Veterinary

Immunology
Principles and Practice
Michael J. Day
BSc BVMS(Hons) PhD DSc DiplECVP FASM FRCPath FRCVS
Professor of Veterinary Pathology
Division of Veterinary Pathology, Infection and Immunity
School of Veterinary Science
University of Bristol
Langford, Bristol, UK

in collaboration with

Ronald D. Schultz
BS MS PhD DACVM
Professor and Chair
Department of Pathobiological Sciences
School of Veterinary Medicine
University of Wisconsin-Madison
Madison, Wisconsin, USA

MANSON PUBLISHING/THE VETERINARY PRESS

CRC Press
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 Contents
Foreword 5 Antigen uptake 74
Abbreviations 6 Antigen processing and presentation 77
Antigen presentation by CD1 79
Preface 8 Antigen presentation by B cells and
Key to Symbols 8 nonprofessional APCs 79
Cytokines 80
1 An Overview of the Immune System: Innate and Key points 82
Adaptive Immunity and the Inflammatory Response 9 8 The Biology of T Lymphocytes 83
Introduction 9 Introduction 83
History of immunology 9 The T-cell receptor 83
The immune system: an overview 10 T-cell development and maturation 86
The evolution of the immune system 16 T-cell activation 86
Key points 18 The role of CD4+ T lymphocytes 88
2 Antigens and Antibodies 19 Cytotoxicity 90
Introduction 19 Memory cells 94
Antigens 19 γδ lymphocytes 95
Antibodies 22 Natural killer T cells 95
Immunoglobulin classes 22 Key points 96
Antigen–antibody interaction 28 9 The Biology of B Lymphocytes 97
Key points 29 Introduction 97
3 The Complement System 30 Antigen recognition by B cells 97
Introduction 30 Development and maturation of B lymphocytes 98
The classical and lectin pathways 31 Activation of the B lymphocyte 98
The alternative pathway 32 B-cell receptor diversity 100
The terminal pathway 34 The immunoglobulin class switch 102
Biological consequences of complement Affinity maturation 102
activation 34 Kinetics of the humoral immune response 103
Tests of complement function 37 B1 and B2 lymphocytes 103
Key points 38 Memory B lymphocytes 104
Monoclonal antibodies 104
4 Serological Testing 39 Key points 106
Introduction 39
Serological tests 40 10 Testing of Cellular Immune Function 107
Key points 48 Introduction 107
Lymphocyte stimulation tests 108
5 Cells and Tissues of the Immune System 49 Tests of cytotoxic function 109
Introduction 49 Tests of phagocytic cell function 110
Primary lymphoid tissue 49 Key points 111
Secondary lymphoid tissue 51
Lymphocytes 54 11 Immune Suppression 112
Distinguishing between immune cells 56 Introduction 112
Lymphocyte recirculation 60 Antigen usage 112
The common mucosal system 64 Antibody-mediated suppression 113
Key points 64 The neuroendocrine–immunological loop 114
Regulatory (suppressor) T lymphocytes 115
6 The Major Histocompatibility Complex 65 Key points 119
Introduction 65
Graft rejection 65 12 Hypersensitivity Mechanisms 120
Major histocompatibility antigens 66 Introduction 120
The major histocompatibility complex 67 The Gell and Coombs classification of
The inheritance of MHC 68 hypersensitivity 120
MHC disease associations 69 Type I hypersensitivity 121
Other applications of tissue typing 70 Type II hypersensitivity 123
Key points 71 Type III hypersensitivity 125
Type IV hypersensitivity 127
7 Antigen Presentation and Cytokines 72 Key points 130
Introduction 72
Antigen presenting cells 72
4 CONTENTS

