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To the memory of Ralph Steinman, 1943–2011

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Preface

We hope this book will be of value to readers at different levels of professional development. First and foremost, it is intended for undergraduates starting their studies of immunology, such as biomedical, medical and veterinary students (and perhaps those from other disciplines with an interest in the subject). Second, it should be of value to graduate students entering research where there is an immunological content. Last, but not least, we also hope it will be useful to more senior scientists and clinicians wanting to learn a bit more about immunology. In writing this book we have tried to help all of these groups to understand how the immune system works, not just by understanding its basic scientific and clinical concepts, but also by appreciating some of the evidence that has increased our knowledge about how and why immune responses have evolved. We also hope to stimulate readers to appreciate immunology as a science that underpins much of current clinical practice and biomedical research.

This book shows how immune defence has evolved in the face of the continual selective pressure exerted by viruses, bacteria and other pathogens, and vice versa. It explains how defence against different types of infectious agents requires different immune mechanisms and shows how pathogens have also evolved to evade these mechanisms. It describes many of the different anatomical, cellular and molecular components involved in immune responses. The book also shows how many immunological mechanisms that have evolved to protect against infection can also cause disease, and how, increasingly, we can use our knowledge of immunology to prevent or treat disease.

We aim to show that the continued development of our understanding of immunology is based crucially on a combination of experimental analysis and clinical observation. Readers will be introduced to some of the techniques currently used in immunological research, as well as a few of historical interest. They will also be introduced to selected clinical case studies to aid in understanding how and why different types of infectious and immunologically-mediated diseases are caused, and we hope that these may be of particular value to undergraduate medical students. By taking this approach, we hope that readers will gain an integrated understanding of both the basic and clinical aspects of key areas of immunology, all too often treated separately in other texts. We expect that readers will end up understanding not only the role of immune responses in infection and disease, but also how our current understanding of immunity is still deficient in so many areas. We are strongly of the opinion that the only way to increase our understanding, with the goal of more effective immune intervention, is through a balanced combination of clinical and experimental approaches.

The first chapter provides a straightforward overview of immunity and immune responses, both beneficial and harmful. The second chapter covers in more depth the nature of pathogenic organisms and their interactions with the immune system, including mechanisms that pathogens have evolved to defend themselves against immune responses. The next four chapters collectively cover in more detail the induction and regulation of immune responses at the whole organism, tissue, cellular and molecular levels. The final chapter deals with the less welcome aspects of immunity, including allergies and autoimmune diseases, and also introduces some general principles of transplant reactions and tumour immunity.

Acknowledgements

Many colleagues have assisted us in the development of this book at informal and formal levels. Those who have contributed by giving us suggestions and reviewing draft chapters include Helen Chapel, Paul Crocker, Tim Elliott, Simon Hunt, Sarah Marshall, Alan Mowat, Caetano Reis e Sousa, Adrian Smith and Tony Williams. We are grateful to all of these colleagues for their detailed inputs. We are also grateful for the advice and assistance given to us by the team at Wiley, Gregor Cicchetti, Andreas Sendtko and Anne Chassin du Guerny in particular, for the sterling work of our Graphic Designer Ruth Hammelehle who managed to convert our roughly penciled sketches into meaningful figures, and to Nitin Vashisht at Thomson Digital. Finally, we would not have been able to write this book without the patience, encouragement and support of our wives, Shelley and Karen.

A Note to the Reader

Chapters

We endeavoured to write this book so that it can either be read in its entirety from beginning to end or, alternatively, the chapters can be read separately in any order. Those with little background in immunology can begin by reading the Introduction and Chapter 1 which provides an outline of ‘The Immune System’. Readers who would like an accessible overview of the main areas of immunology might read Chapter 2 on ‘Infection and Immunity’, and/or Chapter 7 on ‘Immunity, Disease and Therapy’. These readers, and those who already have specialist knowledge, as well as all those interested in further detail can then turn to Chapter 3 on ‘Functional Anatomy of the Immune System’, Chapter 4 on ‘Innate Immunity’, Chapter 5 on ‘T Cell-Mediated Immunity’ and/or Chapter 6 on ‘Antibody-Mediated Immunity’.

Boxes

The information provided in boxes provides examples of some key techniques used in immunology, explains some aspects described in the text in a little more detail, and encourages the reader to consider broader related areas such as evolutionary aspects.

Case Studies

We have included some selected case studies in Chapters 2 and 7 to highlight the typical clinical presentation of different types of infectious and immunologically-mediated diseases, and to relate these to their underlying pathogenesis or treatment. A few others are also included in Chapters 3--6.

