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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Parasitic infections remain a significant cause of morbidity and mortality in the world today. Often endemic in developing countries many parasitic diseases are neglected in terms of research funding and much remains to be understood about parasites and the interactions they have with the immune system. This book examines current knowledge about immune responses to parasitic infections affecting humans, including interactions that occur during co-infections, and how immune responses may be manipulated to develop therapeutic interventions against parasitic infection.
For easy reference, the most commonly studied parasites are examined in individual chapters written by investigators at the forefront of their field. An overview of the immune system, as well as introductions to protozoan and helminth parasites, is included to guide background reading. A historical perspective of the field of immunoparasitology acknowledges the contributions of investigators who have been instrumental in developing this field of research.
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Contents
Cover
Title Page
Copyright
List of Contributors
Introduction: Immunoparasitology: the making of a modern immunological science
Origins
Development of immunoparasitology as an experimental science
The immunological renaissance
Early breakthroughs and disappointments in parasite vaccine development
Effector mechanisms and effector choice in parasitic infection
Parasites define roles for regulatory T cells
Parasites help define the roles of regulatory cytokines and the plasticity of CD4+ T cell subsets
Parasites as triggers of the innate immune response
Lessons from helminth immunology about allergic and fibrotic disease
Returning from mouse to man
Andrade's challenge and the future of immunoparasitology
Acknowledgments
Section 1
Chapter 1: Notes on the Immune System
1.1 The immune system
1.2 Innate immune processes
1.3 The complement cascade
1.4 Innate recognition
1.5 Pattern recognition receptors
1.6 Innate immune cells
1.7 Communication in the immune system
1.8 Adaptive immunity
1.9 The role of the MHC in the immune response
1.10 T cell activation and cellular-mediated immunity
1.11 B cells and the humoral response
1.12 Cell trafficking around the body
1.13 Cellular immune effector mechanisms
1.14 Hypersensitivity reactions
Section 2
Chapter 2: Introduction to Protozoan Infections
2.1 The protozoa
2.2 Amoebozoa
2.3 Excavata
2.4 Harosa
2.5 Protozoa that are now fungi
2.6 Taxonomy and the evolution of the parasitic protozoa
2.7 Genomic and post genomic exploration of protozoan biology
2.8 Summary
2.9 General information on protozoa
Chapter 3: Apicomplexa: Malaria
3.1 Malaria
3.2 Recognition of malaria parasites
3.3 Innate effector mechanisms
3.4 Adaptive immunity
3.5 Memory responses
3.6 Immune evasion
3.7 Immunopathology
Chapter 4: Apicomplexa: Toxoplasma gondii
4.1 Introduction
4.2 Life cycle and pathogenesis
4.3 Innate immune responses
4.4 Evasion strategies
4.5 Adaptive immune responses
4.6 CNS infection
4.7 Conclusions
Chapter 5: Apicomplexa: Cryptosporidium
5.1 Life cycle
5.2 Clinical presentation
5.3 General immune responses in cryptosporidiosis
5.4 Innate effector mechanisms
5.5 Adaptive immunity
5.6 Memory responses
5.7 Antigens eliciting the immune response
5.8 Immune evasion
5.9 Immunopathology in the gut and intestinal tract
Chapter 6: Diplomonadida: Giardia
6.1 The life cycle and pathogenesis of Giardia infection
6.2 Recognition of Giardia by the immune system
6.3 Innate effector mechanisms against Giardia
6.4 Adaptive immunity against Giardia
6.5 Memory responses
6.6 Antigens eliciting the immune response
6.7 Immune evasion
6.8 Immunopathology
6.9 Summary
Chapter 7: Kinetoplastids: Leishmania
7.1 The pathogenesis of Leishmania infection
7.2 Life cycle
7.3 Parasite transmission and avoidance of immune responses
7.4 Innate effector mechanisms: the role of neutrophils in Leishmania infection
7.5 Adaptive immunity: lessons from L. major infections of mice
7.6 Arginase promotes Leishmania parasite growth
7.7 Memory responses
Chapter 8: Kinetoplastids: Trypanosomes
8.1 The African trypanosomes (Trypanosoma brucei ssp.)
8.2 Pathogenesis of sleeping sickness
8.3 Variant surface glycoprotein – the key to trypanosome-host interactions
8.4 The humoral response to African trypanosomes
8.5 T cell responses in African trypanosome infections
8.6 Innate defence mechanisms: trypanosome lytic factor
8.7 Immunopathology and VSG
8.8 Summary
Chapter 9: Kinetoplastids: Trypanosoma cruzi (Chagas disease)
