CLINICAL IMMUNOLOGY OF THE DOG AND CAT Second Edition Michael J Day BSc BVMS (Hons) PhD DSc DiplECVP FASM FRCPath FRCVS Professor of Veterinary Pathology Langford, Bristol, UK Manson Publishing/The Veterinary Press http://avaxhome.ws/blogs/ChrisRedfield Dedication To Lara, Christopher and Natalie Disclaimer The authors and Publisher have made every effort to ensure that therapeutic recommendations (particularly those concerning immunomodulatory and cytotoxic drug selection and dosage) set out in the text are in accord with current recommendations and practice. However, in view of ongoing research, changes in government regulations and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for any added warnings and precautions. The cytotoxic drugs detailed in this book are not licensed for veterinary use. All of these agents are potentially hazardous to the patient and to persons handling or administering them. Veterinary surgeons who prescribe such drugs to patients in their care must assume responsibility for their use and safe handling. Veterinary surgeons who are not familiar with the use of cytotoxic agents should seek further information and advice from a specialist. Copyright © 2008 Manson Publishing Ltd ISBN: 978-1-84076-098-9 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means without the written permission of the copyright holder or in accordance with the provisions of the Copyright Act 1956 (as amended), or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 33–34 Alfred Place, London WC1E 7DP, UK. Any person who does any unauthorized act in relation to this publication may be liable to criminal prosecution and civil claims for damages. A CIP catalogue record for this book is available from the British Library. For full details of all Manson Publishing Ltd titles please write to: Manson Publishing Ltd, 73 Corringham Road, London NW11 7DL, UK. Tel: +44(0)20 8905 5150 Fax: +44(0)20 8201 9233 Email: [email protected] Website: www.mansonpublishing.com Commissioning editor: Jill Northcott Project manager: Paul Bennett Copy editor: Peter Beynon Layout: DiacriTech, Chennai, India Colour reproduction: Tenon & Polert Colour Scanning Ltd, Hong Kong Printed by: Grafos SA, Barcelona, Spain CONTENTS Preface (First Edition) 6 3 The Basis of Immune-Mediated Disease 75 M. J. Day Preface (Second Edition) 7 The spectrum and interrelationship of immune-mediated disease 75 Contributors 8 Immunological mechanisms underlying allergic disease 76 Abbreviations 8 Immunological mechanisms underlying autoimmune disease 78 Key to Symbols 10 Genetic defects underlying immunodeficiency disease 88 1 Basic Immunology 11 The induction of lymphoid neoplasia 88 M. J. Day Major histocompatibility complex and Introduction 11 other genetic associations with The immune system: an overview 11 immune-mediated disease 90 Antigens 12 Further reading 93 Antibodies (immunoglobulins) 14 Antigen–antibody interactions 16 4 Immune-Mediated Haematological Disease 94 Complement 16 M. J. Day and A. J. Mackin Cells of the immune system 21 Introduction 94 Tissues of the immune system 29 Immune-mediated haemolytic anaemia Lymphocyte recirculation 34 in the dog 94 The major histocompatibility complex 36 Immune-mediated haemolytic anaemia Cytokines 39 in the cat 106 T lymphocytes 41 Immune-mediated thrombocytopenia B lymphocytes 45 in the dog 108 Antigen presentation 46 Immune-mediated thrombocytopenia T lymphocyte activation 50 in the cat 114 B lymphocyte activation 52 Cold agglutinin disease 115 Cytotoxicity 53 Immune-mediated neutropenia Immunoregulation 54 in the dog 115 Immunological memory 57 Feline blood group antigens 115 Immunological tolerance 58 Canine blood group antigens 116 Age-related changes in the immune system 58 Blood transfusion reactions 117 Further reading 59 Blood transfusion protocol 119 Neonatal isoerythrolysis 119 2 Immunopathological Mechanisms 61 Further reading 120 M. J. Day Introduction 61 5 Immune-Mediated Skin Disease 122 Type I hypersensitivity 62 M. J. Day and S. E. Shaw Type II hypersensitivity 66 Introduction 122 Type III hypersensitivity 67 Cutaneous disease caused by type I Type IV hypersensitivity 69 hypersensitivity 124 Superantigens 73 Contact hypersensitivity 142 Amyloidosis 73 Cutaneous vasculitis 145 Further reading 74 Pemphigus and bullous pemphigoid 148 CONTENTS Cutaneous lupus erythematosus 157 9 Immune-Mediated Endocrine Disease 241 Dermatomyositis 160 M. J. Day and S. E. Shaw Dermatouveitis 162 Introduction 241 Erythema