13 The Immune Response to Infectious Agents 131 19 Immunodeficiency 183

Introduction 131 Introduction 183
The immune response to viral infection 131 Primary immunodeficiency 183
The immune response to bacterial infection 134 Secondary immunodeficiency 189
The immune response to helminth infection 135 Key points 191
The immune response to protozoal infection 136 20 Vaccination 192
The immune response to fungal infection 138 Introduction 192
Key points 140 Passive immunization 192
14 Cancer Immunology and Immune System Neoplasia 141 Active immunization 193
Introduction 141 Types of vaccine 193
Tumour antigens 142 Future vaccine developments 197
The antitumour immune response 142 Basic principles of vaccination 198
Immunotherapy to enhance the antitumour Adverse consequences of vaccination 199
immune response 142 Key points 202
Tumours of the immune system 143 21 Immunotherapy 203
Key points 150 Introduction 203
15 Immunological Tolerance 151 Immunosuppressive agents 203
Introduction 151 Immunostimulatory agents 207
Neonatal tolerance 151 Allergen-specific immunotherapy 208
Adult tolerance 152 Intravenous immunoglobulin therapy 209
Oral tolerance 152 Recombinant cytokine therapy 209
Oral tolerance as immunotherapy 153 Cytokine gene therapy 210
Self-tolerance 153 Monoclonal antibody therapy 210
Key points 154 Antigen-specific immunotherapy 211
Parasite therapy 212
16 Autoimmunity and Autoimmune Disease 155 Gene therapy 212
Introduction 155 Stem cell therapy 212
Autoimmune disease 156 Adjunct immunotherapy 212
The genetic basis for autoimmunity 156 Key points 214
Age susceptibility to autoimmune disease 157
Hormonal influence on autoimmunity 157 22 Case Studies in Clinical Immunology 215
Primary versus secondary autoimmune disease 158 Introduction 215
Immunodiagnostic tests for autoimmunity 162 The basis of immune-mediated disease 215
Key points 165 How common is immune-mediated disease? 216
Immunodiagnosis 216
17 Allergy 166 Case 1. Canine immune-mediated haemolytic
Introduction 166 anaemia 217
Factors predisposing to allergic disease 167 Case 2. Canine immune-mediated
The hygiene hypothesis 168 thrombocytopenia 218
Allergic diseases in animals 169 Case 3. Canine systemic lupus erythematosus 220
Diagnosis of allergic disease 172 Case 4. Feline blood transfusion 222
Key points 174 Case 5. Feline multiple myeloma 224
Case 6. Equine purpura haemorrhagica 226
18 Immune System Ontogeny and Neonatal Immunology 175
Case 7. Bovine thymic lymphoma 227
Introduction 175
Case 8. Canine atopic dermatitis 228
Immune system ontogeny 175
Case 9. Equine severe combined
Passive transfer of maternal immune protection 175
immunodeficiency 229
Neonatal vaccination 177
Case 10. Canine lymphocytic thyroiditis 230
Failure of passive transfer 178
Case 11. Canine immune-mediated polyarthritis 232
Primary immunodeficiency 179
Case 12. Canine drug reaction 233
Neonatal isoerythrolysis 180
Case 13. Canine trapped neutrophil syndrome 235
Early life immune development 181
Case 14. Feline lymphoid leukaemia 236
Key points 181
Case 15. Equine neonatal isoerythrolysis 238
Glossary 239
Index 251
 Foreword
Veterinary immunology is one of the most recent, and
the most important, basic and clinical sciences in
veterinary medicine. Veterinary immunology became
an important part of the veterinary curriculum
approximately 40 years ago when most veterinary
medical students were introduced to concepts of basic
immunology during their first or second year of
veterinary school. Clinical immunology was either a
minor part of the basic immunology course or it was
taught at a later time as part of the medicine courses.
During the past 40 years, information regarding basic
and clinical immunology in veterinary medicine has
increased beyond the scope of a single course.
However, this textbook, Veterinary Immunology –
Principles and Practice, includes both basic and
clinical concepts of veterinary immunology.
The author is a veterinary immunologist engaged
in both basic and clinical research studies in
immunology and immunopathology. The book
provides not only the veterinary medical student, but
also the graduate veterinarian, with excellent
information on the basic and clinical aspects of
veterinary immunology. The basic aspects of the
science are made easily understandable to those with
a limited or no knowledge of immunology. At the
same time the book provides an excellent insight into
the complexity of diseases caused by or prevented via
innate and/or adaptive immunity. The book is equally
valuable to those with little or no understanding of
clinical medicine, as well as to those with an excellent
knowledge of basic clinical medicine. This is
accomplished through the author’s unique
presentation style in which the basic concepts of
immunology are introduced and explained, often in
the context of the mechanism for an immune-
mediated disease or the immunological mechanism
for prevention or treatment of a disease. The author
has also ‘sifted and winnowed’ through the
complexities of basic medical immunology in order to
provide the reader with factual information that
applies to most veterinary species. This book, unlike
many introductory immunology textbooks available
for medical students and undergraduate or graduate
students in the biological sciences, does not focus on
the myriad of information on the immunology of the
mouse, a favourite species of many immunologists
5
who perform in-vivo studies. Ironically, most
immunologists are of the opinion that because the
mouse’s immune system is easily manipulated for in-
vivo and ex-vivo immunological studies, it serves as a
model for all other species. Unfortunately, this is
often not true and many of the veterinary species
differ significantly among each other as well as with
the mouse regarding basic and clinical mechanisms of
diseases caused by and/or prevented via their immune
system. The species differences, when known, are
defined in this book. Information on differences
among species should make this book a valuable
reference for all immunologists, especially those with
an interest in real animal studies. Information is
included on food animal species, but the focus in the
clinical immunology sections is on companion animal
species, especially the dog and cat. The author has
written a more detailed book, Clinical Immunology
of the Dog and Cat, which is beautifully illustrated
with graphs and figures, including histopathology
sections of immune-mediated diseases in these
species. Similarly, this book is very well illustrated,
but for obvious reasons does not contain the detail
found in Clinical Immunology of the Cat and Dog.
I especially like this book because the veterinary
immunology course taught to second-year veterinary
medical students at the University of Wisconsin-
Madison first presents the ‘Basics of Veterinary
Immunology’ via eighteen didactic lectures, followed
by ‘Clinical Immunology’ via twelve ‘Clinical
Correlates’. Additionally, there are approximately
fifty hours in the course that includes: laboratory
exercises, such as vaccinating calves and puppies;
performing clinical immunology tests for the
diagnosis of diseases of companion and food animals;
and other laboratory procedures (phagocytic tests,
lymphocyte function tests and multiple serological
tests). This book provides a very helpful way of
understanding these diagnostic tests, animal
immunization and immune-mediated diseases.
This is a ‘must buy book’ for veterinary students
everywhere and for most, if not all, graduate
veterinarians who want to know, and those who need
to know, more about basic and clinical veterinary
immunology.
Ronald D. Schultz
6 Abbreviations
AChR acetylcholine receptor FAD flea allergy dermatitis
AD atopic dermatitis Fc crystallizable fragment (of Ig)
ADCC antibody-dependent cell-mediated cytotoxicity FcR Fc (Ig heavy chain) receptor
AGD agar gel diffusion FeLV feline leukaemia virus
AIDS acquired immune deficiency syndrome FHV feline herpesvirus
AIHA autoimmune haemolytic anaemia FIP feline infectious peritonitis
AINP autoimmune neutropenia FISS feline injection site sarcoma
AITP autoimmune thrombocytopenia FITC fluorescein isothiocyanate
ALL acute lymphoblastic leukaemia FIV feline immunodeficiency virus
ALP alkaline phosphatase FLA feline leucocyte antigen
ANA antinuclear antibody FOCMA feline oncornavirus-associated cell membrane
APC antigen presenting cell antigen
APTT activated partial thromboplastin time GALT gastrointestinal-associated lymphoid tissue
ASIT allergen-specific immunotherapy GCSF granulocyte colony-stimulating factor
AST aspartate aminotransferase GITR glucocorticoid-induced TNF-receptor-regulated
BALT bronchial-associated lymphoid tissue (gene)
BCR B-cell receptor GMCSF granulocyte–macrophage colony stimulating
BLAD bovine leucocyte adhesion deficiency factor
BLV bovine leukaemia virus GMP guanosine monophosphate
BoLA bovine leucocyte antigen GTP guanosine triphoshate
BSA bovine serum albumin GVHD graft-versus-host disease
BVDV bovine viral diarrhoea virus HAI haemagglutination inhibition
C3bR receptor for the third component of HAT hypoxanthine, aminopterin and thymidine
complement HEV high endothelial venule
CALT conjunctiva-associated lymphoid tissue HGPRT hypoxanthine–guanine phosphoribosyl
CD cluster of differentiation transferase
CDV canine distemper virus HIV human immunodeficiency virus
CFT complement fixation test HLA human leucocyte antigen (human MHC)
CH constant region of the heavy chain IBD inflammatory bowel disease
CH50 total haemolytic complement (assay) IBH insect bite hypersensitivity
CL constant region of the light chain IBR infectious bovine rhinotracheitis
CLAD canine leucocyte adhesion deficiency ICAM-1 intercellular adhesion molecule 1
CLE cutaneous lupus erythematosus IDST intradermal skin test
CLL chronic lymphoid leukaemia IEL intraepithelial lymphocyte
CMI cell-mediated immunity IFA immunofluorescent antibody (test)
CNS central nervous system IFN interferon (e.g. IFN-γ)
ConA concanavalin A Ig immunoglobulin
COX cyclooxygenase IGHA gene encoding the IgA heavy chain
cpm counts per minute IL interleukin
CR1 complement receptor 1 IMHA immune-mediated haemolytic anaemia
CRP C-reactive protein IMP inosine monophosphate
CTLA-4 cytotoxic T lymphocyte antigen 4 IMTP immune-mediated thrombocytopenia
DAF decay accelerating factor IVIG intravenous injection of immunoglobulin
DAMP damage-associated molecular pattern KCS keratoconjunctivitis sicca
DAT direct antiglobulin test KIR killer inhibitory receptor
DEA1 dog erythrocyte antigen 1 LAK lymphokine activated killer (cell)
DLA dog leucocyte antigen LFA-1 lymphocyte function-associated antigen 1
DNA deoxyribonucleic acid LGL large granular lymphocyte
DOI duration of immunity LPS lipopolysaccharide
DTH delayed-type hypersensitivity M cell microfold cell
EAE experimental autoimmune encephalomyelitis MAC membrane attack complex
EBP eosinophilic bronchopneumopathy MAdCAM mucosal addressin cell adhesion molecule
ELA equine leucocyte antigen MALT mucosa-associated lymphoid tissue
ELISA enzyme-linked immunosorbent assay MASP-2 MBL-associated serine protease 2
EPI exocrine pancreatic insufficiency MBL mannan-binding lectin
ER endoplasmic reticulum MBP myelin basic protein
ES excretory–secretory (proteins) MCH mean cell haemoglobin
Fab antigen-binding fragment (of Ig) MCHC mean corpuscular haemoglobin concentration
 ABBREVIATIONS 7

