms. An extreme case involves the Ebola virus, which sporadically erupts in West Africa. This is an example of a pathogen that transfers to humans from other animals, in this case mainly fruit bats. As is typical of a pathogen that is not adapted to a new host, Ebola rapidly kills most of the patients it infects. It is also highly contagious, spreading quickly from human to human in a population. The standard approach to containing such an outbreak is to isolate the community, give such medical relief as is possible (there is no cure), and wait until the survivors are no longer infectious (about two months). Interestingly, the rate of mortality amongst patients is much higher early in an outbreak than towards the end, indicating that the selection pressure on the virus in the course of the outbreak favours less virulent strains. Drug therapy Once an outbreak is under way, people who are infected may be treated in a number of ways to combat the disease or ameliorate the symptoms. The most frequent treatment is some form of antibiotic. These are chemicals that are naturally produced by fungi or bacteria to impede the growth of competing microbes, penicillin being the famous first example to be discovered. Today, most antibiotics are manufactured synthetically, although some still involve an element of biosynthesis, e.g. streptomycin. Broad spectrum antibiotics target a wide range of bacteria, whereas narrow spectrum antibiotics act against specific types of bacteria. Antibiotics affect bacteria in a wide range of different ways. Some attack the bacterial cell wall or cell membrane, others interfere with essential enzymes or with protein synthesis. Antibiotics only work against bacteria; other types of drugs that are used as bactericides are sulphonamides and quinolones. Viruses are addressed with antiviral drugs that target particular viral proteins which are as different as possible from any found in the human body. These attack the virus at different stages in its life cycle: • before it enters the cell, e.g. pleconaril, which is used against the common cold Rhinovirus, and the virus causing meningitis; • during viral synthesis, e.g. zidovudine (AZT) countering HIV, and so-called ’antisense’ antivirals against dengue fever; • at the release phase from the cell, e.g. Relenza and Tamiflu used against flu. © H ERIOT-WATT U NIVERSITY 51 52 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES Another approach to counter viruses is to stimulate the immune system, e.g. interferon used against hepatitis B and C. All of these drugs are subject to the development of drug resistance, as exposure of the microbes to the drug exerts strong selection pressure in favour of those bacteria and viruses less seriously affected by the drug. Individuals who have been exposed to infection may be injected with antibodies to provide passive immunity to a disease. This may be used to counter tetanus, rabies, rubella, hepatitis A and B. Immunisation The theory of immunisation is covered in the next topic. By exposing a person to the surface proteins (antigens) of a pathogen (usually by injection), their immune system will be stimulated to develop the lymphocyte memory cells necessary to initiate a rapid, strong secondary response if the pathogen itself is encountered. This is the principle behind the provision of annual winter flu injections and the MMR, TB and tetanus vaccination programmes. Clearly, immunisation is not a treatment for those already infected, and it does depend on an informed guess as to exactly which strains of pathogen are likely to be encountered. Control measures: Questions Go online Q9: What is the most suitable treatment for a person who has flu caused by the H1N1 virus? a) Antibiotics b) Immunisation c) Isolation .......................................... Q10: Long-term resistance to tetanus is achieved by: a) Antibiotics b) Antivirals c) Immunisation .......................................... Q11: A person who has contracted the bacterial infection tetanus should be treated with: a) Antibiotics b) Antibodies c) Antivirals .......................................... © H ERIOT-WATT U NIVERSITY TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 3.5 Learning points Summary Methods of transmission of pathogens • Pathogens may be transmitted by direct physical contact, water, food, body fluids, inhaled air or vector organisms. Control of spread of pathogens • The spread of pathogens can be controlled by quarantine and antisepsis. • The role of individual responsibility by means of good hygiene, care in sexual health and appropriate storage/handling of food. • The role of community responsibility by means of quality of water supply, safe food webs, and appropriate waste disposal systems. • The role of vector control in reducing the spread of pathogens. Epidemiological studies of infectious diseases • Epidemiology is the study of the causes and patterns of spread of disease. • The patterns of spread of disease are: • 3.6 ◦ sporadic (occasional occurrence); ◦ endemic (regular cases occurring in an area); ◦ epidemic (unusually high number of cases in an area); ◦ pandemic (a global epidemic). Control measures include preventing immunisation or a combination of these. transmission, drug therapy, Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of the control of spread of pathogens before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Control of spread of pathogens Describe the role of community responsibility in the control of the spread of pathogens. (6 marks) .......................................... © H ERIOT-WATT U NIVERSITY 53 54 TOPIC 3. THE TRANSMISSION AND CONTROL OF INFECTIOUS DISEASES 3.7 End of topic test End of Topic 3 test Go online Q12: Complete the paragraph by selecting words from the list. Some words may be used more than once. (12 marks) contact, water, , body fluids, Pathogens may be transmitted by direct or organisms. The spread of pathogens can be controlled by inhaled . quarantine and , care Individuals have a responsibility to control disease by means of good health and appropriate storage/ of food. The role of community is in supply, safe food , and appropriate to ensure the quality of disposal systems. Communities may also reduce the spread of disease by means of control. programmes of Word list: air, antisepsis, food, handling, hygiene, physical, sexual, vector, waste, water, webs. .......................................... Q13: Explain how quarantine helps control the spread of disease. (2 marks) .......................................... Q14: State two ways in which health authorities ensure drinking water is safe. (2 marks) .......................................... Q15: Name a vector-borne disease and state one way in which its spread may be controlled. (2 marks) .......................................... Q16: What is an endemic disease? (1 mark) .......................................... Q17: Explain how an endemic disease, e.g. flu, can become an epidemic. (1 mark) .......................................... © H ERIOT-WATT U NIVERSITY 55 Topic 4 Active immunisation Contents 4.1 Active immunisation and vaccination . . . . . . . . . . . . . . . . . . . . . . . 56 4.1.1 Active immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Vaccine clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 59 4.2 4.3 Herd Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunisation programmes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 67 4.4 The evasion of specific immune responses by pathogens . . . . . . . . . . . . 4.4.1 Antigenic variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 70 4.4.2 Antigenic variation in different pathogens . . . . . . . . . . . . . . . . . 4.4.3 Direct attack on the immune system . . . . . . . . . . . . . . . . . . . . 72 75 4.4.4 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 78 4.6 4.7 79 80 Extended response question . . . . . . . . . . . . . . . . . . . . . . . . . . . . End of topic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Learning objectives By the end of this topic, you should be able to: • describe the development of active immunisation; • explain the purpose of vaccinations, the development of vaccines and associated public health programmes; • describe the way in which some pathogens evade the specific immune response. 