9.1 Life cycle and transmission
9.2 Immune control and disease
9.3 Innate recognition of T. cruzi
9.4 Adaptive immunity
9.5 Regulation of immune responses and parasite persistence
9.6 Conclusions
Section 3
Chapter 10: Introduction to Helminth Infections
10.1 Acanthocephala
10.2 Nematodes
10.3 Pentastomida
10.4 Platyhelminthes
10.5 The evolution of parasitism within the helminths: divergent phyla with common themes
10.6 Genomic and post-genomic exploration of helminth biology
10.7 Summary
Chapter 11: Nematoda: Filarial Nematodes
11.1 The life cycle and pathogenesis of filarial nematode infections
11.2 Animal models of filariasis
11.3 Immune responses mounted against filarial nematodes
11.4 Innate immunity
11.5 Adaptive immunity
11.6 Immune evasion
11.7 Immunopathology
Chapter 12: Nematoda: Ascaris lumbricoides
12.1 Introduction
12.2 Ascaris infection displays an over-dispersed frequency distribution
12.3 Life cycle
12.4 Pathogenesis of infection
12.5 Animal models of Ascaris infection
12.6 Immune responses generated against the migratory phase of Ascaris
12.7 The cytokine response to Ascaris lumbricoides
12.8 The humoral response to Ascaris lumbricoides
12.9 Antigens eliciting immune responses in Ascaris infection
12.10 Conclusions
Chapter 13: Nematoda: Hookworms
13.1 Pathogenesis of hookworm infection
13.2 The life cycle of hookworms
13.3 Animal models of hookworm infection
13.4 Innate immune responses to hookworms
13.5 Adaptive immunity
13.6 Cytokine responses
13.7 Antibody responses
13.8 Antigens eliciting the immune response
13.9 Memory responses
13.10 Immunoregulatory aspects of the anti-hookworm immune response
13.11 Conclusion
Chapter 14: Nematoda: Trichuris
14.1 Trichuris infection
14.2 Life cycle and pathogenesis
14.3 Immunity to Trichuris
14.4 Recognition by the immune system
14.5 Innate immune responses
14.6 Adaptive immune responses
14.7 Immune memory
14.8 Vaccines
14.9 Trichuris as a therapeutic
14.10 Summary
Chapter 15: Nematoda: Trichinella
15.1 Life cycle
15.2 Pathogenesis
15.3 Adaptive immunity
15.4 Immunopathology
15.5 Evasion strategies
Chapter 16: Trematoda: Schistosomes
16.1 The schistosome life cycle
16.2 Immunological recognition of schistosomes
16.3 Innate effector mechanisms
16.4 Adaptive immunity
16.5 Memory responses
16.6 Schistosome antigens eliciting immune responses
16.7 Immune evasion
16.8 Schistosomiasis and immunopathology
Chapter 17: Cestoda: Tapeworm Infection
17.1 The life cycle of tapeworms
17.2 Epidemiology
17.3 Pathology
17.4 Innate immunity
17.5 Adaptive immunity
17.6 Antigens eliciting the immune responses
17.7 Immunomodulation or evasive mechanisms
17.8 Echinococcosis
17.9 Conclusions
Section 4
Chapter 18: Co-infection: Immunological Considerations
18.1 Co-infection is the rule rather than the exception
18.2 Interactions between co-infecting parasites
18.3 The Th1/Th2 paradigm in co-infection
18.4 Co-infection can alter disease severity
18.5 Modelling parasite interactions during co-infection
18.6 Co-infection as a therapy?
18.7 Consideration of co-infection in an ecological framework
18.8 Concluding remarks
Chapter 19: HIV and Malaria Co-infection
19.1 The endemicity of HIV and malaria
19.2 HIV infection
19.3 Immunopathogenesis of HIV
19.4 Interactions between malaria and HIV
19.5 Effect of co-infection on treatment of HIV and malaria infections
19.6 Combined effects of HIV and malaria on susceptibility to other diseases
19.7 Malaria and HIV vaccines
19.8 Summary
Chapter 20: HIV and Leishmania Co-infection
20.1 Leishmania parasitaemia is increased in HIV-Leishmania co-infection
20.2 Leishmania infection increases viral replication rate
20.3 Cell specific interactions between HIV-1 and Leishmania
20.4 Immune response interactions between HIV-1 and Leishmania
20.5 Immune reconstitution inflammatory syndrome in HIV-1/Leishmania co-infection
Chapter 21: Gastrointestinal Nematodes and Malaria
21.1 Introduction
21.2 Results from field studies in humans are conflicting
21.3 Immune responses in GI nematode and malaria co-infections
21.4 Stereotypical but different
21.5 Animal models of GI nematode-malaria co-infection
21.6 Conclusions
Chapter 22: Malaria and Schistosomes
22.1 The epidemiology of schistosomiasis and malaria co-infection
22.2 Study design for malaria/schistosome co-infection studies
22.3 Antibody responses
22.4 Cytokine responses
22.5 Contribution of experimental models to the understanding of Schistosoma mansoni and Plasmodium co-infection
22.6 Conclusions
Section 5
Chapter 23: Hygiene and Other Early Childhood Influences on the Subsequent Function of the Immune System
23.1 Introduction
23.2 The Hygiene Hypothesis (or ‘Old Friends’ hypothesis)
23.3 Epidemiological transitions
23.4 Compensatory genetic variants
23.5 The critical organisms and their immunological role
23.6 Helminth infections and allergic disorders
23.7 Helminths and non-allergic chronic inflammatory disorders: human data
23.8 Animal models of helminth infection used to test the Hygiene Hypothesis
23.9 Non-helminthic ‘Old Friends’
23.10 Mechanisms of immunoregulation
23.11 Conclusions
Chapter 24: Nematodes as Therapeutic Organisms
24.1 Evidence that parasitic nematodes can protect humans from allergy and autoimmunity
24.2 Mechanism of action
24.3 Nematode molecules involved in preventing allergic/autoimmune disease
24.4 Clinical aspects
Chapter 25.1: Vaccination Against Malaria
25.1.1 Malaria vaccines: proof of concept
25.1.2 Vaccine development
25.1.3 Pre-erythrocytic vaccines
25.1.4 Erythrocytic vaccines
25.1.5 Transmission-blocking vaccines
25.1.6 Whole organism vaccines
25.1.7 P. vivax vaccines
25.1.8 Concluding remarks
Chapter 25.2: Current Approaches to the Development of a Vaccine Against Leishmaniasis
25.2.1 Vaccination against leishmaniasis
25.2.2 Anti-amastigote vaccines
25.2.3 Anti-saliva vaccines
25.2.4 Transmission prevention vaccines
25.2.5 Role of an adjuvant in vaccine development
25.2.6 Future directions
Chapter 25.3: Vaccination Against Hookworms
25.3.1 The need for a vaccine
25.3.2 The Human Hookworm Vaccine Initiative
25.3.3 The history of hookworm vaccines: experiments in dogs
25.3.4 Antibody production against canine hookworm
25.3.5 Vaccination against hookworm with irradiated larvae
25.3.6 Lessons from vaccination with irradiated larvae
25.3.7 Research identifying target proteins for an anti-hookworm vaccine
25.3.8 A human hookworm vaccine phase 1 clinical trial based on Na-ASP2
25.3.9 The HHVI takes a different approach
25.3.10 Developments through the last century and the future
Chapter 25.4: Current Approaches to the Development of a Vaccine Against Filarial Nematodes
25.4.1 Introduction to anti-filarial nematode vaccines
25.4.2 Anti-O. volvulus and anti-LF vaccines are a valid approach to advance control measures against onchocerciasis and lymphatic filariasis
25.4.3 Future directions for vaccine development
25.4.4 Discovery of new vaccine candidates
Abbreviations Used in This Book
Glossary
Index
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Library of Congress Cataloging-in-Publication Data
Immunity to parasitic infection / edited by Tracey Lamb. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-97247-2 (hardback) – ISBN 978-0-470-97248-9 (pbk.) I. Lamb, Tracey. [DNLM: 1. Parasitic Diseases–immunology. 2. Immune System–physiology. 3. Immunity–physiology. 4. Parasitic Diseases–therapy. WC 695] 616.9′6071–dc23 2012023208
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover designer: Dan Jubb
Set in, India
First Impression 2012
List of Contributors
Tracey J. Lamb (Editor)
Department of Pediatrics, Emory University School of Medicine, 2015 Uppergate Drive, Atlanta, Georgia 30322, USA.
Judith A. Appleton
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hunderford Hill Road, Ithaca, NY 14853, USA.
Michael Arrowood
Division of Foodborne, Waterborne and Environmental Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333, USA.
Jeffrey M Bethony
Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Washington DC, USA.
Lisa K. Blum
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hunderford Hill Road, Ithaca, NY 14853, USA.
Aubrey Cunnington
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Christina Dold
Oxford Vaccine Group, Oxford University, Department of Pediatrics, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Headington, Oxford, OX3 7LJ, UK.
Soraya Gaze
Queensland Tropical Health Alliance, James Cook University, Cairns, QLD 4878, Australia.
Nebiat G. Gebreselassie
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Hunderford Hill Road, Ithaca, NY 14853, USA.
Yasuyuki Goto
Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
David B. Guiliano
School of Health, Sport and Bioscience, University of East London, Stratford Campus, London, E15 4LZ, UK.
Margaret M. Harnett
Institute of Infection, Immunity and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow, G12 8TA, UK.
William Harnett
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow, G4 0NR, UK.
Achim Hoerauf
Institute of Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany.