multiforme and toxic Canine hypothyroidism 241 epidermal necrolysis 162 Feline hyperthyroidism 246 Sebaceous adenitis 165 Lymphocytic parathyroiditis 246 Alopecia areata 166 Diabetes mellitus 247 Pseudopelade 167 Hypoadrenocorticism 249 Canine granulomatous mural folliculitis 168 Polyendocrine disease 250 Plasma cell pododermatitis 168 Further reading 250 Feline atrophic auricular polychondritis 169 Further reading 170 10 Immune-Mediated Urinary and Reproductive Disease 251 6 Immune-Mediated Musculoskeletal and M. J. Day and A. J. Mackin Neurological Disease 172 Introduction 251 M. J. Day and D. Bennett Immune complex glomerulonephritis 251 Introduction 172 Glomerular basement membrane Immune-mediated polyarthritis 172 autoimmunity 259 Myositis 190 Chronic interstitial nephritis 259 Myasthenia gravis 193 Reproductive immunology 260 Polyneuritis 195 Further reading 262 Degenerative myelopathy of German Shepherd Dogs 196 11 Immune-Mediated Ocular Disease 263 Granulomatous meningoencephalitis 197 M. J. Day and S. M. Crispin Necrotizing meningoencephalitis 197 Ocular immunity 263 Necrotizing leukoencephalitis 197 Immune-mediated conjunctival disease 264 Greyhound meningoencephalitis 198 Immune-mediated diseases of the Polyarteritis nodosa 198 cornea 270 Steroid-responsive meningitis–arteritis 199 Immune-mediated diseases of the uvea 275 Further reading 199 Immune-mediated diseases of the canine retina 281 7 Immune-Mediated Alimentary Disease 201 Immune-mediated diseases of the M. J. Day and E. J. Hall canine sclera and episclera 282 Gastrointestinal immunology 201 Further reading 286 Immune-mediated gastrointestinal disease 204 12 Immunodeficiency Disease 287 Immune-mediated hepatic disease 221 M. J. Day Immune-mediated disease of the Introduction 287 exocrine pancreas 225 Secondary immunodeficiency 287 Further reading 225 Primary immunodeficiency 291 Therapy for immunodeficiency disease 313 8 Immune-Mediated Respiratory and Further reading 313 Cardiac Disease 228 M. J. Day and C. Clercx The respiratory immune system 228 Immune-mediated respiratory disease 230 Immune-mediated cardiac disease 238 Further reading 239 4 CONTENTS 13 Immune System Neoplasia 315 16 Immunotherapy 391 M. J. Day and J. M. Dobson M. J. Day Introduction 315 Introduction 391 Lymphoma 318 Immunomodulatory drugs 391 Lymphomatoid granulomatosis 337 Monoclonal antibodies in Lymphoid leukaemia 338 immunotherapy 398 Multiple myeloma 339 Antigen-specific immunotherapy 403 Waldenström’s macroglobulinemia 342 Gene therapy 407 Plasmacytoma 342 Transplantation and stem cell therapy 408 Myeloproliferative disease 342 Further reading 411 Histiocytoma 344 Cutaneous and systemic histiocytosis 346 17 Vaccination 413 Histiocytic sarcoma 346 M. J. Day Mast cell tumour 349 Introduction 413 Systemic mastocytosis 354 The aim of vaccination 413 Further reading 354 Basic requirements of a vaccine 413 Types of vaccine 413 14 Multisystem and Intercurrent Immune- Vaccines of the future 418 Mediated Disease 356 Duration of immunity 420 M. J. Day Vaccine licensing 423 Introduction 356 Adverse effects of vaccination 424 Systemic lupus erythematosus 356 Vaccine guidelines 429 Autoimmunity and lymphoma 363 Further reading 430 Myasthenia gravis and thymoma 364 IgA deficiency, hypersensitivity and Glossary 432 autoimmunity 367 Further reading 368 Index 442 15 Diseases of Lymphoid Tissue 369 M. J. Day Introduction 369 Diseases of the thymus 369 Lymph node diseases 374 Diseases of lymphatic vessels 382 Diseases of the tonsil 384 Diseases of the spleen 384 Further reading 390 5 PREFACE (First Edition) Clinical Immunology of the Dog and Cat is a many people. I would firstly like to acknowledge unique textbook that leads the reader from basic the role of my contributors in co-writing a number immunological principles to their practical of the chapters. These clinical colleagues are each application in the diagnosis and treatment of internationally recognized leaders within their immune-mediated diseases of the major companion disciplines, and it has been a pleasure to have the animal species. The book is primarily designed as a opportunity to work with them. They have reference source for veterinary surgeons in general generously allowed me to reproduce photographs or specialist practice who may require easily from their collections and have provided the accessible and up-to-date information on this majority of information on therapy and manage- important group of diseases. Sufficient immuno- ment