MCP membrane co-factor protein rHuCSF recombinant human granulocyte colony-

MCV mean cell volume stimulating factor
MDA maternally-derived antibody rHuGMCSF recombinant human granulocyte-monocyte
MHC major histocompatibility complex colony-stimulating factor
mRNA messenger RNA rHuIFN-α recombinant human IFN-α
MS multiple sclerosis RIG retinoic acid inducible gene (receptor)
NADPH nicotinamide adenine dinucleotide phosphate RNA ribonucleic acid
NALT nasal-associated lymphoid tissue RT-PCR reverse transcriptase-polymerase chain
NFAT nuclear factor of activated T cells reaction
NFκB nuclear factor κB SAA serum amyloid A
NI neonatal isoerythrolysis SCID severe combined
NK natural killer (cell) immunodeficiency/immunodeficient
NKT natural killer T-cell SI stimulation index
NKR natural killer receptor SLA swine leucocyte antigen
NO nitric oxide SLE systemic lupus erythematosus
NOD nucleotide-binding oligomerization domain SNP single nucleotide polymorphism
(receptor) SRBC sheep red blood cell
NOS nitric oxide synthase SRID single radial immunodiffusion
OLA ovine leucocyte antigen STAT signal transducer and activator of
OVA ovalbumin transcription
PALS periarteriolar lymphoid sheath TAP transporter protein (TAP1/TAP2)
PAMP pathogen-associated molecular pattern Tc T cytotoxic (cell)
PBMC peripheral blood mononuclear cell TCR T-cell receptor
PBS phosphate buffered saline Tg thyroglobulin
PCR polymerase chain reaction TGF transforming growth factor
PCV packed cell volume Th T helper (cell)
PEG polyethylene glycol TLR Toll-like receptor
PHA phytohaemagglutinin TMS trimethoprim–sulphonamide
PI persistently infected TNF tumour necrosis factor
pIgR polymeric immunoglobulin receptor TNS trapped neutrophil syndrome
PRR pattern recognition receptor TPMT thiopurine methyltransferase
PT prothrombin time Treg T regulatory (cell)
PTH parathyroid hormone TSH thyroid-stimulating hormone
PWM pokeweed mitogen UPC urine protein:creatinine (ratio)
PWMS post-weaning multisystemic wasting syndrome VH variable region of the heavy chain
(of pigs) VL variable region of the light chain
RA rheumatoid arthritis WHO World Health Organisation
RAO recurrent airway obstruction X-SCID X-linked severe combined immunodeficiency
RF rheumatoid factor
8 Preface
Veterinary Immunology – Principles and Practice has the
simple aim of providing undergraduate veterinary
students with core knowledge of veterinary immunology,
while emphasizing the clinical relevance of this subject
area. Veterinary students often struggle with the
complexity of the immune system and find it difficult to
relate immunological concepts to veterinary practice. In
many universities, immunology is taught to veterinary
undergraduates at a superficial level and the subject is also
often delivered by basic scientists with an inappropriate
focus on murine or human systems. Despite this,
immunology is a key subject in the veterinary curriculum;
it links together subject areas, such as biochemistry,
microbiology, parasitology and pathology, with clinical
medicine. One of the main clinical applications of
immunology is the practice of vaccination, and all
graduating veterinarians must have a solid understanding
of the principles of vaccinology.
There are relatively few textbooks of veterinary
immunology to support the delivery of undergraduate
courses in this subject. I hope that Veterinary
Immunology – Principles and Practice will fill a key niche
in providing students with an affordable and practical
reference that will also have relevance as they progress
through a practice career. The key features of this book
include:
• A sufficient level of detail of core knowledge,
without this being diluted by minutiae.
• Clear definition of learning objectives and bullet-
point summaries of key points, with key words
highlighted throughout the text in bold font and
listed in a glossary.
• An affordable price for a full colour text supported
by numerous diagrams and photographic images.
• An emphasis on clinical examples, with a series of
15 clinical case studies that present core information
Key to symbols
neutrophil
T cell
B cell eosinophil
plasma cell mast cell
natural killer cell
dendritic cell (APC)
macrophage (APC) platelets
related to clinically significant immune-mediated
diseases. This aspect is truly unique to this text and
is found in no other reference book on this subject.
These case studies should very clearly indicate to the
student the major clinical relevance of immunology.
They provide a bridge between this book and the
more practitioner-orientated Clinical Immunology of
the Dog and Cat. Both of these books share
fundamental aspects of presentation (e.g.
diagrammatic symbols), which should make it
straightforward to progress from one to the other.
This book is born from the lecture course in veterinary
immunology that I have delivered over the past 20 years
to students at the University of Bristol. I am delighted to
have had the opportunity of working with Professor Ron
Schultz on this project. Ron has made insightful
suggestions on the text and ensured that the content also
covers the curriculum needs of students in North
America. I am very grateful to Ron for sharing his vast
experience in veterinary immunology and helping shape
this major new resource. Both of us share a passion for
this subject and the teaching of it to veterinary
undergraduates. However, it is our belief that Veterinary
Immunology – Principles and Practice will not only have
relevance to the student market, but should serve as a
simple reference for veterinarians already in practice.
I would like to acknowledge the support and
enthusiasm for this project from Michael Manson and
Commissioning Editor Jill Northcott. This is my fourth
book for Manson Publishing, but the first truly
undergraduate textbook. My thanks go to the
production team of Kate Nardoni (project manager),
Susan Tyler (illustrator) and Peter Beynon (copy editor)
for their professional input into the finished product.
M.J. Day
endothelium or MHC class I
capillary
immunoglobulin Fc receptor
T-cell receptor antigen
antigenic
peptide
MHC class II