56 TOPIC 4. ACTIVE IMMUNISATION 4.1 Active immunisation and vaccination An individual will develop an immunological memory (Topic 2.6) against a foreign antigen as a result of exposure to that antigen. This may be caused by natural exposure to the antigen, e.g. by contracting the disease, which was the way children in Britain became immune to measles, mumps and rubella before 1988. Alternatively, an injection of vaccine containing the antigen can be given to stimulate the development of artificial immunity. Since 1988, all British children have been offered such artificial immunisation before their first birthday as part of their routine vaccination schedule. The first well-documented use of artificial immunisation was in China in the 16 th century, and the practice was recorded from India, Africa and Turkey in the 18 th century at about the same time that it began to be practised in Britain and other countries of western Europe. The disease involved was smallpox, which can kill up to 60% of those infected (and up to 80% of children under five years of age). The technique was inoculation, in which scabs taken from an infected person were introduced (either whole or powdered) into an incision on the arm of an uninfected person. Surprisingly, perhaps, rather than promptly killing a high proportion of the patients, this technique caused a relatively mild infection which had the desired effect of protecting them in subsequent exposures to the disease. It did, however, depend on the presence of the disease in the community for the necessary supply of scabs. The process of using a source of antigens other than the pathogen itself was first introduced by Edward Jenner (and others) in the late 18 th century. He used pus from scabs caused by cowpox to inoculate patients who later proved to be immune to the much more serious and related disease smallpox. Nearly a century later, the procedure was significantly refined by Louis Pasteur. Because of the early use of cowpox in the process, the treatment was called vaccination (vacca is Latin for cow). Although the terms vaccination and inoculation are now often used interchangeably, strictly speaking vaccination refers to the use of some weakened form of a pathogen, whereas inoculation uses the real thing (and is consequently a much more dangerous business). Inoculation is also the term used for the addition of a culture of microbes to a growth medium in the lab. There is no doubt that vaccination is the single most important discovery in the control of disease. Without it, serious diseases such as polio and smallpox would still be claiming millions of lives around the planet every year. © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 4.1.1 57 Active immunity Learning objective By the end of this section, you should be able to: • state that active immunity can be developed by vaccination with antigens from infectious pathogens; • explain that vaccination creates an immunological memory; • state that vaccines include antigens from infectious pathogens, including inactivated pathogen toxins, dead pathogens, parts of pathogens and weakened pathogens; • state that the antigens in vaccines are usually mixed with an adjuvant to enhance the immune response. Immunity against a pathogen can be developed in a number of ways. fundamentally, immunity may either be active or passive: Most • active immunity involves the development of immunological memory, either as a result of exposure to the pathogen’s antigens (naturally acquired) or through exposure to the same antigens in a vaccination (artificially acquired); • passive immunity involves the acquisition of antibodies, either naturally across the placenta or from breast milk, or artificially through an injection (e.g. in the treatment of rabies). Of these, only the development of artificial active immunity by means of vaccination programmes is of practical importance, although the valuable role of breast feeding in protecting infants should also be stressed in the course of antenatal classes. Vaccination Vaccination is the deliberate introduction of pathogen antigens into the body, usually by injection but, in some cases, orally or nasally. Exposure to the antigen induces a primary response from the adaptive immune system, in particular leading to the development of an immunological memory in the form of memory B- and T-lymphocytes. In a second or subsequent exposure to the same antigen, a secondary response is triggered. As soon as the antigen is detected, memory cells begin rapid division to generate large numbers of B-lymphocyte plasma cells. These cells release their antibodies into the circulation, leading to such a quick build up of antibodies that the invading pathogen is neutralised before it can cause any harm. However, while vaccination greatly reduces the chance of infection, it cannot entirely eliminate it. © H ERIOT-WATT U NIVERSITY 58 TOPIC 4. ACTIVE IMMUNISATION Primary and secondard responses after vaccination Adjuvants In addition to the antigenic ingredient, vaccines contain chemicals which act to modify the immune response engendered by the vaccine, either by increasing the production of antibodies or by making the protection provided last longer, or sometimes only activating T-lymphocytes. The most commonly used adjuvant is alum (potassium aluminium sulphate), although several other substances may be used including paraffin oil and bacterial products. Antigens There are a variety of sources used to provide the essential antigens in a vaccine. • Live attenuated microbes - these contain the same antigens as the pathogen, but the microbes have been sub-cultured many times in the laboratory so that they become an ’attenuated’ strain, i.e. they can no longer cause the full-blown disease, although they may cause a very mild form of it. The first vaccine, the smallpox vaccine, consisted of a live attenuated virus. The MMR (measles, mumps and rubella) vaccine falls into this category. • Toxoid - these are inactivated toxins; vaccines include Diphtheria and tetanus (part of DTaP combined immunisation). • Dead pathogens - the microbes are destroyed by heat and chemicals although the dead pathogen still carries the antigens which stimulate the immune response; vaccines for Hepatitis A, polio and cholera fall into this category. • A fragment of a pathogen - the viral coat component can be used as a vaccine; the HPV vaccine has the viral protein coat protein of the Human Papilloma Virus, as does the vaccine for Hepatitis B. © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 59 Administration of vaccines Vaccines are most commonly administered by injection, although some are given as a nasal spray or by mouth. Inhaled (nasal) vaccine can be used against influenza and ingested (oral) vaccines for protection against polio. New techniques of vaccine administration include a patch application, in which a patch containing a matrix of extremely tiny needles delivers a vaccine without the use of a syringe. This method of delivery could be particularly useful in remote areas because its application would not require delivery by a trained medical person. Active immunity: Questions Q1: Complete the following table concerning vaccines using the words and phrases from the list. Component Go online Function Word and phrase list: adjuvant, antigen, creates immunological memory, enhances immune response. .......................................... Q2: State the four different sources of antigen found in vaccines. .......................................... 4.1.2 Vaccine clinical trials Learning objective By the end of this section, you should be able to: • • describe key aspects of the protocol for any vaccine clinical trial as being that the trial should be: ◦ randomised; ◦ double-blind; ◦ placebo-controlled; explain the importance of group size in reducing experimental error and increasing statistical significance. Vaccine Clinical Trials Before a licence can be issued for a vaccine or a drug to be administered to the public, it must be subjected to an intensive series of trials to establish its safety and efficacy. In advance of any human trials, the vaccine must undergo extensive laboratory research, including tests on cell cultures and laboratory animals. These pre-clinical trials allow vaccine researchers to gain a better understanding of how the treatment works and of any side effects. A new cancer drug can take up to six years of testing in the laboratory before it reaches the clinical trials stage. Even then, very few drugs get to the clinical © H ERIOT-WATT U NIVERSITY 60 TOPIC 4. ACTIVE IMMUNISATION trials; only one in every one thousand new drugs reaches the clinical trials. The next step is to seek approval from the regulatory authority of the member state in which the trial is to be conducted. In the UK, this is the Medicines and Healthcare products Regulatory Agency (MHRA). Protocols must be drawn up at this stage for the trials, these may include: • target groups for the trials; • number of subjects involved in these trials; • other treatments with which to be compared; • procedures for collection and interpretation of data. The protocol will now undergo independent scientific review and, at the same time, it must be approved by the ethics committee. These steps are intended to ensure that the trial is foolproof and will respect rights, dignity, safety and well-being of the subjects. In the UK, all clinical trials have to meet the standard set by the European Union Clinical Trials Directive. The process ensures all trials are carried out to the same standard wherever they take place in Europe. The process for clinical trials is summarised below. Summary of clinical trial protocols A protocol is a predefined procedure for conducting a scientific investigation which will allow the method to be standardised so that the study can be repeated exactly. The key features of a vaccine clinical trial protocol are that the procedure should be: • randomised - all subjects in the trial should have an equal chance of being given vaccine or the placebo, usually done by allocating individuals to treatments using some kind of random-number generator; • double-blind - neither the subjects nor the persons carrying out the trial know which subjects are getting the vaccine and which the placebo; • placebo-controlled - the trial subjects are divided into two groups, one receiving the vaccine and the other receiving the placebo, a treatment which is similar in all respects to the vaccine apart from the active ingredient being tested. © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION The importance of group size By this stage in their science studies, all students should be aware that increasing the number of individuals in a study, or repeating the investigation, will make the results more reliable. However, few are usually able to explain why this is so. Before addressing this, a few key concepts need to be defined. Sample Rarely is it possible to study all the individuals in the population being investigated. Even