Jamal Khalife
Centre for Infection and Immunity of Lille INSERM, U1019-CNRS UMR 8204, University Lille Nord de France, Institute Pasteur de Lille, 1, Rue du Professeur Calmette, 59019 Lille Cedex, France.
Pascale Kropf
London School of Hygiene and Tropical Medicine, Immunology and Infection Department, Keppel Street, London, WC1E 7HT, UK.
Joanne Lello
Cardiff School of Biosciences, The University of Cardiff, Biomedical Sciences Building, Museum Avenue, Cardiff, CF10 3AX, Wales, UK.
Alex Loukas
Queensland Tropical Health Alliance, James Cook University, Cairns, QLD 4878, Australia.
Sara Lustigman
Laboratory of Molecular Parasitology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
Henry McSorley
Queensland Tropical Health Alliance, James Cook University, Cairns, QLD 4878, Australia.
Jan Mead
Department of Pediatrics, Emory University School of Medicine, Atlanta VA Medical Center, 1670 Clairmont Road, Dectaur, GA 30033, USA.
Alberto Moreno
Emory Vaccine Center, Yerkes National Primate Research Center, Division of Infectious Diseases, Department of Medicine, Emory University, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
Javier Moreno
National Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda (Madrid), Spain.
Ingrid Müller
Department of Medicine, Section of Immunology, Faculty of Medicine, Imperial College London, UK.
Mathieu Nacher
Equipe EA 35 93, Epidémiologie des parasitoses et mycoses tropicales, Université Antilles Guyane, Campus Saint Denis, Cayenne, French Guiana.
Francis M Ndungu
Kenya Medical Research Institute, KEMRI-Wellcome Programme, P.O. Box 230–80108, Kilife, Kenya.
Maria Victoria Periago
Instituto René Rachou, Belo Horizonte, Minas Gerais, Brazil.
Steven G. Reed
Infectious Disease Research Institute, 1124 Columbia Street, Suite 400, Seattle, WA 98104, USA.
Eleanor M. Riley
London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
Miriam Rodríguez-Sosa
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala Tlalnepantla, Edo. México, 54090 México.
Graham Rook
Centre for Infectious Diseases and International Health, Windeyer Institute for Medical Sciences, University College London (UCL), London, WIT 4JF, UK.
Brent Schneider
Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Washington DC, USA.
Alan Sher
National Institute for Allergy and Infectious Diseases, Bldg. 50, Rm. 6140, MSC 8003, Bethesda, MD 20892, USA.
Steven Singer
Department of Biology and Center for Infectious Disease, Georgetown University, Washington, DC 20057–1229, USA.
Sabine Specht
Institute of Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany.
Jeremy Sternberg
School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 2TZ, UK.
Rick Tarleton
University of Georgia – CTEGD, 145 Coverdell Centre, 500 D.W. Brooks Drive, Athens, GA 30602-7399, USA.
César A. Terrazas
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala Tlalnepantla, Edo. México, 54090 México.
Luis I. Terrazas
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Los Reyes Iztacala Tlalnepantla, Edo. México, 54090 México.
Emma Wilson
Division of Biomedical Sciences, University of California – Riverside, Riverside, CA 92521, USA.
Mark Wilson
Department of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK
Shona Wilson
Division of Microbiology and Parasitology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
Colby Zaph
The University of British Columbia, The Biomedical Research Centre, Department of Pathology and Laboratory Medicine, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
Introduction
Immunoparasitology: the making of a modern immunological science
Alan Sher, PhD
National Institute for Allergy and Infectious Diseases, Bethesda, USA
The field of immunoparasitology has developed from a subspecialty of parasitology into a dynamic immunological discipline with its own unique intellectual territory and conceptual contributions. Much of this evolution has occurred in recent times. Indeed, the word ‘immunoparasitology’ only came into common usage in the last 40, years appearing in the Merriam Webster Dictionary as ‘a branch of immunology that deals with animal parasites and their hosts’. It is significant that the lexicographer who provided this definition grasped that immunoparasitology was now in the realm of the immunologist and no longer a discipline practised primarily by parasitologists. In this introductory chapter, I will briefly trace the history of our field and highlight the important influence that research in immunoparasitology has had on modern immunological thought.
Origins
In considering the origins of immunoparasitology, one is immediately confronted with the issue of why the study of parasitology selectively deals with helminths, protozoa and ectoparasites. Although all of these agents were initially classified as eukaryotes, this definition now makes little taxonomic sense, as pathogenic fungi which are also eukaryotes are not referred to as parasites. Moreover, several parasitic unicellular organisms with primitive genomes (e.g. Giardia and microporidia) which were formerly thought to be protozoa have either been reclassified as fungi and/or been given the more general designation of ‘protists’ due to their unclear evolutionary status (see Chapter ). Clearly, the original classification of protozoa and helminths as parasites was a historical invention, which likely reflected not only their unusual taxonomy but also, perhaps, their identity as common and widespread disease agents of the tropics.
Given this artificial taxonomic classification which came into common usage in the 19th century, one can reach back earlier in history for examples of when host resistance phenomena concerning pathogens now known as parasites were first recognised. Human cutaneous leishmaniasis (Chapter ) is a likely candidate, because it has been known since ancient times that individuals who had healed their skin lesions were protected from further infections. For this reason, Bedouin or some Kurdistani tribal societies traditionally exposed infants to sandfly bites in order to protect them from parasite mediated facial lesions later in life.
Another ancient form of immunisation against leishmaniasis, described in written records from 10th century Persia, is the use of a thorn to transfer infectious material from lesions to uninfected individuals. Ironically, this practice of ‘leishmanisation’, in which humans are inoculated with live, unattenuated organisms that produce self-healing infections, remains the only truly effective procedure for vaccination against parasitic pathogens, although it is now seldom used (Chapter ). Acquired resistance to ‘swamp fever’ (malaria) was also recognised by European colonisers of tropical countries, who came to realise their extreme susceptibility relative to that of the indigenous populations. This, too, was an unwitting exercise in immunoparasitological thought.
The era in which most of the major parasitic infections of man were defined (i.e. the second half of the 19th century and the early 20th) coincided with the age in which the role of the immune system in host defence was first elucidated. While others may deserve consideration for the title of first modern immunoparasitologist, Robert Koch, the great German microbiologist, is a prominent candidate (Figure 1). Using newly developed techniques for identifying malaria parasites stained in blood films, Koch compared the frequency and density of parasitaemia in two distinct populations in Java with either high or low endemicity. The conclusion of this cross-sectional analysis was that protection against malaria is acquired only after heavy and repeated exposure to the parasite. These early observations were soon confirmed and extended by other investigators, who described the basic features of naturally acquired immunity to malaria in man, in part through the later use of live malaria infection to treat neurosyphilis. Although recognised earlier than protozoa as human parasites, the existence of acquired immunity to helminths was less obvious and awaited the next phase in the development of the field.
Figure 1 Some pioneers and early champions of the field of immunoparasitology.