1
An Overview of the Immune
System: Innate and Adaptive
Immunity and the Inflammatory
Response
OBJECTIVES
At the end of this chapter you should be able to:
• Distinguish between innate and adaptive
immunity.
• Discuss how gene duplication within the immune
system provided an evolutionary advantage.
• Give examples of innate immune mechanisms of
the skin and mucosal surfaces.
• Describe the main features of acute and chronic
inflammation.
INTRODUCTION
Immunology is a relatively young and rapidly
developing science that has established itself as a
fundamental cornerstone of human and veterinary
clinical medicine. There are not many veterinary
activities that do not have an immunological aspect.
The husbandry of neonatal domestic livestock and the
essential requirements for colostral immunity, the
crucial role of vaccination in protecting the
population and the individual from infectious disease,
the laboratory diagnosis of a wide range of disorders,
the consequences of chronic disease for immune
function and the myriad of immune-mediated diseases
caused by disturbance of immune homeostasis are all
examples of how basic knowledge of the immune
system impacts on the daily practice of veterinary
medicine. The aim of this book is to provide this basic
knowledge of immune function, but also to clearly
relate this to clinical practice.
This chapter will briefly review the history of
immunology and broadly consider the different
elements of the immune system and how they interact
to create a unified whole. The focus here will be on
the innate immune system, with an introduction to
adaptive immunity, which will be discussed in detail in
subsequent chapters.
9
• List the components of the adaptive immune
system.
• Understand the key role of the dendritic cell in
linking innate and adaptive immunity.
• Understand why it is necessary to regulate the
immune system.
• Define the concept of immunological memory.
• Briefly describe the evolution of the immune
system.
HISTORY OF IMMUNOLOGY
Perusal of the relatively short history of the discipline
of immunology reveals just how integral veterinary
immunology has been to the development of this
science. This brief summary cannot do full justice to
the progressive discoveries that have led to our
current state of knowledge. Most texts record the
birth of immunology, at least in the western world, as
related to the introduction of the concept of
vaccination by Edward Jenner. In 1796, Jenner
performed his famous experiment whereby he
collected fluid from a cowpox vesicle on the hand of
the dairymaid Sarah Nelmes, and inoculated this into
the arm of the eight-year-old boy James Phipps.
Although James developed cowpox lesions, he was
protected when subsequently challenged two months
later with virulent smallpox. It has recently been
suggested that a similar experiment may have been
conducted some 20 years before Jenner by the Dorset
farmer Benjamin Jesty. The next major developments
in immunology were attributed to Louis Pasteur, who
developed vaccines to fowl cholera (1879), anthrax
(1881), swine erysipelas (1892) and rabies (1885). It
is noteworthy how many of the early developments in
immunology related to animal diseases.
10 VETERINARY IMMUNOLOGY - PRINCIPLES AND PRACTICE

In fact, the history of immunological

Table 1. Nobel Prizes in immunology.
developments can be easily appreciated by studying a
list of Nobel Prizes awarded in this discipline (Table
1). These chart the progressive recognition of 1901 Von Behring Discovery of serum antibody
antibody, phagocytic cells and complement through to
current appreciation of the molecular interactions that 1905 Koch Immune response in
underpin immune function. Of note is the 1996 award tuberculosis
to Peter Doherty, a 1962 graduate of the Queensland 1908 Mechnikov & Ehrlich Phagocytosis and antitoxins
veterinary school, who undertook postgraduate
studies on ovine ‘louping-ill’ at the Moredun Research 1913 Richet Anaphylaxis
Institute in Scotland, further demonstrating the role 1919 Bordet Complement
that veterinarians have had in the development of
immunology. In the current century, veterinary 1960 Burnet & Medawar Immunological tolerance
immunology remains a flourishing field of research, 1972 Edelman & Porter Antibody structure
with its own journals (e.g. Veterinary Immunology
and Immunopathology), conferences and societies 1977 Yalow Development of
such as the American Association of Veterinary radioimmunoassay
Immunologists. 1980 Benacerraf, Dausset Discovery of the major
& Snell histocompatibility complex
1984 Jerne, Kohler Production of monoclonal
THE IMMUNE SYSTEM: AN OVERVIEW & Milstein antibodies
1987 Tonegawa Mechanism of antibody
As you progress through this book, it is inevitable that diversity
you will be struck by the complexity of the 1990 Murray & Thomas Transplantation
mammalian immune system. The principal purpose of
the immune system is to provide protection from the 1996 Doherty & Zinkernagel Major histocompatability
myriad of infectious agents responsible for human and complex restriction
animal morbidity and mortality. The immune system
is capable of responding, with varying degrees of
efficacy, to all bacterial, viral, fungal, protozoal and
helminth pathogens. The immune system is
intrinsically involved with the inflammatory and
tissue repair processes of the body; it can initiate
responses to abnormal cells that arise during evolution and these will be discussed in the chapters
neoplastic transformation or that may be that follow.
inappropriately transplanted into the body. Such a The standard building blocks of the immune
potent biological system requires careful management system are depicted in 1. Classically, the immune
and an entire set of regulatory mechanisms to ensure system is considered to comprise of two related
that immune responses are switched off when not halves, the innate and adaptive immune responses.
required, so as not to cause inadvertent damage to The innate (inborn) immune system is older in
normal body tissue. Occasionally, this delicate balance evolutionary terms than the adaptive system. On the
goes awry and the immune system makes evolutionary tree, even relatively primitive life forms
inappropriate responses to innocuous environmental have some form of immunity. As species evolved, the
antigens, dietary antigens or components of the body, array of potential pathogens that could target those
leading to the range of immune-mediated allergic and species evolved in parallel, so there was evolutionary
autoimmune diseases that are so important in human pressure for the evolving species to develop a
and companion animal medicine. progressively more complex immune system to
The immune system of all animal species is survive the race between host and pathogen evolution
comprised of a standard set of building blocks that (see below). As we shall see in subsequent chapters,
interact with each other in predictable fashion. Much the increasing complexity of host immunity was
more is known about experimental rodent and human largely made possible by the process of gene
immunology than that related to domestic animals, duplication, giving rise to related families of
but it is possible to extrapolate many of the immunological molecules. Innate immunity therefore
fundamental principles from the better explored represents the earliest form of immune defence and is
species to our animals. That said, there are numerous intrinsically interlinked with the acute and chronic
intriguing species differences that have arisen during inflammatory responses.
 AN OVERVIEW OF THE IMMUNE SYSTEM 11