in a general election, not all of the people eligible to vote actually do so; in fact, those who vote are a self-selected group who may not at all represent the views of those who do not vote. A scientist might approach the challenge of ensuring fair representation differently. Firstly, not all individuals need be consulted. Rather a much smaller representative group would be selected for study; that is the sample. This sample would be selected randomly, i.e. everyone in the population would have an equal chance of being included. The population would be divided up into different socioeconomic and geographical groupings, and the number of people chosen from each grouping would be in proportion to the size of this grouping in the whole population. This would ensure that all groups are represented in the sample, and no one group has a disproportionate influence. Of course, general elections will never be run this way, as ’one person, one vote’ is a fundamental principal of democracy, but it is exactly the way in which national opinion polls are run. True values versus sample estimates Imagine being asked to estimate the mean height of boys in the second year of the local high school, but only being allowed enough time to measure thirty of them. If the boys are selected randomly, with all having an equal chance of being in the sample, the mean calculated from this group would be representative of the year group. However, that sample mean is very unlikely to be same value as the one that would have been achieved if every boy had indeed been measured to find the true value. A key task in sampling is to ensure that the estimate value derived from a sample is acceptably close to the true value, and this is increasingly likely as the sample size is increased. Experimental error This is not to do with mistakes, although these do of course get made e.g. misreading scales, omitting numbers. Such blunders usually stand out and should be excluded from any analysis. Experimental error is any deviation of the measured value from the true value. It is inherent in any technique, although efforts are always made to minimise it. Suppose a simple task of weighing out chemicals is required. First of all the balance must be properly zeroed and operated at the correct voltage and temperature; these sources of error can be minimised. However, if the balance only measures to 1g, then if the reading is 10g, the balance is really saying that the sample weighs somewhere between 9.50g and 10.49g (to two decimal places). This source of error is a function of the apparatus used, and the larger © H ERIOT-WATT U NIVERSITY 61 62 TOPIC 4. ACTIVE IMMUNISATION the sample size, the less effect it will have. Statistical significance Many biology students seem to have a horror of maths, in which they include statistics. However, there are two principal reasons why this attitude is misplaced: 1. firstly, without statistical analysis, no scientist has any idea of the significance of their experimental results. In that regard, statistics is as important a tool in biology as the microscope; 2. secondly, biologists are not required to understand the mathematics that underpin any of the statistical techniques which they use, although it is essential to be aware of the type of technique that is appropriate to the data to be analysed. Other than that, it is just a case of plugging numbers into a formula. Statistical analysis allows scientists to determine the likelihood of a particular outcome. Results are usually expressed in terms of percentage significance, either 5% (’significant’) or 1% (’highly significant’). These numbers mean that there is only 1 chance in 20 (5% level) or 1 chance in 100 (1% level) that such a result would have occurred by chance. It is only possible to analyse experimental results statistically if samples are randomly selected. Thus, at the end of vaccine clinical trial, if the number of people in the vaccine group who had contracted the disease was lower than the number catching the disease in the placebo group, the results would be analysed to discover the possibility of such a difference arising by purely random processes. The statistical test would assess how likely it would be to get such a large difference if the individual subject’s results had just been randomly placed into two groups irrespective of their treatment. The significance of any difference is very strongly dependent on the size of the sample groups. Quite a large difference may not be found to be statistically significant if the sample size is small, whereas quite small differences may prove significant if the sample size is large. Vaccine clinical trials: Questions Go online Q3: Explain what is meant by the statement that vaccine clinical trials should be randomised, double-blind and placebo controlled. .......................................... Q4: State two ways in which increasing sample size will affect the results of an experiment. .......................................... © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 4.2 63 Herd Immunity Learning objective By the end of this section, you should be able to: • state that herd immunity is important in the control of infectious diseases; • state that herd immunity occurs when a large percentage of a population are immunised; • explain that, as a result of herd immunity, non-immune individuals are protected as there is a lower probability they will come into contact with infected individuals; • explain that the herd immunity threshold depends on the disease, the efficacy of the vaccine and the contact parameters for the population. The creation of herd immunity When a person is immunised against a disease, it provides protection in two ways. Firstly, should that person meet the pathogen a second time, they are very unlikely to develop the disease. Secondly, because the pathogen cannot use them as a host from which to spread to other people, the chance of an infection spreading through the population is reduced. This is the basis of the herd immunity which is crucial in the control of infectious diseases. For an infection to spread through a community, the pathogen must be able to find a new host before its current host’s immune system eliminates it. The fewer contacts the infected person has with unprotected individuals, the less likely this is. When a certain critical level of immunisation in the community is reached, the disease will always fail to spread in that community, although sporadic cases may occur. In this situation, not only are those who have been vaccinated protected, but also others who have not, e.g. people whose immune systems have been suppressed for transplant surgery. This is because they are less likely to come into contact with infected individuals as there are few of them and the disease will only be present in the population for a short time. © H ERIOT-WATT U NIVERSITY 64 TOPIC 4. ACTIVE IMMUNISATION The three stages of creating herd immunity Go online .......................................... © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION Most vaccination programmes and policies are aimed at the creation of herd immunity. The childhood vaccination programme in this country ensures that when any of the diseases involved enter the population, they will not spread to create an epidemic and infect children or adults who have not been previously vaccinated or exposed to the disease. The creation of herd immunity is especially important in areas where people are in close and frequent contact, with the potential for the rapid spread of infection, e.g. schools, densely populated housing. The creation of herd immunity does not always guarantee success in containing the spread of infectious diseases. Mutations can occur in the pathogen which changes the antigen, an entirely new strain may be brought into the country, or batches of vaccine may prove faulty. Additionally, if a sufficiently large percentage of the population fails to get vaccinated, the pathogen will be able to find new hosts sufficiently frequently for the infection to spread and the non-immunised members of the population become very vulnerable to this disease. Herd immunity thresholds The threshold level of vaccination necessary to create herd immunity in a population varies from as low as 40% (for Pandemic Flu - H1N1) to up to 94% (pertussis and measles). This is dependent on several factors concerned with the pathogen: • the virulence of the pathogen involved, i.e. how easily it infects people: higher virulence requires a higher threshold; • the length of time that a person with the disease remains infectious (the period of infectivity): the longer the infective period, the higher the threshold; • the ease of transmission of the pathogen, i.e. how easily the pathogen in passed from individual to individual: the more easily the pathogen is transmitted, the higher the threshold; • the means of transmission of the pathogen: the more effective the means of transmission, the higher the threshold. In addition, some vaccines have a higher efficacy than others, meaning that they establish immunity more efficiently and so require a lower level of immunity in the population to contain any disease outbreak. In order to sustain herd immunity, the population may need to receive regular boosters as some vaccinations lose their efficacy over a period of time. The other factors of importance in determining the threshold level are the contact parameters of the population. This is the extent to which people come into contact with each other or share the same space; the threshold for an isolated rural community will be lower than that for an over-crowded