of the disease entities to complement my logical background is given to make the text of immunopathological observations. value to veterinarians undertaking residency My colleagues, graduate students and training or preparation for specialist examination. technicians within the Departments of Pathology The integrated approach to pathology, clinical and Microbiology and Clinical Veterinary Science pathology and clinical medicine should also be of at the have generated data and benefit to veterinary undergraduates. material that have been incorporated into this The first three chapters of the book summarize book, and I am grateful for their support and for current knowledge of basic cellular and molecular the departmental infrastructure that has allowed me mechanisms in this rapidly evolving discipline and the facilities to produce this work. The majority of describe the multifactorial basis and pathogenesis the colour photographs of clinical cases and gross of the immune-mediated diseases. The following pathology are the expert products of talented nine chapters are system-based and describe the medical photographers: Malcolm Parsons, John immunological basis, clinical signs, diagnostic Conibear and Tracy Townsend-Sweeting (Uni- procedures, therapy and prognosis for those versity of Bristol) and Geoff Griffiths (Murdoch immune-mediated disorders of each system that are University). recognized in the dog and cat. Separate chapters I would like to acknowledge the contribution of deal with multisystems disease and disorders of Jill Northcott, who originally had the idea for this lymphoid tissues, and the final chapter provides an text. The finished product has been expertly and insight into how current research and experimental efficiently created by Manson Publishing, and I am immunotherapies may be applied to clinical grateful to Michael Manson for his enthusiasm for veterinary medicine in future years. the book, and to the skilled production team of One major strength of this work is the use of Paul Bennett (project manager), Peter Beynon (copy extensive full colour diagrams and photographs. To editor), and Sue Tyler and Kate Nardoni (illus- enhance understanding, the diagrams utilize a trators), with whom it has been a pleasure to work. consistent set of symbols for various immunological In writing this preface, it is appropriate that I cells and molecules, and these are defined in the key have the opportunity to acknowledge my three that follows. The range of photographic material mentors (Professor John Penhale, Professor Chris includes examples of clinical cases, radiographs, Elson and Dr. Don Mason), who introduced me to endoscopy, cytology, gross and microscopic this exciting discipline and shaped my early career pathology, immunopathology and electron micros- in immunology. Finally, I am grateful for the copy. The book also contains a list of abbreviations unstinting indulgence of my parents who supported and a list of selected further reading for each my drawn-out education, and the understanding of chapter, mostly papers from readily accessible my own family, who tolerated my long hours of veterinary journals from the past five years. solitary confinement. Clinical Immunology of the Dog and Cat has been an exciting project to develop, but it would Michael J. Day not have been possible without the valued input of 6 PREFACE (Second Edition) I was delighted by the success of the first edition of providing updated information on current Clinical Immunology of the Dog and Cat, which therapeutic aspects of the diseases covered. I was clearly filled a niche in the veterinary textbook pleased to welcome Professor Cecile Clercx to this market and was eventually translated into six group of internationally recognized clinical additional languages. Immunology, however, is specialists, and I thank them all for their insightful probably the fastest moving of the sciences and, editing of the text. since the publication of the first edition in 1999, This is now my third publication with Manson there have been numerous advances that readily Publishing and I am pleased to acknowledge this justify the production of this second edition. In the continuing relationship. The reputation of this area of fundamental immunology there has been a small publishing house is founded on the exception- renewed focus on the importance of the innate ally high standards and quality of printed texts that immune system, with a realization that events at they