Development of immunoparasitology as an experimental science
As the life cycles of the major parasitic infections of humans and livestock were elucidated, scientists began to question the involvement of the immune response in determining the nature of the host-parasite interaction, as well as considering the possible use of vaccination as an intervention strategy in parasitic diseases. Two American scientists, Norman Stoll and William Taliaferro, who produced most of their important work in between the two World Wars, were leading figures in this new research effort.
Stoll (1892–1976), considered by many to be the father of quantitative helminthology, challenged the dogma of his time that argued that worms fail to induce immunity. He did so by documenting the phenomena of self-cure and acquired resistance in farm and experimental animals infected with gastrointestinal helminths, and he went on to perform vaccination trials with parasite extracts.Taliaferro (1895–1973) was Stoll's counterpart in protozoan immunology. Together with his wife Lucy, he conducted experimental infections with trypanosomes and malaria in rodents, documenting both acquired immunity and the role of antibodies in protection against parasite variants.The work of these American pioneers (performed largely at Johns Hopkins, Rockefeller and Princeton) thus demonstrated the existence of immunological resistance to protozoan and helminth infection and revealed the power of animal models in studying the immune response to parasitic pathogens.
The immunological renaissance
The 1960s and 1970s saw an explosion of interest in parasite immunology. This response was fuelled by two important developments of that era. The first was the highly optimistic (and, in retrospect, quite short-sighted) sentiment that most other major infectious disease problems could be contained and even eradicated by the vaccines, drugs, and vector control measures that were being deployed successfully in many settings at that time. This attitude was epitomised in the statement attributed to the then Surgeon General of the United States, William Stewart, that: “It is time to close the book on infectious diseases, and declare the war against pestilence won.”
This bold conclusion, however, clearly did not apply to parasitic diseases, which then continued to represent a global scourge, with no vaccines and a limited number of partially effective and often toxic drugs. For this reason, leaders in the infectious disease community advocated new funding initiatives for the development of intervention strategies for parasitic infection, referring to it as the last frontier for the field.
A key figure in this effort was Kenneth Warren, a schistosomiasis researcher, who, at the Rockefeller Foundation, built an influential international network of grantees known as ‘The Great Neglected Diseases of Mankind’ (or GND for short). Warren also attracted other private foundations (e.g. Edna McConnell Clark, Macy, McArthur) to the field. Warren was himself an immunologist, and many of the investigators he enlisted in the GND programme (e.g. Graham Mitchell, Hans Wigzell, John David, Peter Pearlman, Gus Nossal) were leaders in that field.
The second major development that fuelled the growth of immunoparasitology in the 1970s was the rapid expansion of cellular and molecular immunology that occurred during the same period. The major discoveries made during this era established the cellular basis of the immune response, revealing the fundamentals of immunological specificity and of ‘self/non-self discrimination’ and providing powerful new tools (e.g. T cell clones and monoclonal antibodies) for identifying antigenic targets of immune reactions.
Of critical importance were those parasitologists who were quick to realise the potential of the ‘immunobiological revolution’ and to incorporate its new insights and approaches into their own research. In Britain, these scientists included Sydney Cohen and Neal Brown, who established the roles of humoral immunity in malaria and antigenic variation as an immune evasion strategy, and Bridget Ogilvie. The latter was one of the first to investigate the parallels between the immune response to helminths and allergy, and she had enormous vision in seeing the immunological lessons to be learned from studying worm infections. Later, as Director of the Wellcome Trust, Ogilvie played a key role in promoting the development of modern parasitology research in the UK.
Another important British investigator was James Howard, who, in addition to building a highly innovative parasitology group at the Burroughs Wellcome Research Labs in Beckenham, UK, performed pioneering studies with FY Liew on the function of CD4+ T cells in host resistance and susceptibility to Leishmania major in the murine model (Chapter ). In the USA, Jack Remington played an analogous role in establishing the critical function of cell-mediated immunity in host resistance to Toxoplasma infection (Chapter ). These transitional pioneers helped open up the field of parasitology to modern immunological approaches and laid the groundwork for the major discoveries of the following decades.
Early breakthroughs and disappointments in parasite vaccine development
In addition to the advent of new tools, such as monoclonal antibodies for identifying targets of the immune response, the late 1970s and 1980s saw the development of powerful technology for cloning and expressing pathogen proteins. In the case of parasites, these approaches first came together in the development of protective monoclonal antibodies (mAb), recognising the circumsporozoite protein (CSP) of malaria by Ruth Nussenzweig, and the cloning, sequencing and expression of this major vaccine antigen (Chapter ) by several groups in the early 1980s. This was a major achievement for the field, and it set off a wave of well-funded studies in which the same strategy was used to identify and synthesise potential vaccine immunogens in other major parasitic pathogens. Nevertheless, despite the enormous optimism of these projects, in no case (including malaria CSP itself) was sufficient protection achieved with the recombinant antigens during this era, either in experimental or human trials, to justify further development into operational vaccines.
The widespread failure of this molecularly-based strategy for parasite vaccine development underscored the dearth of information concerning immunological effector mechanisms capable of controlling parasitic infections, and how one administers parasite antigen to specifically trigger them. These important questions had been largely ignored by the molecular vaccine researchers, but were central issues for the new breed of immunoparasitologists studying the cellular immunology of parasitic infection.
Effector mechanisms and effector choice in parasitic infection
The researchers studying the basics of the immune response to parasites had early on focused on the identification of effector mechanisms capable of restricting helminth and protozoan infections. Using in vitro-grown parasite stages as targets, both antibodies and/or cells could be demonstrated to mediate pathogen cytotoxicity or growth inhibition.
An important example of such work was a study by Butterworth and colleagues, demonstrating antibody-dependent cytotoxicity against schistosome larvae by human eosinophils (Chapter ). However, it soon became clear that multiple immune mechanisms were capable of killing parasites or interfering with their growth in vitro, and that what was needed was the identification of immune responses capable of controlling parasitic infection in vivo.
In early studies, it was recognised that helminths induce immune responses that are quite distinct from those induced by protozoa. Whereas worm infections were associated with elevated levels of IgE, eosinophilia and mastocytosis that are manifestations of immediate-type hypersensitivity, protozoan infections generally lacked these responses and, instead, often displayed cell-mediated immune reactions (e.g. delayed-type hypersensitivity). It was natural to propose that these different immune effectors played important roles in host resistance to the parasites that triggered them.
With the discovery that both immediate-type and delayed-type hypersensitivity responses are mediated by the same T cell subpopulation defined by the presence of the CD4 molecule, the field was presented with an interesting paradox. Moreover, this effector choice dichotomy was not limited to worm versus protozoan infections. Thus, when certain Leishmania major strains were used to infect BALB/c and C57BL6 mice, a similar immediate versus delayed type response dichotomy was observed, accompanied by either exacerbation or healing of infection (Chapter ).
An explanation for this effector dichotomy came with the discovery that CD4+ T helper (Th) cells consist of multiple subsets defined by their cytokine secretion patterns, with Th1 cells producing interferon (IFN)-γ and inducing cell-mediated immunity, while Th2 cells promote immediate hypersensitivity responses through the production of interleukin (IL)-4, IL-5 and IL-13.