inner city. © H ERIOT-WATT U NIVERSITY 65 66 TOPIC 4. ACTIVE IMMUNISATION The herd immunity thresholds for some diseases are shown in the following table. Likely transmission methods Disease Herd immunity threshold Diphtheria Saliva 84 % Measles Airborne 86 - 94 % Mumps Airborne droplet 78 - 86 % Pertussis Airborne droplet 92 - 94 % Polio Faecal-oral route 82 - 86 % Rubella Airborne droplet 82 - 85 % Smallpox Social contact 80 - 85 % Pandemic flu Social contact about 40 % Herd immunity thresholds for vaccine-preventable diseases In addition to being used in disease prevention, the establishment of herd immunity is also used to fight ongoing outbreaks of a disease. Herd Immunity: Questions Go online Q5: Explain why herd immunity will protect individuals who are not immune to a disease when an infected person arrives in their community. .......................................... Q6: Explain how each of the following aspects of a pathogen affects the herd immunity threshold: • low virulence; • short infectious period; • easily transmitted. .......................................... © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 4.3 67 Immunisation programmes Learning objective By the end of this section, you should be able to: • explain the reasons for public health immunisation programmes; • state that public health immunisation programmes seek to establish herd immunity to a number of diseases; • explain the difficulties caused when widespread vaccination is not possible because of malnutrition, poverty or a vaccine being rejected by a percentage of the population. The purposes of public health immunisation programmes are to protect vulnerable individuals, either directly by vaccination or indirectly by establishing herd immunity. The winter flu vaccination programmes are an example of protecting vulnerable individuals rather than attempting to reach a threshold of immunity. On the other hand, the childhood vaccination programmes are very strongly geared to that aim. Childhood vaccinations in Scotland Many people will be aware that the routine immunisation of children and infants has dramatically reduced the incidence of infectious diseases, for example measles and whooping cough (pertussis), and has led to the global eradication of smallpox. However, for those not recently involved in the rearing of young children, it might come as a surprise just how many vaccinations are routinely given to our children. While some are tempted to say that the diseases involved are rare and it seems unfair to put young children through the trauma of repeated injections, it only takes a moment’s reflection to appreciate that the risks of any vaccination are minimal compared to the potential impact of the disease itself, and that the only reason the diseases are rare is the fact that the vast majority of children are immunised against them. (Note: the following list is not in the syllabus!) © H ERIOT-WATT U NIVERSITY 68 TOPIC 4. ACTIVE IMMUNISATION Childhood vaccinations Challenges to widespread vaccination As there are always groups within a community who cannot be vaccinated for various reasons, e.g. pregnant women, transplant patients, people whose immune systems are deficient, it is vital that all those for whom the vaccination poses no significant threat are immunised so that the herd immunity threshold is reached. There are three key challenges to achieving these threshold values: • malnutrition weakens the immune system so that even if children have been vaccinated, they will be less able to fight off infection; • children living in poverty show much lower vaccination rates than more affluent children as a result of lower engagement with the public health system; • vaccination as a process may be rejected by groups on religious or other grounds. Whereas the first two points can only be addressed by means of improving living standards, and are closely inter-related, the latter must be addressed by means of sensitive education and publicity. © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 69 Immunisation programmes: Questions Q7: Apart from protecting vulnerable individuals, what do public health immunisation programmes attempt to establish? .......................................... Q8: Explain how each of the following reduces the effectiveness of vaccination programmes: • malnutrition; • poverty; • rejection of vaccination. .......................................... © H ERIOT-WATT U NIVERSITY Go online 70 TOPIC 4. ACTIVE IMMUNISATION 4.4 The evasion of specific immune responses by pathogens Learning objective By the end of this section, you should be able to: • state that many pathogens have evolved mechanisms that evade the specific immune system which has consequences for vaccination strategies; • state that antigenic variation is a process by which a pathogen is able to change its surface proteins; • state that antigenic variation may be brought about by: ◦ small genetic mutations that gradually change the surface antigens; ◦ sudden large genetic change when two different strains undergo genetic recombination; • explain that antigen variation allows some pathogens to avoid the effect of immunological memory; • describe role and impact of antigenic variation in diseases like malaria, trypanosomiasis and influenza; • state that some pathogens directly attack the immune system; • explain that HIV attacks lymphocytes, which is the major cause of AIDS; • explain that tuberculosis (TB) survives within phagocytes and so avoids immune detection. The specific immune system is one of the primary limitations on the replication of pathogens within the body; these immune responses target specific antigens expressed by the pathogen. However, as a result of a long association with us, many pathogens have evolved mechanisms that allow them to evade the specific immune system and cause infection. Clearly, such developments must be taken into account when public vaccination strategies are formulated. 4.4.1 Antigenic variation Antigenic variation is a process by which a pathogen is able to change its surface proteins so that it can evade the host immune responses. The antigenic profile (sometimes called antigenic diversity), will change as the pathogen passes through the host population or in the original infected host. Antigenic variation is particularly important for pathogens as it allows them to: • target hosts which are long-lived or susceptible to the pathogen; • infect a single host on more than one occasion; • transmit the disease easily. © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION Antigenic variation can occur in two distinct ways: 1. the slow accumulation of small genetic mutations (antigenic drift) that gradually change the surface antigens; 2. a sudden large genetic change (antigenic shift) brought about when two different strains undergo genetic recombination. Antigenic variation These processes will be explored in more detail when changes in influenza viruses are studied. © H ERIOT-WATT U NIVERSITY 71 72 TOPIC 4. ACTIVE IMMUNISATION Pathogens which undergo antigenic variation have a selective advantage over more genetically stable ones. Antigenic variation happens through three genetic processes: 1. gene mutation; 2. recombination; 3. gene switching, which occurs when certain members of a family of genes are switched on while others in the family shut down - it is a process that is common during embryonic development. The resulting pathogens are immunologically different from the parental strains. Thus, pathogens which can vary their antigenic signature are able to avoid triggering the immunological memory which had been developed in response to their parental strain. Antigenic variation: Question Q9: List the genetic processes which cause antigenic variation. Go online .......................................... 4.4.2 Antigenic variation in different pathogens Viruses The influenza virus genome is fragmented and can go through a high rate of genetic re-assortment during replication. This can result in the emergence of a new virus that codes for a new haemagglutinin (HA) and/or neuraminidase (NA); the two large glycoproteins on the outside of the viral particles. Most flu epidemics are due to the emergence of these new virus strains (usually type A) and can be brought about via antigenic shift and antigenic drift. Drift and shift in flu viruses © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION Antigenic shift in flu viruses can occur when: • an aquatic bird passes a bird strain of influenza A to an intermediate host such as a chicken or pig and a person passes a human strain of influenza A to the same chicken or pig - when the viruses infect the same cell, the genes from the bird strain mix with genes from the human strain to yield a new strain, which can spread from the intermediate host to humans; • an avian strain of influenza A (without undergoing genetic change) jumps directly from a duck or other aquatic bird to humans; • an avian strain of influenza A (without undergoing genetic change) jumps directly from a duck or other aquatic bird to an intermediate animal host and then to humans. This genetic change enables influenza strains to jump from one animal species to another, including humans. What happens, in fact, is that when two strains of the pathogen recombine, any one of the eight influenza proteins can be replaced by a different protein acquired as a result of genetic re-assortment. In this case, the RNA that codes for the HA is replaced for one from another source (i.e. from avian or porcine sources). This is illustrated below; the change of the glycoproteins (HA) on the surface of the viral particles is