produce, and I am grateful to Mike Manson this level of antigen recognition determine the and Jill Northcott for their expertise in developing nature of the ensuing adaptive immune response. and marketing projects such as this. Both have also Additionally, there has been recent clarification of been very patient with the protracted gestation of the role of regulatory (suppressor) T lymphocytes in this volume, the birth of which was promised some the immune response and identification of several years before the actual event! I am very pleased to functional subsets of these cells. In parallel with this acknowledge the team that has worked on this research has been an explosion of knowledge in the second edition, including Paul Bennett (project field of companion animal immunology, largely manager), Peter Beynon (copy editor) and Sue Tyler driven by the molecular revolution, which in turn is and Kate Nardoni (illustrators). underpinned by publication of the canine (and, Finally, it would be remiss of me not to soon, the feline) genome. Techniques have been acknowledge the continued patience and support of developed that have allowed us to explore and my family who, when welcoming visitors to the quantify the role of key immunological molecules in house, point out ‘that’s the study … where we keep canine and feline immune responses, and this Dad’. technology has rapidly translated to the clinical diagnostic labora tory with the advent of PCR-based Michael J. Day tests for the diagnosis of infection or detection of clonality of neoplastic lymphoid populations. These advances are all discussed within this second edition. In order to incorporate these advances in understanding, by necessity this second edition of Clinical Immunology of the Dog and Cat has grown. There is an additional chapter devoted to respiratory and cardiac disease and, given the continued focus of companion animal practitioners on vaccine-related issues, a new chapter is devoted entirely to the subject of vaccinology. The second edition also includes approximately 200 new photographic images, an updated list of further reading (specifically papers published since the first edition in 1999), and an extensive glossary of terms. As ever, I am indebted to my contributors for their continued enthusiasm for this book and for 7 CONTRIBUTORS Professor David Bennett BSc BVetMed PhD ILTM Professor Edward J. HallMA VetMB PhD DipECVIM- DSAO MRCVS ca MRCVS Professor of Small Animal Clinical Studies Professor of Small Animal Internal Medicine Division of Companion Animal Sciences School of Clinical Veterinary Science Faculty of Veterinary Medicine , Langford, Bristol, UK University of Glasgow, Glasgow, UK Professor Andrew J. MackinBSc BVMS MVS DVSc Professor Cécile Clercx DVMPhD DipECVIM-ca DSAM FACVSc DACVIM MRCVS Professor of Small Animal Internal Medicine Hugh G. Ward Endowed Chair of Small Animal Department of Veterinary Clinical Sciences Medicine Faculty of Veterinary Medicine College of Veterinary Medicine University of Liège, Liège, Belgium Mississippi State University, Mississippi, USA Professor Sheila Crispin MA VetMB BSc PhD DVA Dr. Susan E. ShawBVSc MSc FACVSc DipACVIM DVOphthal DipECVO FRCVS DipECVIM-ca MRCVS Cold Harbour Farm Senior Lecturer in Veterinary Dermatology Kendal, Cumbria, UK School of Clinical Veterinary Science , Langford, Bristol, UK Dr. Jane M. Dobson MA DVetMed DipECVIM-ca MRCVS Senior Lecturer in Veterinary Clinical Oncology Department of Clinical Veterinary Medicine University of Cambridge, Cambridge, UK ABBREVIATIONS AA amyloid amyloid-associated protein BUN blood urea nitrogen ACAID anterior chamber-associated immune deviation CALT conjunctiva-associated lymphoid tissue ACE angiotensin converting enzyme CAV canine adenovirus AChR acetylcholine receptor CBC complete blood count AD atopic dermatitis CC a chemokine in which the two amino terminal ADCC antibody-dependent cell-mediated cytotoxicity cysteine residues are adjacent AIDS acquired immune deficiency syndrome CD cluster of differentiation AIEC attaching and invading E. coli CDV canine distemper virus AIHA autoimmune haemolytic anaemia CGL chronic granulocytic leukaemia AITP autoimmune thrombocytopenia CH chronic hepatitis AL amyloid amyloid (immunoglobulin) light chain CH total haemolytic complement (assay) 50 protein CIC circulating immune complex ALL acute lymphoblastic leukaemia CLAD canine leukocyte adhesion deficiency AMD acute myeloproliferative disease CLE cutaneous lupus erythematosus