1
antigen

body surface
T Treg
polyreactive
antibody T
B
enzymes
specific
complement and
antibody
neutrophil antimicrobial
plasma
peptides dendritic
cell
cell

T secondary
macrophage
lymphoid vascular
tissue recirculation
B
NK cell

innate adaptive

1 The immune system. This diagram depicts the various components of the innate and adaptive immune systems responding to challenge by a
foreign antigen. Innate immune defence is provided by epithelial barriers, resident phagocytic and specialized lymphoid cells, polyreactive
antibodies and the alternative pathway of the complement system. The dendritic cell is the key link between innate and adaptive immunity and
transports sampled antigen to the regional lymphoid tissue. T and B lymphocytes of the adaptive immune system are activated within lymphoid
tissue and these potent and antigen-specific cells are mobilized to migrate through the vascular system to the site of antigen exposure in order
to mount the effector immune response. Once antigen is eliminated, the system must be switched off by the action of specific regulatory
populations of lymphocytes.

2
INNATE IMMUNITY
The innate immune system is particularly active at
those anatomical sites that are most likely to be the
first point of contact with potential pathogens: the
skin, respiratory tract, gastrointestinal tract,
urogenital tract, mammary gland and ocular mucosa.
The epithelial barriers that cover these surfaces are
considered part of the innate immune system. Many
of these physical barriers have a range of site-specific
modifications that further contribute to their ability to
exclude pathogens, for example:
• The cutaneous keratinized stratified squamous
epidermis is a relatively inhospitable environment
bathed in sebum and sweat, both of which
contain numerous antimicrobial substances. 2 Cutaneous innate immunity. The innate immune defences of the
Colonies of endogenous cutaneous bacteria skin include the inhospitable nature of keratinized squamous
(microflora) live normally on the skin and epithelium, the secretion of antimicrobial substances in sebum and
compete with any potential cutaneous microbial sweat, the presence of a cutaneous microflora and a range of
pathogen for space and nutrients in this leucocytes, including the intraepithelial lymphocytes and dendritic
environment (2). cells (Langerhans dendritic cells) and phagocytic cells within the
dermal microenvironment.
12 VETERINARY IMMUNOLOGY - PRINCIPLES AND PRACTICE

• The respiratory mucosa is lined by ciliated 3

columnar epithelial cells, the cilia of which beat
in unison to transport mucus and debris upwards
from the lower bronchial tree to the oropharynx,
where this material can be swallowed (3a, b).
This transport mechanism is often referred to as
the ‘muco-ciliary escalator’. Glandular secretions
released onto the respiratory surface contain
antimicrobial substances and the population of
alveolar macrophages patrols these spaces in the
lung to remove particulate debris by phagocytosis
(4).
• The small intestinal mucosa has a similar (a)
epithelial barrier, with mucus-producing goblet
cells and secreted antimicrobial substances,
including the various enzymes contained within
the bile (5). The peristaltic action of the gut wall
provides continued directional movement of
luminal content, which discourages local
colonization by pathogens. The intestinal tract
has a rich microbial flora, which again is present
in order to compete with pathogens for space and
nutrients in this location.

As mentioned above, these physical barriers are often

bathed by secretions that are enriched in antimicrobial
molecules that can cause direct damage to the
pathogen (e.g. digestion of bacterial cell walls). These
molecules include enzymes, such as lysozyme and
phospholipase A, and small antimicrobial peptides
such as the α-defensins produced by Paneth cells in
the crypts of the intestine and by epithelial surfaces of
the skin, the oral mucosa and the respiratory and
urogenital tracts. The surfactant proteins that coat the
alveolar surfaces of the lung are also antimicrobial.
Pathogens coated by these molecules (e.g. surfactant
proteins A and D) are more readily removed by
alveolar macrophages (see Chapter 3 and Chapter 5).
Other secreted molecules include the polyreactive
antibodies (see Chapter 2), which can potentially bind
to a range of foreign invaders, and molecules of the
alternative pathway of the complement system (see
Chapter 3).
Should any potential pathogen breach this ‘first
line’ epithelial barrier, then the innate immune system
must have back-up protective mechanisms. The key to
innate immunity is that these mechanisms must be
readily and continually available for ‘instant action’
when required. These mechanisms must be able to
cope with the wide spectrum of potential pathogens
that might attempt to enter the body via any of the
routes described above, and so they are relatively
nonspecific in their action.
A number of leucocyte types satisfy the
requirement of being continuously present, rapidly
activated and nonspecific in targeting pathogens.
These include the phagocytic cells (neutrophils and
macrophages), the dendritic cells, the mast cells, the
(b)
3a, b Respiratory tract innate immunity. (a) The columnar epithelial
cells lining the respiratory mucosa are ciliated. The directional
beating of these cilia moves particulate debris and mucus from the
lower respiratory tract to the oropharynx, where it is removed by
swallowing (the ‘muco-ciliary escalator’). The structure of the cilia is
shown in the electronmicrograph (b). Other innate immune defences
include the antimicrobial secretions of mucosal glands and the
leucocytes resident in the lamina propria.
natural killer (NK) cells and a specialized
subpopulation of T lymphocytes that reside within the
epithelial barriers (the intraepithelial lymphocytes,
IELs). Together, the cells and molecules of the innate
immune system can provide instant defence from
infection, but this defence is relatively weak and may
only be able to hold the invading pathogens at bay for
short periods of time.
The collective effect of the molecules and cells of
the innate immune system in responding to insult by
pathogens, trauma or a local immune response is
termed inflammation. The inflammatory response to
such stimuli is initiated by tissue resident (or sentinel)
 AN OVERVIEW OF THE IMMUNE SYSTEM 13