Importantly, the immune response dichotomies seen in experimental and human parasitic infection provided the first well-defined demonstrations of the in vivo relevance of this concept. Of particular importance was the murine L. major model, where healing was linked with Th1 and exacerbation of infection with Th2 induction. At the same time, helminth infection was revealed to be a potent and robustly consistent stimulus for Th2 responses, and IL-4 (and, later, IL-13) were shown to participate in resistance to gastrointestinal nematodes. Thus, work on parasitic infection models contributed enormously to the development of the concept of immunological effector choice.
Parasites define roles for regulatory T cells
An exciting by-product of the work on CD4 T lymphocyte subsets in the L. major model was the discovery that Th2 cells promote infection by down-modulating the host protective Th1 response. At that time, the concept that CD4 T cells could regulate immune responses was novel, as CD8+ T cells were thought to be specifically endowed with regulatory (‘suppressor’) function. Nevertheless, the situations in which Th2 lymphocytes were found to regulate Th1 effector function in vivo in parasitic infection were later shown to be limited to a few models and. in the case of L. major, to some – but not all – parasite isolates.
However, with the discovery that CD25+Foxp3 T regulatory (Treg) cells play a major role in dampening immune responses, it became clear that this CD4+ T cell subset has a more generalised function in regulating host resistance to microbes. Once again, many of the pioneering in vivo observations supporting this concept were made in parasitic infection models of mice. As discussed below, studies on parasitic infection later led to the discovery that effector cells can, themselves, be induced to display regulatory activity.
Parasites help define the roles of regulatory cytokines and the plasticity of CD4+ T cell subsets
The growing interest in T cell subsets and immune regulation in parasite-infected hosts led naturally to a focus on the cytokine mediators of these functions. Major discoveries were made that helped define the in vivo activities of two cytokines in particular: IL-10 and IL-27. Although IL-10 was originally described as a product of Th2 cells, we now know that it can be produced by a variety of T cell subsets, including Tregs, as well as appropriately stimulated myeloid cells. Early work established that IL-10 could dampen immune responses through its down-regulation of antigen presenting cell (principally macrophage and dendritic cell (DC)) effector function.
However, when IL-10 deficient mice were infected with Toxoplasma gondii, they became more susceptible, rather than more resistant, to parasite-induced mortality. This was because, in the absence of IL-10, the host mounts an uncontrolled pro-inflammatory cytokine response, resulting in tissue damage and shock. In a contrasting set of studies, treatment with anti-IL-10R antibodies was shown to trigger healing of mice chronically infected with L. major. These findings indicated that, while IL-10 is critical in protecting the host against parasite-induced immunopathology, its induction can promote parasite persistence in different settings. Similarly, the discovery of the in vivo anti-inflammatory properties of IL-27 (an IL-12 family cytokine that was originally thought to be a Th1-promoting cytokine) came from studies on infection with Toxoplasma and other parasites.
While IL-27 is produced largely by myeloid cells, T cells represent one of the major sources of IL-10. As noted above, the suppressive effects of Treg can be attributed to IL-10. However, it was work in protozoan models that established for the first time the role of Th1 cells as a biologically important source of the IL-10 that can suppress both immunopathology in T. gondii infection and promote the survival of non-healing strains of L. major.
Interestingly, in the former situation, the same IL-10 producing cells can display IFN-γ dependent effector function against the parasite, making them dual effector-regulatory cells. In later work with the T. gondii model, the opposite situation was also demonstrated: Treg CD4+ T cells were shown to acquire the ability to produce IFN-γ as an effector cytokine. Thus, work on parasite models has contributed enormously to our understanding of the plasticity of cytokine expression in CD4+ T cell subsets.
Parasites as triggers of the innate immune response
In approaching the problem of T helper polarisation, immunoparasitologists deduced that events occurring soon after parasite entry must be dictating the subsequent choice of T cell subset induced. These events consist of specific signals delivered by the innate immune system in response to parasite recognition. With the discovery that the cytokines IL-12 and IL-4 potently influence Th1 and Th2 differentiation respectively, it made sense that the selective triggering of one or the other mediator by different parasites would explain their ability to mediate CD4+ T cell polarisation. Indeed, mice deficient in IL-12 or IL-4 showed greatly reduced Th1 or Th2 responses following infection with intracellular protozoa or helminths, respectively.
The above findings prompted a search for the cellular sources of IL-12 and IL-4 in the innate immune system and the receptor on these cells that trigger cytokine production in response to parasite recognition. DCs, macrophages and neutrophils were documented as major sources of the Th1-polarising cytokine IL-12, and Toll-like receptors as the likely NFκ-B trigger of IL-12. However, at the same time, it became clear that, although DCs can promote Th2 responses, this is not the result of their production of IL-4. Instead, more recent work in helminth infection has documented a role for basophils as the source of the IL-4 involved in Th2 differentiation (Chapter ), although there is debate as to whether the IL-4 derived from this source is actually initiating the Th2 response or merely amplifying a Th2 population already triggered by a signal from another innate cellular source, such as DCs.
The study of helminth Th2 response initiation has also contributed to the recent discovery of novel innate lymphoid populations (collectively designated as ILC2) that produce IL-4 and other Th2 cytokines in response to IL-25 and IL-33 stimulation and participate in worm expulsion. The parasite-host receptor interactions that trigger these innate Th2 signals remain to be defined, and are currently an exciting frontier in this rapidly expanding field.
Lessons from helminth immunology about allergic and fibrotic disease
As noted above, early immunoparasitologists were quick to grasp the commonalities between the immune response to worms and the allergic response and were fascinated with the paradox of why the former is host-beneficial while the latter is host-detrimental. In dissecting the key immunological hallmarks of helminth immunity (IgE, eosinophils and mast cells/basophils), immunoparasitologists have made major contributions to understanding their role in allergic tissue inflammation, along with the cytokines (e.g. IL-10, IL-13, IL-25, IL-33) and the cells (e.g. Treg, Th1) that regulate their function.
The recognition that helminth Th2 responses are carefully modulated by the host and as a consequence trigger minimal pathology has helped promote a version of the ‘hygiene hypothesis’ that proposes that elimination of helminth infection as a consequence of economic development has led to a worldwide increase in allergic disease (Chapter ). Indeed, the field of helminth immunology is currently enjoying a resurgence, largely based on the insights it has provided to the role of Th2 responses in tissue sites and the mechanism of their regulation. In this context, the study of the immunopathology induced by schistosome eggs in liver and lung (Chapter ) has yielded important basic information on Th2-driven granuloma formation and fibrosis. In the case of the latter topic, it has also revealed major roles for IL-13 and other cytokine mediators in the fibrotic process.
Returning from mouse to man
The field of immunoparasitology has contributed to modern immunology largely through discoveries made in murine experimental models. Nevertheless, it is clear that, to be relevant, the concepts that have emerged must be also be valid in humans. Since mechanistic experiments (e.g. the demonstration of passive immunity in malaria by Cohen and colleagues) are feasible only in rare instances, the findings obtained have been gleaned largely from descriptive longitudinal studies on parasitic infection.