illustrated by a colour change on the surface of the virus. Diagrams of a highly pathogenic avian strain virus and a human strain The influenza pandemic of 1918-19 was caused by a virus which had a HA protein normally found in swine influenza strains. Antigenic shift results in a more immediate and extensive change in the genetic information of this ’newly formed’ pathogen. These changes in the haemagglutinin and neuraminidase types are used to characterise the various strains of the flu viruses. Some of the variants that caused notable epidemics are shown below. © H ERIOT-WATT U NIVERSITY 73 74 TOPIC 4. ACTIVE IMMUNISATION Flu pandemics since 1890: the ’Spanish’, ’Asian’ and ’Hong Kong’ strains of flu involve avian variants; the ’swine’ strain has porcine variants In terms of the global impact, the 1918 Spanish Flu pandemic was by far the worst, with an estimated 50 to 100 million deaths worldwide. Antigenic drift is a result of genetic point mutations accumulated by the viral genome over an extended period of time. This drift results in small antigenic changes in the pathogen population and will reduce the efficacy of B and T cell memory during the host immune response. Antigenic drift is prominent in the influenza virus, and is becoming more and more evident in the rapid evolution of rhinoviruses and enteroviruses. Antigenic drift contributes to our susceptibility to influenza infections year after year. The human immunodeficiency virus (HIV) exhibits antigenic drift within the particular host due to its high rate of replication. Protozoa Antigenic variation occurs in diseases such as malaria and trypanosomiasis and is one of the reasons why they are still so common in many parts of the world. Protozoa represent the most biologically complex pathogens presented to the human immune system. Trypanosomes (causing sleeping sickness) and Plasmodium (causing malaria) use antigenic variation to evade immune responses and prolong the duration of infections. Trypanosomes exhibit unique processes of gene conversion, whereby any one of hundreds of genes coding for variable surface glycoproteins can be expressed. As the Trypanosomes multiply inside the host, the host makes antibodies against them. After five to seven days, these antibodies destroy most of the Trypanosomes and the symptom decreases. About this time, a new wave of Trypanosomes appears because these are unaffected by antibodies generated against the previous wave. The immune system has to start over again. This process continues, essentially indefinitely, until the death of the host. During this time, the body continues to make primary responses against new antigens. One consequence of this is that the immune system becomes quite exhausted and the blood levels of the antibody (immunoglobulin IgM) increase dramatically, but to no useful effect. © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 75 In the protozoa Plasmodium falciparum, an aetiological agent (aetiology is the study of causes or origins) for malaria undergoes gene switching, resulting in the variable expression of surface proteins produced on infected red blood cells during the erythrocytic, asexual phase. These protozoan processes of antigenic variation lead to a gradual exhaustion of the host immunity in the terminal stages of disease. Antigenic variation in different pathogens: Questions Q10: Explain what is meant by gene conversion in Trypanosomes. .......................................... Go online Q11: How does gene conversion provide Trypanosomes with the ability to evade the host immune system. .......................................... 4.4.3 Direct attack on the immune system Learning objective By the end of this section, you should be able to: • explain why the absence or failure of some components of the immune system results in increased susceptibility to infection; • explain how HIV attacks lymphocytes and is the major cause of acquired immunodeficiency in adults; • explain how the pathogen which causes Tuberculosis (TB) can survive within phagocytes and avoids immune detection. Some pathogens directly attack the immune system by destroying lymphocytes. The Human Immunodeficiency Virus (HIV) is the best known example. HIV and AIDS Acquired Immune Deficiency Syndrome (AIDS) is the fatal condition that results from infection with HIV. AIDS itself is not a disease but describes the opportunistic diseases that infect and are often fatal to an HIV-positive individual. It is widely accepted that HIV develops into AIDS, although there have been a few cases where people have remained completely symptomless. HIV is carried in the blood, semen, vaginal fluids and breast milk, but it is unable to survive outside of the human body for long so can only be transmitted by the exchange of body fluids. The main ways in which HIV can be transmitted between people are: • intimate sexual contact; • intravenous drug use and blood transfusions; • from mother to child across the placenta and through breast milk. The vast majority of infections occur as a result of sexual intercourse, both heterosexual and homosexual. The virus that causes this disease is a lentivirus (slow virus) that © H ERIOT-WATT U NIVERSITY 76 TOPIC 4. ACTIVE IMMUNISATION infects both the immune and central nervous systems over a period of years. Many people experience flu-like symptoms when they are first infected and become HIVpositive, but serious symptoms do not generally appear until years later. As the HIV multiplies, it weakens the immune system by destroying the T-helper cells that mediate the immune response, as shown below. Eventually the immune system is destroyed, making sufferers more susceptible to diseases. As sufferers are immunocompromised, these diseases are more harmful and are frequently fatal. As the T-helper cells are destroyed and the immune system is less able to defend the body opportunistic infections occur, such as: • oral thrush, caused by the fungus Candida albicans; • Kaposi’s sarcoma, a rare form of skin cancer; • tuberculosis; • a rare form of pneumonia caused by Pneumocystis carinii. Graphs of HIV concentration and T-cell concentration Initially, it was thought that HIV and AIDS only affected homosexuals and drug users because most of the first cases were seen in these two groups. It is now known that anyone can be infected with HIV, but there is still a lot of stigma associated with the disease. Direct attack on the immune system: Question Q12: Why does HIV cause AIDS? Go online .......................................... © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION 4.4.4 77 Tuberculosis Tuberculosis (TB) is a contagious disease caused by the bacteria Mycobacterium tuberculosis (human) and M. bovis (cattle). It is transmitted in the same way as the common cold - by droplets from the respiratory tract of individuals that have the active disease. When they cough, sneeze, talk or spit, tiny droplets containing the bacterium are expelled from their lungs, which may then be inhaled by other people. Only a few bacilli are required for a person to become infected, making this disease easily transmissible. It is also possible to become infected with M. bovis via contact with susceptible animals and their products (e.g. unpasteurised milk); this form of TB is more common in economically less developed countries. Not all people infected with TB are actually infectious. Only those who actually develop TB symptoms are infectious, but, if untreated, they can potentially infect 10-15 others every year. It is estimated that at any one time a third of the world’s population is infected with TB, but only a small number will develop the disease. However, tuberculosis continues to kill more than two million people every year, a figure that is rising as the AIDS epidemic increases and drug-resistant TB spreads. TB can be categorised into three types: 1. in the majority of cases, the immune system of the infected person kills the bacteria and the person experiences no further symptoms; 2. latent TB, in which the sufferer does not experience any symptoms, but the bacteria remain in the body, surviving within phagocytes and thus avoiding detection - latent TB can sometimes develop into an active TB infection, especially if the infected person’s immune system is weakened; 3. active TB, in which the immune system fails to kill or contain the infection and it slowly spreads to the person’s lungs. The bacteria that cause tuberculosis can remain inactive in a human for many years, but can become active if its host’s immune system has been weakened. This causes serious complications for people who are already immunocompromised, such as those infected with HIV. It accounts for the majority of AIDS deaths. Tuberculosis spreads rapidly in overcrowded areas and outbreaks are often seen among the poor and homeless. The incidence of TB in economically more developed countries was considerably reduced when the standards of housing and nutrition improved. The introduction of a vaccine further decreased the impact of TB and it was thought that it had almost been eradicated from the developed world. However, it is now making a comeback as inner city poverty, homelessness, drug resistance, AIDS and migration to big cities are all rising. Drug resistance in Mycobacterium is also developing by natural selection, particularly as a result of people failing to complete courses of antibiotics. Tuberculosis: Question Q13: How does TB evade detection by the immune system? .......................................... © H ERIOT-WATT U NIVERSITY Go online 78 TOPIC 4. ACTIVE IMMUNISATION 4.5 Learning points Summary Active Immunity • Active immunity can be developed by vaccination