Questions in the Text

Scattered through the book are questions related to the topics under consideration. These are designed to make readers think critically and in more depth about important problems, and are designed to be of use for self-learning and in tutorials and seminars. As far as we know, many of these questions do not have definitive answers. (If they do, we will not apologise for our own lack of understanding since we believe that it is only through testing ones knowledge that one really begins to learn, and we are certainly not ashamed to reveal our own incomplete grasp of the subject!). Some of the questions may prove particularly challenging for the novice reader and it may be best for such readers to read a chapter in its entirety before attempting to answer many of the questions.

Learning Outcomes

At the end of each chapter we have highlighted some key questions which will enable readers to review their understanding of each topic. We have also included a few questions (‘General’ and ‘Integrative’) which will, we hope, encourage the reader to think about the broader areas covered in that chapter, and to considers these areas in relation to others covered elsewhere in the book.

Further Study Questions

At the end of Chapters 3--6 respectively are a few ‘Further Study Questions’ designed to stimulate further investigation by the reader. They could for example form the basis of extended essays, perhaps to be set by tutors. Because many of these questions are deliberately open-ended, we also have also provided a few hints as to how they might be approached.

Website

The accompanying website www.wiley-vch.de/home/immunology is based on the figures and legends from the book. These have been arranged and modified so that each set tells a coherent story that will be particularly useful for revision purposes.

Further Reading

We have deliberately avoided giving detailed bibliographical references. It is our experience that these are rarely used by students, and the speed of change in immunology means that many will be out-dated by the time the book is read. As a starting point, in terms of publications, the interested reader may wish to consult specialist articles in the Annual Reviews and Advances series, as well as Immunological Reviews, for comprehensive information on many topics. Journals in the Trends (e.g. Immunology Today) and Nature Reviews series provide particularly timely updates on key areas, while the Current Opinion series also provides some helpful pointers for readers who are ready to engage with the current primary literature. Some of the top primary research journals such as Nature Immunology, Immunity and the Journal of Experimental Medicine also contain valuable review articles. You will find many others. We consider that becoming proficient in navigating the immunological literature is an essential part of the learning process, and we hope that after reading this book you will continue to enjoy exploring immunology!

Introduction

1 Introduction

Why explore immunology? Because it is clinically important, it is academically challenging and exciting, and it holds out the promise of important advances in understanding and treating disease. In this book we aim to give the reader an understanding of how the immune system works, of how our understanding of its working has developed from both clinical and experimental evidence, and where some major gaps and problems in our understanding lie. In this short introduction we will give you some idea of the different areas of immunology that will be discussed in more detail in the following chapters. Throughout most of the book we will use real clinical and experimental examples to illustrate the importance of immunology to all those with an interest in the biomedical and biomedical sciences.

2 Immune Responses

Recovery from influenza and resistance to re-infection, vaccines, hay fever, asthma, treatment of rheumatoid arthritis, rejection of transplanted kidneys, the diagnosis of leukaemia and a potential cure for cancer – all of these involve immunology. Immunology is the study of the immune system and of its multiple, complex responses. Most immunologists consider that the immune system has evolved to defend the host against infectious agents, some of which have the potential to cause real harm. These agents, ranging in type from viruses, bacteria and fungi to worms, are called pathogens. However the immune system can respond to almost any foreign molecule including proteins, carbohydrates, nucleic acids – even molecules such as dinitrophenol that have never existed in nature. For our purposes, at this stage, these types of molecule can be loosely and collectively termed antigens.

The immune system constantly patrols our entire body for any signs of infection. If it occurs, rapid changes are induced at the local site of infection, typically leading to inflammation which we all know so well – think of the redness, swelling, sense of heat and pain (and pus) if you have a boil on your skin or a stye in your eye. At the same time, other changes are more slowly induced away from the site of infection in specialised organs of immunity such as the lymph nodes – these include the painful swellings in your neck you will sometimes feel f you have a really bad sore throat. All these changes are caused by specialised cells of immunity, some of which are selectively involved in different types of infection and at different sites of the body. These cells use a vast array of specialised molecules to talk to neighbouring and more distant cells, and some of these can also cause changes in organs very distant from the site of infection – if you have a fever it is because some of them act on part of your brain. All these different organs, cells and molecules work together to bring about a highly coordinated and tightly regulated series of events, an immune response, which endeavours to bring about the elimination of the infectious agent.

The immune responses is a reactive, homeostatic response to changes in the host's internal and external environment. Importantly, in vertebrates such as ourselves, some types of immune response ensure that when an infectious agent has been eliminated the individual is protected against subsequent encounters with the same agent – if you have had measles as a child you will (almost certainly) never get it again. This phenomenon, termed immunological memory, thus ensures that a state of immunity is generated that can last a lifetime.