4 5 Intestinal innate 5
immunity. The small
intestine is endowed
with numerous innate
immune defences,
including peristaltic
movement, an
epithelial barrier,
secreted antimicrobial
substances, mucus
production by goblet
cells and the presence
of intraepithelial T
lymphocytes and
4 Alveolar macrophages. A population of macrophages resides in the phagocytic cells within
alveolar space and phagocytoses any particulate debris that might the lamina propria.
bypass innate defences higher up the respiratory tract. These cells
develop a prominent ‘foamy’ cytoplasm when activated.

cells of the innate immune system, including tissue 6

macrophages, dendritic cells and mast cells. These
cells bear surface receptors that allow them to
respond to structural or secreted components of
pathogens or to a range of molecules released by
damaged or dying tissue cells (collectively referred to
as alarmins). Engagement of the sentinel cell receptors
leads to those cells releasing an array of soluble
mediators, which are responsible for the ensuing
inflammatory response. These mediators include
cytokines and chemokines (see Chapter 7) and
vasoactive molecules (see Chapter 3). An
inflammatory response involves the accumulation of
fluid, plasma proteins and blood leucocytes at the site
of such insult. The aims of the inflammatory response
are to neutralize the inciting cause (e.g. a pathogen), 6 Acute inflammation. This section of canine skin displays acute
to contain pathogens and prevent their systemic inflammatory changes. There is vasodilation and tissue oedema, with
spread and to promote tissue repair once the pathogen margination and egress of leucocytes (chiefly neutrophils) from
is eliminated. The inflammatory response has two vessels into the tissue. Those neutrophils distant from the vessel may
distinct phases, known as acute and chronic be migrating along a chemotactic gradient towards the trigger of the
inflammation. inflammatory response (e.g. a local bacterial infection).
Acute inflammation begins within minutes of
tissue insult and classically is characterized by the
presence of the five cardinal signs of inflammation:
pain, swelling, heat, redness and loss of function of
the affected tissue. These changes relate to alterations
in the capillary vasculature of the affected tissue.
Capillary dilation (vasodilation) leads to increased undergo such extravasation are the neutrophils and
local blood flow and reduced velocity of this flow, this migration occurs within the first few hours of the
while increased permeability leads to loss of fluid acute inflammatory response (6). In parallel with
from blood to tissue (oedema) and associated loss of these changes, the stretching of the vessel wall exposes
plasma proteins. The endothelial cells lining the blood the collagen beneath the endothelium to the flowing
vessels express surface adhesion molecules (see blood and initiates coagulation involving the platelets
Chapter 5), which permit the adhesion of leucocytes and coagulation factors. The relevance of this
and the migration of these cells between the stretched mechanism is that it provides a means of preventing
endothelial cells into the tissue. The first leucocytes to spread of pathogens into the bloodstream.
14 VETERINARY IMMUNOLOGY - PRINCIPLES AND PRACTICE
Recruited neutrophils migrate in a directed
fashion towards the target pathogen in tissue via the
process of chemotaxis (see Chapter 3). The neutrophil
must then recognize and bind the target, a process
that involves the engagement of surface receptors on
the neutrophil by molecules expressed on the surface
of the pathogen. These may be components of the cell
wall of the organism or serum proteins (e.g.
antibodies and complement) that have precoated the
organism to increase the likelihood of recognition
(opsonization; see Chapter 3). Following recognition
the organism is engulfed by cytoplasmic extensions
and drawn into the neutrophil cytoplasm in a process
known as phagocytosis. Once in the neutrophil
cytoplasm, the organism is enclosed within a vacuole
(the phagosome). The phagocytosed organism is then
destroyed via the effects of the respiratory burst or by
the release of lytic enzymes and antimicrobial peptides
into the vacuole.
The respiratory burst involves assembly of the
nicotinamide adenine dinucleotide phosphate
(NADPH) complex and uptake of oxygen by the
neutrophil. This leads sequentially to the generation
of large quantities of hydrogen peroxide (catalysed by
superoxide dismutase) and then hypohalides, such as
OCl-, when myeloperoxidase catalyses the reaction
between H2O2 and halide ions such as Cl- or SCN-.
The second means by which a neutrophil can
destroy the phagocytosed target involves the fusion of
cytoplasmic granules (lysosomes) with the phagosome
to form the phagolysosome. This process results in the
release of lysosomal enzymes (e.g. lysozyme, proteases
and acid hydrolases) and antimicrobial peptides (e.g.
defensins) into the phagolysosome. The enzymes are
able to digest the wall of the organism and the
antimicrobial peptides act by inserting into and
disrupting the structure of the cell wall of the target.
As suggested above, the acute inflammatory
response takes place against the background of a
complex network of soluble inflammatory mediators
that are released at the site of inflammation. These
include the initiating alarmins, histamine (derived
from mast cells and a potent vasodilator), the kinins
(such as bradykinin), chemokines (involved in the
recruitment of leucocytes from the bloodstream) and
cytokines (involved in recruitment and activation of
leucocytes), molecules of the alternative pathway of
complement (see Chapter 3), coagulation factors and
the vasoactive lipids (collectively eicosanoids). The
eicosanoids are derived from arachidonic acid
released from phospholipids of damaged cell
membranes by the action of phospholipases.
Arachidonic acid may be converted to leukotrienes
(e.g. leukotriene B4) by the action of lipoxygenase, or
to a range of prostaglandins (e.g. prostaglandin E2),
thromboxanes (e.g. thromboxane A2) and
prostacyclins (e.g. prostaglandin I2) by the
cyclooxygenases (COX) COX-1 and COX-2. Some of
these molecules interact with nervous system sensors
(pain receptors; nociceptors) and neuropeptides may
be released from nerve endings within inflamed tissue.
The second stage of the inflammatory response
(chronic inflammation) begins 24–48 hours after the
initiating insult and is characterized by the
recruitment of blood monocytes into the tissue. These
cells differentiate into tissue macrophages and provide
the second line of innate immune defence. While
neutrophils are rapidly mobilized and effective
phagocytic cells, they have a short life span and
cannot undertake repeated phagocytosis and
destruction of targets. Although macrophages are less
rapidly recruited, they are more potent and long-lived
phagocytes that are capable of multiple phagocytic
events. Macrophages have a role in activating
adaptive immunity (see Chapter 7). In addition, they
have a role in tissue repair by phagocytosing the
apoptotic debris left after neutrophils have died by
apoptosis (preventing inadvertent damage to tissue by
viable enzymes within these cells), by phagocytosing
necrotic tissue and by releasing enzymes capable of
connective tissue remodelling.
Macrophages recognize and phagocytose target
organisms in a similar fashion to neutrophils. One of
the major enzymatic pathways of these cells involves
the generation of nitric oxide synthase (NOS), which
generates nitric oxide (NO) from arginine. NO in turn
reacts with superoxide anions to produce substances
such as nitrogen dioxide radicals, which are highly
toxic to phagocytosed organisms. Macrophages able
to generate NO are known as M1 cells and are
important in the chronic inflammatory response. A
second subset of macrophages (M2 cells) uses arginase
to convert arginine to ornithine. These cells are
noninflammatory, but they promote tissue repair and
have a role in the postinflammatory process.
The chronic inflammatory response may be
accompanied by systemic signs of illness in addition to
local tissue inflammation. This effect largely relates to
the release of a series of proinflammatory cytokines
from activated macrophages. These include
interleukin (IL)-1, IL-6 and tumour necrosis factor
(TNF)-α (see Chapter 7). They interact directly with
nerve cells in damaged tissue and are absorbed into
the circulation, where they are able to access the brain
to bind to receptor molecules that mediate pyrexia
(altering the hypothalamic body temperature set
mechanism), lethargy (promoting sleep-inducing
molecules) and anorexia (acting on the hypothalamic
satiety centre). These circulating cytokines also
stimulate the production of a collection of acute phase
proteins by the liver. The acute phase proteins include