with antigens from infectious pathogens. • Vaccination creates an immunological memory. • Vaccines include antigens from infectious pathogens, including inactivated pathogen toxins, dead pathogens, parts of pathogens and weakened pathogens. • The antigens in vaccines are usually mixed with an adjuvant to enhance the immune response. Vaccine Clinical Trials • • Key aspects of the protocol for any vaccine clinical trial are that the trial should be: ◦ randomised; ◦ double-blind; ◦ placebo-controlled. The importance of group size in reducing experimental error and increasing statistical significance. Herd Immunity • Herd immunity is important in the control of infectious diseases. • Herd immunity occurs when a large percentage of a population are immunised. • As a result of herd immunity, non-immune individuals are protected as there is a lower probability they will come into contact with infected individuals. • The herd immunity threshold depends on the disease, the efficacy of the vaccine and the contact parameters for the population. Immunisation programmes • The reasons for public health immunisation programmes. • Public health immunisation programmes seek to establish herd immunity to a number of diseases. • Difficulties arise when widespread vaccination is not possible because of malnutrition, poverty or a vaccine being rejected by a percentage of the population. The evasion of specific immune responses by pathogens © H ERIOT-WATT U NIVERSITY TOPIC 4. ACTIVE IMMUNISATION Summary continued 4.6 • Many pathogens have evolved mechanisms that evade the specific immune system which has consequences for vaccination strategies. • Antigenic variation is a process by which a pathogen is able to change its surface proteins. • Antigenic variation may be brought about by: ◦ small genetic mutations that gradually change the surface antigens; ◦ sudden large genetic change when two different strains undergo genetic recombination. • Antigen variation allows some pathogens to avoid the effect of immunological memory. • The role and impact of antigenic variation in diseases such as malaria, trypanosomiasis and influenza is to continuously alter the surface antigens of the pathogens, leading to sporadic epidemics and the failure of vaccination programmes. • Some pathogens directly attack the immune system. • HIV attacks lymphocytes, which is the major cause of AIDS. • Tuberculosis (TB) survives within phagocytes and so avoids immune detection. Extended response question The activity which follows presents an extended response question similar to the style that you will encounter in the examination. You should have a good understanding of public health immunisation programmes before attempting the question. You should give your completed answer to your teacher or tutor for marking, or try to mark it yourself using the suggested marking scheme. Extended response question: Public health immunisation programmes State the aim of public health immunisation programmes and explain why they may fail to protect non-immunised individuals. (6 marks) .......................................... © H ERIOT-WATT U NIVERSITY 79 80 TOPIC 4. ACTIVE IMMUNISATION 4.7 End of topic test End of Topic 4 test Q14: Complete the paragraphs by selecting words from the list. (12 marks) Go online can be developed by with antigens from An immunological . This is known as immunity. Vaccines include infectious from infectious pathogens, including inactivated pathogen , dead pathogens, parts of pathogens and weakened pathogens. The antigens in to enhance the response. vaccines are usually mixed with an for any vaccine clinical trial are that the trial should be Key aspects of the , double-blind and placebo-controlled. Group size is important in reducing and increasing significance. experimental Word list: active, adjuvant, antigens, error, immune, memory, pathogens, protocol, randomised, statistical, toxins, vaccination. .......................................... Q15: Explain the term ’antigenic variation’. (1 mark) .......................................... Q16: Describe one way in which pathogens develop antigenic variation. (2 marks) .......................................... Q17: State the role of antigenic variation in diseases like malaria, trypanosomiasis and influenza. (1 mark) .......................................... Q18: State the impact of antigenic variation in such diseases. (1 mark) .......................................... Q19: Explain how HIV leads to the development of AIDS. (2 marks) .......................................... Q20: State how TB evades immune detection. (1 mark) .......................................... © H ERIOT-WATT U NIVERSITY 81 Topic 5 End of unit test 82 TOPIC 5. END OF UNIT TEST End of Unit 4 test Q1: Go online An example of the body’s physical barriers to infection is: (1 mark) a) epidermis b) histamines c) sebum .......................................... Q2: Histamines are released by: (1 mark) a) mast cells b) NK cells c) phagocytes .......................................... Q3: Cytokines stimulate the: (1 mark) a) apoptosis b) non-specific immune response c) specific immune response .......................................... Q4: Autoimmune diseases are caused by an incorrect response by: (1 mark) a) B-lymphocytes b) macrophages c) T-lymphocytes .......................................... Q5: Community responsibility for control of pathogen spread involves: (1 mark) a) good hygiene b) sexual health c) waste disposal .......................................... Q6: A disease which is always present in a population is: (1 mark) a) endemic b) epidemic c) pandemic .......................................... Q7: Vaccines contain pathogen: (1 mark) a) antibodies b) antigens c) antiseptics .......................................... © H ERIOT-WATT U NIVERSITY TOPIC 5. END OF UNIT TEST Q8: Herd immunity thresholds are less likely to be reached because of: (1 mark) a) malnutrition b) poor personal hygiene c) unsafe food webs .......................................... Q9: Name an example of the body’s non-specific chemical defences against pathogens and state its function. (2 marks) .......................................... The graph shows the immune response of two people, one of whom has been vaccinated against a disease and the other not. Q10: Which of the two lines on the graph represents the response of a person who has been vaccinated against the disease? (1 mark) a) A b) B .......................................... Q11: Explain the response of a person who has been vaccinated against the disease. (1 mark) .......................................... Q12: In the later stages of the infection, a person infected with HIV would show a different pattern to either of these curves. Describe this difference. (1 mark) .......................................... Q13: Explain this difference. (1 mark) .......................................... © H ERIOT-WATT U NIVERSITY 83 84 TOPIC 5. END OF UNIT TEST The following diagram shows clonal selection in lymphocytes. Q14: Describe what is shown in the upper half of the diagram. (1 mark) .......................................... Q15: Explain the lower half of the diagram. (2 marks) .......................................... Q16: State how some T-lymphocytes activate B-lymphocytes. (1 mark) .......................................... Q17: State two ways in which pathogens may be transmitted. (1 mark) .......................................... Q18: How does quarantine control the spread of a pathogen? (1 mark) .......................................... Q19: State the three key aspects of the protocol for any vaccine clinical trial. (1 mark) .......................................... Q20: Describe the importance of group size in vaccine clinical trials. (2 marks) .......................................... Q21: Explain how antigenic variation enables a pathogen to evade the specific immune response. (2 marks) .......................................... .......................................... © H ERIOT-WATT U NIVERSITY GLOSSARY Glossary Acquired immunity immunity developed throughout a person’s life time; can be induced either naturally or artificially Arthropods invertebarate animals with a segemented body, jointed limbs and an external exoskeleton, e.g. insects, crustaceans and arachnids Enterovirus a virus which causes diseases such as polio and meningitis Erythrocytic asexual phase the pathogenic portion of the vertebrate phase of the life cycle of malarial organisms that takes place in the red blood cells Gene conversion occurs during DNA genetic recombination and at high frequencies during meiosis; it is one of the ways a gene may undergo mutation HA (haemagglutinin) a protein that mediates the binding of the virus to target cells Influenza A a virus which causes influenza in birds and mammals; Influenza B and C are mainly confined to humans Innate immunity inborn immunity Lysis cell breakdown Lysozyme an enzyme found in tears, saliva, and mucus which can destroy bacteria NA (neuraminidase) involved in the release of progeny virus from infected cells Phagocytes white blood cells that protect the body by ingesting/phagocytosing harmful foreign particles, bacteria, and dead or dying cells Phagocytosis the engulfing of pathogens or solid material into a vesicle with which lysosomes then fuse, releasing their digestive enzymes into it Rhinovirus one of the viruses which cause the common cold © H ERIOT-WATT U NIVERSITY 85 86 GLOSSARY Trypanosomiasis diseases caused by the protozoa Trypanosomes such as sleeping sickness and Chagas disease © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 1 Answers to questions and activities 