AML acute myeloid leukaemia CLL chronic lymphocytic leukaemia ANA antinuclear antibody CMD chronic myeloproliferative disease APC antigen presenting cell CMI cell-mediated immunity ARD antibiotic responsive diarrhoea CML chronic myeloid leukaemia ASIT allergen-specific immunotherapy CNS central nervous system BALF bronchoalveolar lavage fluid ConA concanavalin A (mitogen) BALT bronchial-associated lymphoid tissue CMMM canine masticatory muscle myositis BCG bacille Calmette–Guérin CPM canine polymyositis BLAD bovine leukocyte adhesion deficiency CRFK Crandall Rees feline kidney cell line BMZ basement membrane zone CR1 complement receptor 1 8 ABBREVIATIONS CSF cerebrospinal fluid IDDM insulin-dependent diabetes mellitus CSK/CSKC chronic superficial IDST intradermal skin test keratitis/keratoconjunctivitis IEL intraepithelial lymphocyte CT computerized tomography IEP immunoelectrophoresis CXC a chemokine in which the two amino terminal IFN interferon (e.g. IFN ) cysteine residues are separated by one amino acid Ig immunoglobulin (IgG, IgM, IgA, IgD, IgE) DAF decay accelerating factor IGF-1 insulin-like growth factor-1 DAMP damage-associated molecular pattern IL interleukin (e.g. IL-1) DEA dog erythrocyte antigen i/m intramuscular DGGE denaturing gradient gel electrophoresis IMHA immune-mediated haemolytic anaemia DIC disseminated intravascular coagulation IMNP immune-mediated neutropenia DLA dog leukocyte antigen (canine MHC) IMTP immune-mediated thrombocytopenia DLE discoid lupus erythematosus i/p intraperitoneal DLH domestic longhair (cat) IPE idiopathic pericardial effusion DNA deoxyribonucleic acid ITP idiopathic thrombocytopenia DOI duration of immunity i/v intravenous/intravascular DOP duration of protection KCS keratoconjunctivitis sicca DSH domestic shorthair (cat) KIR killer-cell inhibitory factor DTH delayed-type hypersensitivity LAK lymphokine-activated killer (cells) EAE experimental allergic encephalomyelitis LFA-1 lymphocyte function-associated EBP eosinophilic bronchopneumopathy antigen 1 EGC eosinophilic granuloma complex LPC lymphoplasmacytic colitis ELISA enzyme-linked immunosorbent assay LPE lymphoplasmacytic enteritis EM erythema multiforme LPL lamina propria lymphocyte EMG electromyogram LPR lymphoplasmacytic rhinitis EPEC enteropathogenic Escherichia coli LPS lipopolysaccharide EPI exocrine pancreatic insufficiency LSEC liver sinusoidal endothelial cell Fab antigen-binding fragment (of Ig) MAC membrane attack complex FACS fluorescence-activated cell sorter MAdCAM mucosal addressin cell adhesion molecule FAD flea allergy dermatitis MALT mucosa-associated lymphoid tissue Fc crystallizable fragment (of Ig) MBP myelin basic protein FCV feline calicivirus MCP macrophage chemotactic protein/membrane co- FcR Fc (Ig heavy chain) receptor factor protein FeFV feline foamy virus MG myasthenia gravis FeLV feline leukaemia virus MHC major histocompatibility complex FHV feline herpesvirus MMP matrix metalloproteinase FIA feline infectious anaemia MRI magnetic resonance imaging FIE feline infectious enteritis mRNA messenger RNA FIP feline infectious peritonitis NALT nasal-associated lymphoid tissue FIV feline immunodeficiency virus NBT nitroblue tetrazolium (test) FLA feline leukocyte antigen (feline MHC) NCIWF National Cancer Institute Working Formulation GALT gut-associated lymphoid tissue NFAT nuclear factor of activated T cells GBM glomerular basement membrane NK natural killer (cells) G-CSF granulocyte colony stimulating factor NLE necrotizing leukoencephalitis GITR glucocorticoid-induced TNF receptor-related gene NME necrotizing meningoencephalitis GM-CSF granulocyte-macrophage colony stimulating NRIMHA non-regenerative immune-mediated factor haemolytic anaemia GME granulomatous meningoencephalitis NSAID non-steroidal anti-inflammatory drug GP glycoprotein OspA outer surface protein A (of Borrelia burgdorferi) GSD German Shepherd Dog OVA ovalbumin HAT hypoxanthine, aminopterin, thymidine (medium) PAA pancreatic acinar atrophy HEV high endothelial venule PALS periarteriolar lymphoid sheath HLA human leukocyte antigen (human MHC) PAMP pathogen-associated molecular pattern HSP heat shock protein PAS periodic acid-Schiff (stain) HUC histiocytic ulcerative colitis PCR polymerase chain reaction IBD inflammatory bowel disease PCV packed cell volume (haematocrit) ICAM-1 intercellular adhesion molecule 1 PHA phytohaemagglutinin (mitogen) ICGN immune complex glomerulonephritis PIE pulmonary infiltration with eosinophilia 9