molecules such as C-reactive protein (CRP), which
may act as an opsonin promoting phagocytosis, serum
amyloid A (SAA), which may act as a leucocyte
 AN OVERVIEW OF THE IMMUNE SYSTEM
chemoattractant and has some immunosuppressive
function, and haptoglobin, which binds iron and
thereby sequesters it from bacteria which have an
obligate metabolic requirement for this molecule. The
acute phase proteins may be detected in the blood and
are useful indicators of the presence of inflammation.
The overall effect of the acute and chronic
inflammatory responses, often in concert with
adaptive immunity (see below), is to destroy and
remove pathogens and promote tissue repair. There
are, however, some initiators of inflammation that are
very difficult to eliminate. These include intracellular
pathogens able to subvert the protective mechanisms
described above (e.g. Mycobacterium bovis), large
structures (e.g. tissue migrating parasites) or inert
irritants such as metal particles, suture materials or
vaccine adjuvants. These substances tend to induce
chronic and persistent inflammatory foci that become
‘walled-off’ from normal tissue by formation of a
granuloma (7). A granuloma may have a necrotic
core, containing foreign material plus some
neutrophils or eosinophils, and be surrounded by
macrophages. These macrophages may fuse together
to form multinucleate giant cells (8). These cells are in
turn surrounded by a zone of fibrous connective
7 8
7 Chronic inflammation. This is a section of lung from an alpaca
with Mycobacterium infection. The lesion is a granuloma with a
necrotic core containing degenerate neutrophils and bacteria (not
visible) that is walled-off by a layer of macrophages with scattered
lymphocytes.
15
tissue. A ‘sterile’ granuloma (e.g. one induced by
suture material) has this typical composition, whereas
an ‘infectious’ granuloma containing antigenic
material may also include many lymphocytes.
The final stage of the inflammatory response is
tissue repair which may largely be regulated by M2
macrophages. These cells produce fibroblast and
blood vessel growth factors, including the cytokine
transforming growth factor (TGF)-β, which promote
the deposition of collagen and growth of new vessels
that replace areas of necrotic tissue. The fibrous repair
(scar tissue) may be devoid of normal tissue elements
in tissues that are incapable of regeneration.
The population of sentinel dendritic cells plays a
key role in bridging the innate and adaptive immune
response. As we shall see in Chapter 7, this class of
cells has a pivotal role in sampling foreign antigens as
they broach barrier defences and transporting this
antigen, via lymphatic vessels, from the site of
infection to the closest area of organized lymphoid
tissue. This antigen sampling and transport permits
activation of the adaptive immune response so that
the dendritic cell provides the link between these two
halves of immunity.
8 Multinucleate giant cells. Section of skin from a cat with localized
pyogranulomatous dermatitis. Within the inflammatory infiltrate
there are multinucleate foreign body giant cells representing fused
macrophages. The cell at the base of the image contains two large
cytoplasmic vacuoles. No specific infectious cause for this reaction
was identified and it may have been triggered by a penetrating
foreign body.
16 VETERINARY IMMUNOLOGY - PRINCIPLES AND PRACTICE
ADAPTIVE IMMUNITY
The adaptive immune response is younger than the
innate immune response in evolutionary terms and is
more specific and considerably more potent in its
effects. The constituents of the adaptive immune
response are the lymphoid cells: These include:
• The T lymphocytes and the cytokine and
chemokine messenger proteins released by these
cells that direct and regulate the adaptive immune
response.
• The B lymphocytes, which transform to late-stage
plasma cells that produce and secrete antibody.
The lymphoid cells of the adaptive immune response
reside in, and circulate between, the various lymphoid
tissues of the body (e.g. the lymph nodes, spleen and
mucosal lymphoid tissues). In the adaptive immune
response, antigen is first transported from a site of
infection by a dendritic cell to the regional lymphoid
tissue. That dendritic cell in turn activates antigen-
specific T lymphocytes, which further activate
antigen-specific B lymphocytes. These activated,
antigen-specific lymphocytes must then be mobilized
from the regional lymphoid tissue and sent to the site
of infection, a process that involves these cells moving
in the lymphatic and blood circulation and interacting
with the endothelial lining of blood vessels. Once
these cells reach the site of infection, they are able to
mount a full-scale ‘effector’ response that is
considerably stronger than that permitted by innate
immunity. As these processes take some time to occur
(in the order of 4–7 days), there is a delay before
adaptive immunity ‘takes over’ from the innate form
of defence. This sequence of events will be discussed
in more detail in Chapter 13. The final component of
adaptive immunity is the development of a regulatory
response that will switch off the system when it is no
longer required (i.e. when the pathogen has been
eliminated) so as not to cause damage to normal body
tissue. However, once this is achieved, the immune
system retains the memory of that immune response.
Immunological memory is another key feature of the
adaptive immune response. Memory allows the
generation of a much more effective secondary
immune response if that same antigen is ever re-
encountered, and this phenomenon underpins the
application of vaccination in clinical medicine.
The military analogy is often used to explain
these immunological phenomena and it may be
helpful to consider the immune system as an army at
war with invading pathogens (9). In this context, the
innate immune system might be equated to the
frontier defences of the body and the dendritic cells to
messengers that may be dispatched from the frontier
to the fort (regional lymphoid tissue) where the army
of the adaptive immune response is marshalled. The
messengers provide information that enables the army
to select those troops best equipped to deal with the
particular invader, to activate those troops and to
dispatch them to the frontier, where they provide
reinforcements to the innate system in the battle
against the pathogen. These reinforcements may
eliminate the invaders and then this adaptive army
might be disbanded when instructed by regulatory
cells that step in once the battle is won. This simplistic
overview of the immune system will be expanded as
we progress through the chapters of this book.
THE EVOLUTION OF THE IMMUNE SYSTEM
The evolution of the mammalian immune system has
been widely studied. Even very primitive organisms
have an innate immune system that functions to
protect those organisms from potential pathogens.
The innate immune system may have had its origins in
the unicellular amoeba. These organisms move within
their aquatic environment and engulf food particles
that they encounter. The discrimination between food
and another amoeba may be a receptor-mediated
recognition process. These features of amoebae are
similar to those of the macrophage and it is suggested
that phagocytic cells may have had their origin from
these precursors.
The immune system of primitive species relies
largely on the activity of a range of nonspecific innate
antimicrobial molecules and the action of phagocytes
and cytokine-like proteins. The ability to distinguish
self from non-self is also an ancestral property of the
primitive immune system. Sponges, earthworms and
starfish are all capable of ‘graft rejection’ when
experimentally grafted with tissue from distinct
species, but such rejection is mediated by the innate
immune system. An excellent example of an ancestral
immunological molecule that is relatively conserved
throughout evolution is the Toll-like receptor (see
Chapter 7). These molecules were first described in
the fruit fly Drosophila and homologues are present
in mammalian species and are thought to be active
even in plants.
As organisms and the pathogens that target them
co-evolved, there were continual requirements for the
development of a more complex immune system. The
development of adaptive immunity has been described
as the immunological ‘big bang’ and is thought to
have occurred in an ancestor of the jawed fish. The
key feature of adaptive immunity is the ability to
generate diversity in antigen receptor molecules. The
event that led to development of this ability is thought
to relate to integration of a circle of extra-
chromosomal DNA (a ‘transposable element’)
containing the ancestral recombination activation
genes (RAG-1 and RAG-2) into a region of the
genome encoding an ancestor gene encoding a
 AN OVERVIEW OF THE IMMUNE SYSTEM 17