However, clever use of ethically acceptable interventional studies, for example those tracking immune responses and reinfection following chemotherapy, have yielded important insights into mechanisms of immunoregulation, host resistance and immunological memory in human parasitic disease. With the advent of powerful new tools, such as multifunctional flow cytometry and gene expression profiling, these studies now offer greatly increased analytical depth and have expanded, particularly in the malaria field, where the animal models for studying human P. falciparum and P. vivax infections are limited (Chapter ). The new developments in human cellular immunology have also advanced the interpretation of vaccine trials, providing correlates of both protection and failed protection that can be analysed using systems approaches.
Andrade's challenge and the future of immunoparasitology
At a schistosome vaccine meeting in the 1980s the distinguished Brazilian pathologist, Zilton Andrade made the highly quoted statement: “Schistosomiasis has done more for immunology, than immunology for schistosomiasis.” His words were a challenge to the attendees at the conference to translate their knowledge of the immune response directly into vaccine development, rather than merely using parasites to study the immune system. The issue raised by Professor Andrade is complex, since we still lack the understanding required to rationally design effective immunisation strategies protective against complex pathogens.
Milestones in the history of immunoparasitology.
1900Robert Koch's demonstration of naturally acquired immunity in human malaria.1920Basic parameters of acquired immunity in malaria defined in infected populations and neurosyphilis patients receiving ‘malariatherapy’.1924William Taliaferro describes antibody-mediated control of trypanosome infection in a rat experimental model.1927von Wagner-Jauregg awarded Nobel Prize for malariatherapy.1928Norman Stoll defines phenomena of self-cure and protection in intestinal nematode infection.1929Taliaferro publishes landmark volume, The immunology of parasitic infections.1961Cohen and McGregor demonstrate passive transfer of resistance to malaria in Gambian children.1964Reaginic (IgE) antibodies described in helminth infection by Ogilvie1965Discovery of antigenic variation in malaria by Brown and Brown and classic analysis of phenomenon in African trypanosomes by Gray1967Nussenzweig demonstrates protection against malaria mediated by irradiated sporozoites1967Demonstration of schistosome egg granuloma as manifestation of cell-mediated immunity by Warren, using lung injection model developed by von Lichtenberg (1962).1975Eosinophils described as effector cells against schistosome larvae by Butterworth.1980Enhanced susceptibility of BALB mice to cutaneous Leishmaniasis demonstrated by Howard and Liew to be form of immunologic suppression mediated by CD4 T cells.1980Monoclonal antibodies against circumsporozoite protein (CSP) shown by Nussenzweigs to confer protection against malaria.1984–1985Gene encoding malaria CSP cloned and sequenced by McCutchan and Godson.1986Th1 and Th2 subsets of CD4+ T lymphocytes identified by Mosmann and Coffman.1987Development of RTS,S vaccine initiated at Glaxo Smith Kline and Walter Reed.1988–9Opposing roles of Th1 and Th2 subsets in resistance to Leishmania described by Scott and Locksley.1993–8Functions of IL-12 and IL-10 in host resistance to parasitic infection elucidated by Gazzinelli, Scott, Wynn and Trinchieri.1997–8Initiating roles for dendritic cells in the host response to protozoan infection demonstrated by Reis e Sousa and Kaye.1999IL-13 revealed by Wynn to be a major determinant of helminth-induced Th2 tissue pathology and fibrosis.2002–2007Demonstration of roles of Treg and IL-10 producing Th1 cells in control of parasitic infection and disease by Belkaid, Sacks and Jankovic.2003Function of IL-27 as negative regulator of CD4+ T cell effector function in protozoan infection demonstrated by Hunter.2010Innate lymphoid cell subsets discovered as drivers of Th2 responses in helminth infection.2011Partial efficacy of RTT,S vaccine against malaria confirmed in large phase three clinical trials.Nevertheless, through successive refinements to the original concept of the Nussenzweigs of immunisation with CSP, a partially effective malaria vaccine that has now given reproducible results in multiple trials has emerged. This vaccine, known as RTS,S, is a recombinant protein that fuses a part of the P. falciparum CSP with the hepatitis B virus surface antigen as a carrier matrix and is administered with a proprietary liposome-based adjuvant system produced by Glaxo Smith Kline (Chapter ). RTS,S is believed to function through the production of antibodies and T cells that inhibit hepatocyte infection and parasite development, although the contribution of each of these mechanisms is poorly understood. Strikingly, the improving efficacy of RTS,S is very much the product of empirical changes in its formulation, not the malaria Ag construct itself, which was developed over 14 years ago.
The RTS,S story, while a milestone for the field, sends a clear message for future priorities for the field. First, it responds to Andrade's challenge by vindicating the need to understand better the immune effector mechanisms that can act against parasites and how best to induce them – questions that are core issues in cellular immunology. At the same time, it points to the glaring deficiency that we have in immune correlates of protection in humans, as well as the need both for extensive further research and for the development of novel, more powerful tools for carrying out this analysis. Indeed, in the case of malaria vaccination, the RTS,S vaccinees themselves represent a potential goldmine for identifying these correlates within a group uniformly exposed to the same immunogens and adjuvant.
This introductory chapter has chronicled the emergence of immunoparasitology in the latter part of the 20th century, as well its contributions to modern immunology. Host parasite systems will undoubtedly continue to provide key models for the study of immune function and, at the time of writing, they have established themselves as major tools for the study of mucosal immune responses.
While the goal of global vaccines against parasitic pathogens still eludes us, we can now, at last, point to tangible progress. It is a tempting, but perhaps not unreasonable, dream that the young scientists entering this field today may, in their future careers, both directly contribute to and witness the deployment of immunisation campaigns against parasitic diseases.
Acknowledgments
I thank Dragana Jankovic, David Sacks, Stephanie James and Tom Nutman for helpful discussions. Supported by the Intramural Research Program of the NIAID, NIH.
REFERENCES FOR FURTHER READING
Origins of immunoparasitology
Handman, E (2001). Leishmaniasis: current status of vaccine development. Clinical Microbiology Reviews 14(2), 229–243.
Stanisic, DI et al. (2010). Robert Koch redux: malaria immunology in Papua New Guinea. Parasite Immunology 32(8), 623–632.
Doolan, DL et al. (2009). Acquired immunity to malaria. Clinical Microbiology Reviews 22(1), 13–36.
Development of immunoparasitology as an experimental science
Hankins, R (2004). The Development of Parasite Immunology as an Institutionally Supported Approach to Studies of Parasitism 1918–1945. In: Priory Medical Journals (online).
The immunological renaissance
Spellberg, B (2008). Dr. William H. Stewart: mistaken or maligned? Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America 47(2), 294.
Ogilvie, BM (1964). Reagin-Like Antibodies in Animals Immune to Helminth Parasites. Nature 204, 91–92.
Howard, JG et al. (1982). Genetically determined response mechanisms to cutaneous leishmaniasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 76(2), 152–154.
Warren, KS et al. (1988). The great neglected diseases of mankind: biomedical research network. Rockefeller Foundation.