1 Non-specific defences The immune system: Questions (page 3) Q1: To protect the body against pathogens, some toxins and cancer cells. Q2: Skin epithelial cells and lysozyme in tears and saliva. Q3: It degrades bacterial walls. Q4: This is immunity that is inborn, non-specific, and does not change over time. Any two examples from: • phagocytosis by phagocytes; • skin epithelial cells; • mucus membranes of the lungs and gut; • ciliated cells of the respiratory tract; • lysozyme in tears. Q5: A type of white blood cell which engulfs bacteria. Non-specific defences - physical and chemical: Questions (page 5) Q6: Any two from: • dry dead cells; • tiny hairs; • mucus in the trachea. Q7: Sebum contains antimicrobial fatty acids and the stomach produces acid secretions. The cellular basis of inflammation: Questions (page 9) Q8: In connective tissue, especially around nerves and blood vessels. Q9: It stimulates vasodilation and increases permeability of capillary walls. Q10: Cytokines Q11: Phagocytes / macrophages / neutrophils Q12: Phagocytosis Q13: Complement system Q14: Fibrinogen and fibrin © H ERIOT-WATT U NIVERSITY 87 88 ANSWERS: TOPIC 1 Phagocytes: Questions (page 12) Q15: Cytokines Q16: To stimulate the specific immune response. Q17: Antigen molecules on the cell surface. Q18: Engulfing and digesting solid particles. Natural killer (NK) cells: Questions (page 14) Q19: Self-destructive enzymes Q20: Apoptosis Extended response question: The inflammatory response (page 15) Suggested marking scheme Each line represents a point worth one mark. The concept may be expressed in other words. Words which are bracketed are not essential. Alternative answers are separated by a solidus (/); if both such answers are given, only a single mark is allocated. In checking the answer, the number of the point being allocated a mark should be written on the answer paper. A maximum of eight marks can be gained. 1. Mast cells. . . 2. . . .release histamine. 3. Histamine causes vasodilation. . . 4. . . .and increases capillary permeability. 5. Mast cells also secrete cytokines. 6. Cytokines act as signalling molecules. 7. The increased blood flow and the secretion of cytokines lead to. . . 8. . . .the delivery of antimicrobial proteins. . . 9. . . .and clotting elements to the site of infection/damage. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 1 89 End of Topic 1 test (page 15) Q21: The immune system protects the body against pathogens. Sebum on the skin contains fatty acids with antimicrobial properties. Pathogens find the dry outer layers of the skin to be a hostile environment. Mast cells release histamine. Histamine causes vasodilation. Cytokines act as signalling molecules. Increased blood flow leads to delivery of clotting elements. Phagocytes are attracted by cytokines. Q22: The white blood cells involved in the non-specific response are phagocytes and natural killer (NK) cells. Both phagocytes and NK cells release cytokines which stimulate the specific immune response. Phagocytes target pathogens which they recognise by the antigen molecules on their cell surface. They then destroy them by engulfing and digesting them in a process called phagocytosis. The NK cells release enzymes which induce infected cells and pathogens to produce the self-destructive enzymes of apoptosis pathways. Q23: To protect the body against pathogens. Q24: • It has antimicrobial chemicals/sebum on its surface. • Its dry outer layers are a hostile environment for pathogens. Q25: Mast cells Q26: Causes vasodilation AND increases capillary permeability. Q27: Cytokines Q28: They attract phagocytes (to the site of infection). Q29: • Antimicrobial proteins. • Clotting elements. © H ERIOT-WATT U NIVERSITY 90 ANSWERS: TOPIC 1 Q30: • Phagocytes. • Natural killer/NK cells. Q31: Antigens on the cell surface. Q32: Engulfing (and digesting) of solid particles. Q33: Self-destructive enzymes Q34: Apoptosis © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 2 2 Specific cellular defences Immune surveillance: Questions (page 20) Q1: Mast cells Q2: Neutrophils Q3: Cytokines Q4: Lymph nodes Q5: They present fragments of the cell membrane of engulfed pathogens, which carry the antigens which uniquely identify the pathogen, on their cell surface. Clonal selection theory: Questions (page 22) Q6: 1. In the red bone marrow, haematopoietic stem cells divide to produce daughter cells. 2. As a result of genetic rearrangement, during differentiation these immature lymphocytes each develop a different antigen receptor on their cell membranes. 3. Those immature lymphocytes, which carry a receptor that will bind with an antigen from the body’s own tissues, are destroyed in the bone marrow. 4. The lymphocytes that carry other antigen receptors are released from the bone marrow and move through the circulatory system to the lymph glands or thymus gland where they mature into inactive lymphocytes. 5. Most of these inactive lymphocytes will never encounter an antigen to match their receptor. 6. Inactive lymphocytes, which do meet an antigen matching their receptor, become activated and divide to produce many clones of themselves. Q7: The way in which lymphocytes are developed to respond to specific antigens. Q8: 1 T- and B-lymphocytes: Questions (page 25) Q9: Antigens on foreign cells, cells infected by pathogens and toxins released by pathogens. Q10: They have specific surface proteins. Q11: A failure of immune system regulation, leading to a response by T-lymphocytes to self antigens. Q12: They secrete antibodies into the blood and lymph. Q13: A hypersensitive B-lymphocyte response to an antigen that is normally harmless. © H ERIOT-WATT U NIVERSITY 91 92 ANSWERS: TOPIC 2 The action of T-lymphocytes: Questions (page 27) Q14: Apoptosis Q15: By engulfing pathogens. Q16: Cytokines Q17: Antigens expressed on the surface of antigen-presenting cells. The action of B-lymphocytes: Questions (page 29) Q18: Antigen-presenting cells/macrophages, T-lymphocytes Q19: A group of cells which are produced by mitosis from a single parent cell. Q20: Antibodies Q21: The antibody will only attach to one particular antigen. Q22: An antigen-antibody complex Q23: They block their binding sites. Q24: They cause them to cluster together/agglutinate. Q25: Antibodies attach to the surface of the pathogens. The antigen-antibody complex stimulates the complement system. Complement proteins form pores in the pathogen membrane, causing lysis. Immunological memory: Questions (page 31) Q26: Activated lymphocytes in the lymph nodes Q27: They are rapidly stimulated to divide and produce a new clone of lymphocytes. Q28: It is faster and involves greater production of antibodies. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 2 93 Extended response question: Clonal selection theory (page 33) Suggested marking scheme Each line represents a point worth one mark. The concept may be expressed in other words. Words which are bracketed are not essential. Alternative answers are separated by a solidus (/); if both such answers are given, only a single mark is allocated. In checking the answer, the number of the point being allocated a mark should be written on the answer paper. A maximum of six marks can be gained. 1. Clonal selection theory explains the way in which lymphocytes are developed to respond to specific antigens which invade the body. 2. Antigens are molecules on the surface of pathogens and other foreign cells or materials which activate the immune system. 3. Lymphocytes have a single type of receptor on the cell membrane. 4. This receptor is specific to one antigen. 5. Antigen binding leads to repeated lymphocyte division. . . 6. . . .which results in a clonal population of lymphocytes. End of Topic 2 test (page 34) Q29: Constantly monitoring the tissues: white blood cells. Identify pathogens to the immune system: antigens. Released by damaged cells: cytokines. Attracted to infected tissues: monocytes. Located on the cell membrane of lymphocytes: receptors. Receptor only binds to one antigen: specific. A response by T-lymphocytes to the body’s own antigens: autoimmune. A hypersensitive response by B-lymphocytes: allergic. © H ERIOT-WATT U NIVERSITY 94 ANSWERS: TOPIC 2 Q30: T-lymphocytes destroy infected cells by inducing apoptosis. T-lymphocytes secrete cytokines that activate B-lymphocytes. Antigen-presenting cells activate the production of a clone of T-lymphocytes. B-lymphocytes are activated by antigen-presenting T-lymphocytes. Each B-lymphocyte clone produces a specific antibody molecule. Antigen-antibody complexes render pathogens susceptible to phagocytosis. Cell lysis is a response stimulated by an antigen-antibody complex. Q31: They have specific surface proteins that allow them to distinguish between the surface molecules of the body’s own cells and cells with foreign molecules on their surface. Q32: They divide repeatedly to produce clones of B-lymphocytes that secrete antibodies into the lymph and blood. Q33: A second exposure to the same antigen stimulates memory cells to divide rapidly and produce new clones of lymphocytes which produce a secondary response that is much more effective in terms of antibody production. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 3 95 3 The transmission and control of infectious diseases Infectious diseases caused by pathogens: Question (page 41) Q1: Type of pathogen Example of disease Bacteria Pneumonia Fungi Candidiasis Prion CJD Protozoa Malaria Virus Herpes Methods of transmission of pathogens: Question (page 43) Q2: Example of disease Method of transmission Body fluids HIV Direct physical contact MRSA Food Typhoid Indirect physical contact Gastroenteritis Inhaled air Measles Vectors Dengue fever Water Dysentery Control of spread of pathogens: Questions (page 48) Q3: Keeps individuals who have potentially been infected separate from healthy individuals. Q4: The use of chemicals which either kill or inhibit the growth and reproduction of pathogens. Q5: • Care in the storage and handling of food. • Care in sexual health. • Good personal and domestic hygiene. © H ERIOT-WATT U NIVERSITY 96 ANSWERS: TOPIC 3 Q6: • Appropriate waste disposal system. • Safe supply chains of foods. • Supply of water of a quality that is safe to drink. Q7: The spread of diseases which are contracted from vectors can be reduced by removal of vector habitat, the sterile male technique, or the use of pesticides. Epidemiology and the spread of disease: Question (page 50) Q8: The disease occurs occasionally in a population: sporadic. Cases of the disease occur regularly in an area: endemic. There are unusually high numbers of cases in an area: epidemic. Unusually high numbers of cases in many countries: pandemic. Control measures: Questions (page 52) Q9: c) Isolation Q10: c) Immunisation Q11: b) Antibodies Extended response question: Control of spread of pathogens (page 53) Suggested marking scheme Each line represents a point worth one mark. The concept may be expressed in other words. Words which are bracketed are not essential. Alternative answers are separated by a solidus (/); if both such answers are given, only a single mark is allocated. In checking the answer, the number of the point being allocated a mark should be written on the answer paper. A maximum of six marks can be gained. 1. Quality of water supply - drinking water must be safe to drink. 2. Not contaminated with sewage. 3. Free from harmful chemicals and bacteria. 4. Supervision of food chains - enforcing minimum hygiene standards. 5. In abattoirs, restaurants, fast-food outlets, supermarkets, market stalls. (any two) 6. Health education. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 3 7. Waste disposal - refuse collection. 8. Sewage treatment. End of Topic 3 test (page 54) Q12: Pathogens may be transmitted by direct physical contact, water, food, body fluids, inhaled air or vector organisms. The spread of pathogens can be controlled by quarantine and antisepsis. Individuals have a responsibility to control disease by means of good hygiene, care in sexual health and appropriate storage/handling of food. The role of community is to ensure the quality of water supply, safe food webs, and appropriate waste disposal systems. Communities may also reduce the spread of disease by means of programmes of vector control. Q13: Quarantine keeps people who have been potentially exposed to an infection. . . . . .separate from the rest of the population. Q14: • Purify water before supplying it to households. • Ensure sewage and drinking water are kept separate. Q15: Disease: malaria / dengue. (or other suitable) Spread control: removal of areas of stagnant water / other breeding areas, e.g. old tyres. Q16: A disease that is found at a constant low level in a population. Q17: By the introduction of a new strain of the disease against which there is no immunity. © H ERIOT-WATT U NIVERSITY 97 98 ANSWERS: TOPIC 4 4 Active immunisation Active immunity: Questions (page 59) Q1: Component Function Antigen Creates immunological memory Adjuvant Enhances immune response Q2: • Dead pathogens. • Inactivated pathogen toxins. • Parts of pathogens. • Weakened pathogens. (two sources for one mark, all four for two marks) Vaccine clinical trials: Questions (page 62) Q3: Randomised - all subjects in the trial should have an equal chance of being given vaccine or the placebo. Double-blind - neither the subjects nor the persons carrying out the trial know which subjects are getting the vaccine and which the placebo. Placebo-controlled - the trial subjects are divided into two groups, one receiving the vaccine and the other a treatment which is similar in all respects to the vaccine apart from the active ingredient being tested (the placebo). Q4: Increasing sample size reduces the effect of experimental error. . . . . .and increases the statistical significance of the results Herd Immunity: Questions (page 66) Q5: Herd immunity reduces the chances of non-immune individuals coming in contact with an infected person. Q6: • Low virulence - decreases the threshold. • Short infectious period - decreases the threshold. • Easily transmitted - increases the threshold. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 4 Immunisation programmes: Questions (page 69) Q7: Herd immunity Q8: • Malnutrition: weakens the immune system so that even if children have been vaccinated, they will be less able to fight off infection. • Poverty: children living in poverty show much lower vaccination rates than more affluent children, as a result of lower engagement with the public health system. • Rejection of vaccination: vaccination as a process may be rejected by certain groups on religious or other grounds, reducing the percentage of the population which is immunised. Antigenic variation: Question (page 72) Q9: 1. gene mutation; 2. recombination; 3. gene switching. Antigenic variation in different pathogens: Questions (page 75) Q10: It occurs when one of hundreds of genes coding for variable surface glycoproteins are expressed. Q11: A new wave of Trypanosomes appears which are unaffected by the current antibodies. Direct attack on the immune system: Question (page 76) Q12: The HIV virus destroys (T-helper) lymphocytes, which weakens the immunes system and allows other infections to produce the symptoms of AIDS. Tuberculosis: Question (page 77) Q13: It survives within phagocytes. © H ERIOT-WATT U NIVERSITY 99 100 ANSWERS: TOPIC 4 Extended response question: Public health immunisation programmes (page 79) Suggested marking scheme Each line represents a point worth one mark. The concept may be expressed in other words. Words which are bracketed are not essential. Alternative answers are separated by a solidus (/); if both such answers are given, only a single mark is allocated. In checking the answer, the number of the point being allocated a mark should be written on the answer paper. A maximum of six marks can be gained. 1. Public health immunisation programmes seek to establish herd immunity to a number of diseases. 2. Herd immunity occurs when a large percentage of a population are immunised. 3. This percentage is called the herd immunity threshold. 4. Non-immune individuals are protected because there is a lower probability they will come into contact with infected individuals. 5. Difficulties arise when widespread vaccination is not effective because of malnutrition, which weakens the immune system. . . 6. . . .or poverty, which reduces vaccination rates. . . 7. . . .or a vaccine being rejected by a percentage of the population. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 4 End of Topic 4 test (page 80) Q14: An immunological memory can be developed by vaccination with antigens from infectious pathogens. This is known as active immunity. Vaccines include antigens from infectious pathogens, including inactivated pathogen toxins, dead pathogens, parts of pathogens and weakened pathogens. The antigens in vaccines are usually mixed with an adjuvant to enhance the immune response. Key aspects of the protocol for any vaccine clinical trial are that the trial should be randomised, double-blind and placebo-controlled. Group size is important in reducing experimental error and increasing statistical significance. Q15: A process by which a pathogen is able to change its surface proteins so that it can avoid the effect of immunological memory. Q16: Either one of: • The slow accumulation of small genetic mutations (antigenic drift). . . . . .that gradually change the surface antigens. • A sudden large genetic change (antigenic shift). . . . . .brought about when two different strains undergo genetic recombination. Q17: To continuously alter the surface antigens of the pathogens. Q18: Causes sporadic epidemics and the failure of vaccination programmes. Q19: HIV attacks lymphocytes which reduces the effectiveness of the immune system. . . . . .allowing other pathogens to invade and kill the host. Q20: It survives within phagocytes. © H ERIOT-WATT U NIVERSITY 101 102 ANSWERS: TOPIC 5 5 End of unit test End of Unit 4 test (page 82) Q1: a) epidermis Q2: a) mast cells Q3: c) specific immune response Q4: c) T-lymphocytes Q5: c) waste disposal Q6: a) endemic Q7: b) antigens Q8: a) malnutrition Q9: Name: sebum (or other suitable) Function: contains antimicrobial chemicals. Q10: a) A Q11: It is quicker and greater because memory cells have been activated. Q12: The curve would be slower to rise and would peak much lower. Q13: HIV destroys the B-lymphocytes which release the antibodies. Q14: Lymphocytes have a single type of receptor on the cell membrane which is specific to one antigen. Q15: Antigen binding to receptors on lymphocyte ’Y’ leads to repeated lymphocyte division. . . . . .which results in a clonal population of type ’Y’ lymphocytes only. Q16: They secrete cytokines. Q17: Any two from: • body fluids; • food; • inhaled air; • physical contact; • vector organisms; • water. Q18: Individuals who are infected or have been in contact with an infected person are isolated. © H ERIOT-WATT U NIVERSITY ANSWERS: TOPIC 5 Q19: They must be: 1. double-blind; 2. placebo-controlled; 3. randomised. Q20: Increasing group size reduces experimental error. . . . . .and increases statistical significance. Q21: It enables a pathogen to change its surface proteins. Memory cells are no longer activated by the new antigens. © H ERIOT-WATT U NIVERSITY 103