3 Infection and Immunity

3.1 Life in a Micro-Organism-Rich World

The human body contains some 10¹³ cells. The human large intestine contains about 10¹⁴ bacteria. We are constantly interacting with viruses, bacteria, fungi and smaller parasites. In the developing world, interaction with larger parasites such as worms is a continuous, unremitting part of life. Most of these interactions are harmless, indeed some are beneficial – the commensal bacteria that fill our large intestines and coat many other sites exposed to the external world serve to protect us from infection by harmful microbes.

All multicellular organisms provide a potential niche for micro-organisms to colonize and even bacteria can be infected by viral pathogens, the bacteriophages. Our bodies are potentially a rich source of food for microbes and parasites, and without an immune system we would be eaten to death. While many microbes can co-exist peacefully with their hosts, some have the potential to cause damage or even death. It follows that evolutionary pressures will select for mutations in hosts that increase their ability to resist potentially damaging infections and to tolerate colonization with harmless bacteria that may prevent attack by pathogens. In parallel, micro-organisms capable of surviving within a multicellular host will mutate to be able to increase their chances of survival and thus of spreading their gene pools to other hosts. However, micro-organisms evolve much faster than mammals, for example, and thus another challenge for any host immune system is to try to anticipate in advance what possible mutations might arise in micro-organisms in the future, as the host itself will not be able to evolve nearly so quickly. Remarkably, in many cases the immune system does this very successfully.

3.2 Infectious Disease

Fortunately, almost all of us have some capacity to defend ourselves against infection by potential pathogens. Most of us are able to recover from repeated bouts of influenza, year after year. And yet over 14 million people world-wide are infected with tuberculosis of whom around 1.6 million will die of this disease every year. More than a million people die of malaria each year about 1 child every 30 seconds in Africa alone. Acquired immunodeficiency syndrome (AIDS) cases continue to increase dramatically in the developing world. Closely related to the above is the problem of drug resistance, which is on the increase in all forms of infectious disease. There are some strains of Mycobacterium tuberculosis (the causative bacterium of TB) that are resistant to all current antibiotics. Some strains of the malarial parasite are becoming resistant to almost all drugs. Infection with drug (methicillin)-resistant Staphylococcus aureus (MRSA) is a major problem in hospitals, and the human immunodeficiency virus (HIV) is becoming resistant to many of the drugs in clinical use. We are running out of antibiotics – no new class of antibiotic has come into clinical use in the last 20 years (there are some hopeful signs). Microbes will always evolve new ways of defending themselves against antibiotics, so we have an urgent need to understand how to manipulate the immune system to generate even better protective responses against continually-evolving pathogens. This is one of the main focuses of immunological research today.

4 Immunopathology and Immunotherapy

4.1 Immune-Mediated Disease

Pathogens, by definition, can cause disease. Disease can also be caused by the inability to make an effective immune response to a pathogen; this is termed an immunodeficiency disease. Happily such diseases are rare, but we have all seen images of children having to be enclosed in sterile plastic bubbles because of their defective immunity. Disease can further be caused by the immune system making an inappropriate response to a normal component of the host. Most of us know people who are diabetic or who have the crippling joint destruction seen in some forms of arthritis – these are different forms of autoimmune diseases. We also all know people who suffer from allergies, caused by apparently harmless antigens such as pollen in hay fever. Or those who have reactions (sensitivities) to metals such as nickel in jewelry sensitivities to metals such as nickel; we will term these conditions immune-related sensitivities (they are sometimes called allergies and hypersensitivity diseases). Many of us will have heard that these diseases are on the increase in developed countries, asthma being a prime example. Fewer will be aware that this increase is not in general seen in the developing world. We are still puzzling to understand why these changes occur and how we might prevent or explain them.

Thus, it is essential that we deal effectively with pathogens, but it is inconvenient, even life-threatening, when the immune system – often for completely unknown reasons – makes a powerful response against something that is inherently harmless, such as pollen, or against part of the body itself. It is another major goal of immunological research to discover how to switch off these unwanted responses selectively, rather than having to use non-specific drugs, many of which such as steroids have serious side-effects and often render the patient at high risk of infection.

4.2 The Challenge of Transplants, the Problem of Cancer

A different setting where scientists and clinicians really want to know how to manipulate immune responses is after organ transplantation. Many of us will know or know of people who have had kidney transplants because their own organs have failed. Most of us will know that often the only way that transplants can be accepted is by using powerful chemical immunosuppressive agents such as cyclosporin or tacrolimus. Usually transplants come from other people, generally people who are more or less genetically different from the patient. Not surprisingly the immune system of the patient recognizes that these foreign organs are not normal parts of the body and tries to eliminate them. Indeed, the dramatic power of the immune system is manifested by the subsequent rejection episodes that may follow. If we try to turn these off, using available chemical agents, the patient becomes increasingly susceptible to infections, and also to certain cancers some of which may actually be triggered by viral infections.