Remington, JS et al. (1972). A role for activated macrophages in resistance to infection with Toxoplasma. Infection and Immunity 6(5), 829–834.
Early breakthroughs and disappointments in parasite vaccine development
Yoshida, N et al. (1980). Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science 207(4426), 71–73.
Nussenzweig, RS & Nussenzweig, V (1989). Antisporozoite vaccine for malaria: experimental basis and current status. Reviews of Infectious Diseases 11 Suppl 3, S579–585.
Effector mechanisms and effector choice in parasitic infection
Butterworth, AE et al. (1975). Eosinophils as mediators of antibody-dependent damage to schistosomula. Nature 256(5520), 727–729.
Sher, A & Coffman, RL (1992). Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annual Review of Immunology 10, 385–409.
Mosmann, TR et al. (1986). Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 136(7), 2348–2357.
Finkelman, FD et al. (2004). Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunological Reviews 201, 139–155.
Parasite define roles for regulatory cells
Sacks, D & Noben-Trauth, N (2002). The immunology of susceptibility and resistance to Leishmania major in mice. Nature Reviews. Immunology 2(11), 845–858.
Belkaid, Y et al. (2006). Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunological Reviews 212, 287–300.
Parasites help define the roles of regulatory cytokines and plasticity of CD4+ T cell subsets
Belkaid, Y et al. (2001). The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. The Journal of Experimental Medicine 194(10), 1497–1506.
Hunter, CA et al. (2004). The role of IL-27 in the development of T-cell responses during parasitic infections. Immunological Reviews 202, 106–114.
Jankovic, D et al. (2007). Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. The Journal of Experimental Medicine 204(2), 273–283.
Anderson, CF et al. (2007). CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. The Journal of Experimental Medicine 204(2), 285–297.
Oldenhove, G et al. (2009). Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31(5), 772–786.
Gazzinelli, RT et al. (1996). In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. Journal of Immunology 157(2), 798–805.
Parasites as triggers of the innate immune response
Gazzinelli, RT & Denkers, EY (2006). Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nature reviews. Immunology 6(12), 895–906.
Schwartz, C & Voehringer, D (2011). Basophils: important emerging players in allergic and anti-parasite responses. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 33(6), 423–426.
Wills-Karp, M & Finkelman, FD (2011). Innate lymphoid cells wield a double-edged sword. Nature Immunology 12(11), 1025–1027.
Lessons from helminth immunology about allergic and fibrotic disease
Ramalingam, TR et al. (2005). Exploiting worm and allergy models to understand Th2 cytokine biology. Current Opinion in Allergy and Clinical Immunology 5(5), 392–398.
Yazdanbakhsh, M et al. (2002). Allergy, parasites, and the hygiene hypothesis. Science 296(5567), 490–494.
Wilson, MS et al. (2007). Immunopathology of schistosomiasis. Immunology and Cell Biology 85(2), 148–154.
Returning from mouse to man
Pulendran, B et al. (2010). Systems vaccinology. Immunity 33(4), 516–529.
Andrade's challenge and the future of immunoparasitology
Agnandji, ST et al. (2011). First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. The New England Journal of Medicine 365(20), 1863–1875.
Section 1
1
Notes on the Immune System
Tracey J. Lamb
Department of Pediatrics, Emory University School of Medicine, Atlanta, USA
This chapter provides some background to the immune system, outlining the cells involved in carrying out immune responses, the receptors mediating recognition of foreign antigens (such as those carried by parasitic organisms) and the effector mechanisms activated to destroy parasites and contain infection. This outline is not a comprehensive account of the workings of the immune system; instead, these notes focus on the aspects of the immune system that are most relevant to the chapters which follow on specific parasite infections.
Readers are encouraged to refer to the suggestions for further reading cited at the end of this chapter, or to one of the many comprehensive textbooks published, such as Janeway's Immunobiology, for a more detailed account of specific aspects of the immune system.
1.1 The immune system
The body has external physical barriers to prevent infection, such as the skin, the production of sweat containing salt, lysozyme and sebum, and the mucous membranes, which are covered in a layer of mucous that pathogens find hard to penetrate. If these barriers are breached, the body will then mount an immune response and mobilise immune cells to destroy the intruder.
Immune responses are carried out by a variety of different immune cells, all of which initially arise from progenitor stem cells in the bone marrow (Figure 1.1). While most cells mature in the bone marrow, T cells undergo additional development in the thymus. The number of immune cells in the body (homeostasis) is regulated through tight controls on haematopoiesis in the bone marrow, an environment rich in growth factors (such as colony-stimulating factors) and cytokines that support the growth and differentiation of immune cells. The bone marrow and thymus are known as the primary lymphoid organs, because they are the primary sites of immune cell development and maturation.
Figure 1.1 Innate and adaptive immune cells of the human body.
All cells are derived from self-renewing haematopoietic stem cells in the bone marrow, and they arise from myeloid or lymphoid progenitors. Dendritic cells can develop from both lineages and also differentiate from monocytes (pathway not shown).
Figure 1.2 Lymphoid organs in the human body.
Immune cell development occurs in the primary lymphoid organs, whereas secondary lymphoid organs are the sites where immune responses are coordinated.
Once mature, immune cells exit the bone marrow (or the thymus, in the case of T cells) and take up residence in highly organised structures composed of both immune and non-immune cells, known as the secondary lymphoid organs (Figure 1.2). Although immune responses are initiated at the point where the body's external barrier has been breached, the establishment of an immune response – particularly the adaptive arm of the immune response – occurs in the secondary lymphoid organs draining the site of infection.
The immune system has evolved a number of effector mechanisms capable of destroying pathogenic organisms. Immune responses can be classified as innate or adaptive (see Table 1.1). The innate arm of the immune system recognises pathogens non-specifically and generates immediate generic mechanisms of pathogen clearance. The adaptive arm of the immune system is more specific for individual pathogens, and it takes a number of days to develop.
There is a high degree of ‘cross-talk’ between the innate and adaptive arms of the immune system. In general, an adequate adaptive immune response is only activated after initiation by the cells of the innate immune system; conversely, innate immune effector mechanisms become more efficient by interaction with an active adaptive immune response.
1.2 Innate immune processes
The innate immune system is able to mount an immediate immune response to a foreign pathogen, or to whatever is ‘dangerous’ to the human body as embodied by Matzinger's ‘Danger hypothesis’. Innate immune responses are generic and mounted upon recognition of pathogen-associated molecular patterns (PAMPs) commonly found in molecules that are part of, or produced by, pathogenic organisms. PAMPs are recognised by pattern recognition receptors (PRRs – see Figure 1.3), primarily (but not exclusively) expressed on (and in) phagocytic antigen presenting cells (APCs) such as macrophages, dendritic cells (DCs) and some types of granulocytes. PRRs can also recognise host molecules containing damage-associated molecular patterns (DAMPs) – molecules that are often released from necrotic cells damaged by invading pathogens.
Table 1.1 Functions of the innate and adaptive arms of the immune system.