molecule similar to a T- or B-cell receptor (TCR/BCR). creation of a wide diversity in immune system
In parallel, the process of gene duplication, as molecules. The broad evolutionary stages of the
discussed with respect to the immunoglobulin immune system are summarized in Table 2.
superfamily (see Chapter 6 and Chapter 8), allowed

fort
9
barrier
(organized lymphoid tissue)

invading
pathogens inate immune messenger
defence

adaptive immune
army
reinforcements

9 The military analogy. The immune response is often likened to a war between invading pathogens and the army of the immune system. In this
model the innate immune defence might be considered as a relatively weak frontier patrol surveying the outer reaches of the body. If an enemy
invades this territory, a messenger is dispatched to the closest military fort, where a battalion of soldiers that is best equipped to deal with this
type of enemy is mobilized and sent back to the place where the frontier has been breached. These reinforcements allow successful elimination of
the enemy, following which the army is stood down when instructed by regulatory elements.

Table 2. Evolution of the immune system.

Phagocytic cells T and B

and TLRs NK cells Ig MHC lymphocytes Lymph nodes
Invertebrates
Protozoa + - - - - -
Sponges + - - - - -
Annelids + + - - - -
Arthropods + - - - - -
Vertebrates
Elasmobrachs (sharks, skates, rays) + + + - + -
Teleost fish + + + + (some) + -
Amphibians + + + + (some) + -
Reptiles + + + + + -
Birds + + + + + + (some)
Mammals + + + + + +

Adapted from Abbas AK, Lichtman AH (2003) Cellular and Molecular Immunology, 5th Edn. WB Saunders, Philadelphia, p.7.
18 VETERINARY IMMUNOLOGY - PRINCIPLES AND PRACTICE
KEY POINTS
• The two halves of the immune response are
innate and adaptive immunity.
• Innate immunity is evolutionarily older, simple,
fast-acting and nonspecific.
• Innate immunity is important at the mucosal and
cutaneous sites most likely to encounter
pathogens.
• Acute and chronic inflammation mediates the
initial response to tissue damage or infection.
• Acute inflammation involves a series of
vasoactive events allowing recruitment of
neutrophils into affected tissue.
• Chronic inflammation involves the subsequent
recruitment of macrophages into affected tissue.
• Both neutrophils and macrophages are
phagocytic cells, but they achieve this effect
through different mechanisms.
• The systemic signs of chronic inflammation are
mediated by proinflammatory cytokines
interacting with the central nervous system
(CNS) centres regulating physiological function.
• The synthesis of acute phase proteins by the liver
may be detected in the blood and used to
monitor inflammation.
• The sequela to inflammation is tissue repair.
• Some initiators of inflammation are persistent
and lead to the formation of granulomas.
• The dendritic cell is the link between innate and
adaptive immunity.
• The adaptive immune response is made in
organized lymphoid tissue.
• The adaptive immune response is slower, but
more potent and specific, than the innate
response.
• A regulatory system is required to switch off the
immune response when no longer required.
• The adaptive immune system retains memory of
previous antigenic exposure.
• The memory (secondary) immune response is
more potent than the initial (primary) response.
• Early life forms have a simple innate immune
system.
• The immunological ‘big bang’ occurred in an
ancestor of the jawed fish and led to evolution of
the adaptive immune response through the ability
to develop diversity in receptor molecules.