What about malignant tumours (cancer)? A disconcerting fact is that potentially malignant cells are probably appearing within our bodies almost continuously – and yet two in every three people will never develop a malignant tumour. Back in the 1950s, it was first suggested that the immune system is continuously surveying the body and trying to eradicate malignant cells as they arise, a phenomenon that was thus called immune surveillance. Quite a challenge, given that these cells derive from cells that naturally belong to the body! Nevertheless, there is some evidence that this idea is correct, and yet malignant tumours do develop in many people particularly as they get older and past reproductive age. We are still puzzling to understand why this happens in some and not others; while some parts of the puzzle seem to have been solved, such as the links between tobacco smoking and lung cancer, others have certainly not.

Another remarkable idea to emerge in quite recent years is that it may eventually become possible to vaccinate people against cancers. One recent dramatic advance has come with the development of a vaccine against the strain of human papilloma virus (HPV) that is associated with cervical carcinoma; by preventing infection by HPV this vaccine protects women against the development of the cancer. This form of vaccination is called prophylactic because it is given before infection actually occurs. An even bigger challenge will be to discover if and how we can vaccinate people who have actually developed a cancer, and also people who already have an infectious disease (e.g. HIV infection). Since this form of vaccination is designed as a therapy to treat an already existing condition it is termed therapeutic vaccination.

4.3 Immunological Interventions in Disease

Vaccines are, of course, the best-known and most effective examples of immune intervention. Smallpox has been eradicated globally, poliomyelitis exists in only a few areas of a few countries and tetanus is 100% preventable by vaccination. We also have highly successful vaccines against some other infections, such as diphtheria, measles, mumps and rubella. Why do we not have effective vaccines against HIV, tuberculosis, malaria and many other major infectious diseases? It is not for want of trying. All over the world vast sums of money are put into vaccine development, yet researchers still say that successful vaccines against these infections are 5, 10 or even more years away, which in reality means that we have no idea if or when they will actually be available.

Increasing numbers of immune-based treatments are being developed. Apart from the development of some really successful vaccines against infection, the production of therapeutic antibodies is probably the most dramatic success story of immunology to date. For example, some forms of rheumatoid arthritis that are totally resistant to all standard treatments can be halted in their tracks by a genetically-engineered antibody generated against a protein involved in stimulating inflammation. Modern molecular approaches are starting to make real differences and this last example demonstrates how an understanding of the basic mechanisms of immunology can be used to design new therapies using tools derived from the immune system itself.

4.4 Using Immunological Tools for Diagnosis

Leukaemia is a malignant tumour of blood cells. In leukaemias that arise from the lymphocytes – normally helping to defend us against infection – the leukaemic cells can originate from either T or B lymphocytes. The success of treatment depends on giving the best drugs, and these differ for T- and B-derived leukaemias. T and B cells differ in the proteins they carry on their surfaces and highly specific, artificially generated monoclonal antibodies have been developed which bind to molecules expressed by only one or the other. This makes it straightforward to distinguish between the leukaemias and to give the optimal treatment.

Another example comes from breast cancer. In assessing the likely outcome for a patient diagnosed with such a tumour it is crucial to know if the tumour has spread to the glands (actually, the lymph nodes) in the armpit. Using basic histological techniques it can be very difficult to identify small numbers of tumour cells in the node. If however a section of the lymph node is labelled with an antibody to a molecule (cytokeratin) found only in the epithelial cells from which the tumour originates and is stained using special techniques, tumour cells can be made to stand out as bright red on a blue background under the microscope. This enables the clinician to determine if the tumour has spread to the node and to adjust therapy accordingly.

5 Exploring Immunology

Is immunology difficult? Well, immunology is a complex and incompletely understood science that many find difficult to understand. We are tempted to say that if you find it easy you are not doing it properly – there are many areas that still puzzle all immunologists. We hope that we have already shown that immunology is a field of study that impinges importantly on all areas of medicine and biomedical science.

Another difficulty for anyone trying to explain immunology is that it is not possible, at least to our minds, to teach or learn immunology in a linear, incremental way. In comprehending immune responses, understanding one part depends on understanding others, and the understanding of these others depends on understanding the first part. It all seems confusing at first and it is only after covering much of immunology that it starts to form a coherent picture. If you find it confusing at first, in Chapter 1we give you a brief, straightforward overview of the immune system and immune responses, before going into more detail in the rest of the book. Finally, when you have finished reading this book, we hope that you will find yourself fully equipped to continue and develop your interest in this clinically and scientifically important, sometimes frustrating, but always intriguing field by further exploring immunology.