Innate Immune CellsAdaptive Immune CellsImmune recognitionImmune effector mechanismsImmune regulationImmunological memoryFigure 1.3 Some of the main pattern recognition receptors found on antigen presenting cells.
Abbreviations: DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; MD2, myeloid differentiation factor-2; MDA-5, myeloid differentiation-associated gene-5; NOD, nucleotide-binding oligomerisation domain; RIG-I, retinoic acid inducible gene-I; TLR, Toll-like receptor.
1.2.1 Inflammation
Once recognition of PAMPs or DAMPs occurs, a series of innate immune processes are activated by innate immune cells that contribute to pathogen destruction. ‘Inflammation’ is a generic term used to describe the dilation and increased permeability of the blood vessels in response to leukotrienes and prostaglandins secreted by phagocytes upon pathogen recognition. Inflammation results in increased blood flow and in the loss of fluid and serum components from capillaries into tissue, as well as the extravasation of white blood cells to the breached area. Superficially, inflammation is responsible for the visible symptoms swelling, pain and redness in infected tissue.
1.2.2 The acute phase response
The acute phase response is initiated by activation of macrophages upon ligation of PRRs with pathogen-associated molecules. This term is used to describe the production of several different proteins which enhance the containment and clearance of invading pathogens.
The production of acute phase cytokines (interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)) are collectively called endogenous pyrogens, because they stimulate the induction of prostaglandin E2, which acts on the hypothalamus to induce fever. Fever is effective in inhibiting the growth of some pathogens and can also enhance the performance of phagocytes. When uncontrolled, however, fever can be damaging to the body.
IL-6 acts on the liver to induce the production of acute phase proteins which include C-reactive protein, serum amyloid protein and mannose binding lectin (MBL). Acute phase proteins opsonise invading pathogens, promoting their phagocytosis and activating the complement pathway to induce pathogen lysis – the latter a particular feature of mannose-binding lectin (MBL) which activates the lectin-pathway of complement (see below).
1.2.3 Anti-microbial peptides
Anti-microbial peptides vary in length from between 12 and 50 amino acids, and are ionically charged molecules (anionically or cationically). In mammals, there are two large families of anti-microbial peptides: defensins and cathelicidins. These peptides can opsonise pathogens, attaching and inserting into the membrane to modify the membrane fluidity and form a pore that lyses and destroys the pathogen. It has also been suggested that some anti-microbial peptides exert their anti-microbial effects by translocating across the pathogen membrane and inhibiting essential enzymes necessary for nucleic acid and protein synthesis, effectively killing the pathogen by starvation. Anti-microbial peptides are effective against some protozoan pathogens as well as against bacteria.
Figure 1.4 The complement cascade.
The cascade involves nine components (C1-C9) and can be split into three phases: the first phase involves the attachment of C1 to antibodies opsonising the surface of a pathogen; the second phase leads to cleavage of the C2 and C4 components and the formation of C3 convertase, which in turn cleaves C3 to form C5 convertase; the third phase involves the cleavage of C5 by C5 convertase and the deposition of C5b on the surface of the pathogen. C5b activates the formation of the membrane attack complex (MAC) which creates a pore in the membrane, leading to lysis.
1.3 The complement cascade
The complement cascade involves several different components activated in sequence leading to the generation of a cytopathic ‘membrane attack complex’ (MAC). The MAC is a structure that is able to form a pore in the membrane of the invading pathogen, leading to damage and lysis (Figure 1.4). Complement can be activated by three different pathways: the classical pathway, the alternative pathway and the lectin pathway:
The classical pathway is linked to the adaptive arm of the immune system and is activated by antibody recognition of pathogens (specifically IgM or IgG) (Figure 1.4).The alternative pathway is an innate antibody-independent mechanism activated by a variety of ‘danger signals’ and spontaneous hydrolysis of C3.The lectin pathway depends on the binding of MBL to surface proteins of invading pathogens that contain mannose residues.On a molecular level, MBL shares similarity to the complement component C1q, enabling this reaction to occur. Five per cent of the world's population have polymorphisms in the gene encoding MBL which leave people with low levels of MBL. Although the lectin pathway of complement activation has been little studied, it is known to play a role in defence against some protozoan parasites, such as Cryptosporidium (see Chapter 5). Although Cryptosporidium can activate both the classical and lectin pathways of complement, it is the lectin pathway that is most effective at destroying the parasite.
Upon activation of complement the deposition of C5b on the surface of the invading pathogen leads to lysis via the assembly of the MAC. Other components of complement (in particular C3b) are opsonising agents. Phagocytic cells express complement receptors that can detect pathogens opsonised in complement fragments, promoting phagocytosis and pathogen clearance. The by-products of the cleavage of complement components C3 and C5, C3a and C5a (Figure 1.4) are also called anaphylotoxins, and these are potent inflammatory molecules that induce degranulation of mast cells and basophils, leading to the vasodilatory effects and vascular leakage associated with granule release from these cells.
Unwanted complement activation can be damaging to the host tissues, so it is necessary to regulate the process of complement activation. This regulation is carried out by several soluble and membrane-bound complement regulatory proteins, which regulate different points of activation in the complement pathway. C1 inhibitor (C1-INH) controls activation of complement via the classical and lectin-binding pathways, by associating with the C1 complex and causing the separation of C1r and C1s from C1q (see Figure 1.4). Further down the complement pathway, Factor H is able to hinder the formation of C3 convertase, while carboxypeptidase N inactivates the C3a and C5a fragments from cleavage of C3 and C5 respectively. Membrane-bound complement regulatory proteins include decay-accelerating factor (DAF or CD55), which accelerates the decay of C3 convertases, rendering them ineffective at cleaving C3.
1.4 Innate recognition
Innate immune recognition of pathogens and pathogen-associated molecules occur via several families of pattern recognition receptors (PRRs) (Figure 1.3), as well as receptors that recognise molecules that opsonise pathogens, such as MBL or anaphylotoxins (C3a and C5a). For many pathogens (in particular parasitic organisms), there is no complete picture of PAMP-containing molecules and the PRRs that initiate an innate immune response upon infection. However, it is known that innate immune responses can cross strain-specificity within a species of pathogen and, indeed, also species-specificity, because the patterns recognised by PRRs are often commonly occurring repetitive sequences.
The main PRRs that have been studied with respect to parasitic infection are the Toll-like receptors (TLRs) and some of the C-type lectin receptors, but a role for more recently discovered PRRs cannot be ruled out at present. Although APCs are generally the first type of immune cell to recognise pathogens via PRRs, many other types of immune and non-immune cells of the body have been found to express PRRs to some extent. The repertoire of PRRs expressed – and, correspondingly, the type of pathogen that can be recognised by individual cell types – varies.
1.5 Pattern recognition receptors
TLRs were first discovered in Drosophila fruit flies, and they are thought to be a microbe-detection system conserved widely throughout the animal kingdom. There are now ten described members of this family in humans and twelve in mice. The expression of individual TLRs varies with cell type, and not all TLRs are expressed on the cell surface: some are expressed intracellularly on the endoplasmic reticulum (ER) membrane.
