The Reticuloendothelial

System A COMPREHENSIVE TREATISE

Volume 4 Immunopathology

The Reticuloendothelial System A COMPREHENSIVE TREATISE

General Editors: Herman Friedman, University of South Florida, Tampa, Florida

Mario Escobar, Medical College of Virginia, Richmond, Virginia

and Sherwood M. Reichard, Medical College of Georgia, Augusta, Georgia

MORPHOLOGY Edited by Ian Carr and W. T. Daems

BIOCHEMISTRY AND METABOLISM Edited by Anthony J. Sbarra and Robert R. Strauss

PHYLOGENY AND ONTOGENY Edited by Nicholas Cohen and M. Michael Sigel

IMMUNOP ATHOLOGY Edited by Noel R. Rose and Benjamin V. Siegel

PHYSIOLOGY Edited by Sherwood M. Reichard and James P. Filkins

PHARMACOLOGY Edited by John Hadden, Jack R. Battisto, and Andor Szentivanyi

IMMUNOLOGY Edited by Joseph A. Bellanti and Herbert B. Herscowitz

CANCER Edited by Herman Friedman and Ronald B. Herberman

HYPERSENSITIVITY Edited by Peter Abramoff and S. Michael Phillips

INFECTION Edited by John P. Utz and Mario R. Escobar

The Reticuloendothelial

System A COMPREHENSIVE TREATISE

Volume 4 Immunopathology

Edited by NOEL R. ROSE

The Johns Hopkins University Baltimore, Maryland

and

BENJAMIN V. SIEGEL Oregon Health Sciences University

Portland, Oregon

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Main entry under title:

The Reticuloendothelial system.

Includes bibliographies and indexes. CONTENTS: v. 1. Carr, I., Daems, W. T., and Lobo, A. Morphology.-v. 2.

Sbarra, A. J. and Strauss,. R. R. Biochemistry and metabolism. - - v. 4. Rose, N. R. and Siegel, B. V. Immunopathology.

1. Reticulo-endothelial system. 2. Macrophages. I. Friedman, Herman, 1931-II. Escobar, Mario R. III. Reichard, Sherwood M. [DNLM: 1. Reticuloendothelial system. WH650 R437] QP115.R47 ISBN-l3: 978-1-4615-9277-8 DOl: 10.1007/978-1-4615-9275-4

© 1983 Plenum Press, New York

591.2'95 e-ISBN-13: 978-1-4615-9275-4

Softcover reprint of the hardcover 1 st edition 1983 A Division of Plenum Publishing Corporation 233 Spring Street, New York, N.Y. 10013

All rights reserved

79-25933

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

Contributors

LEONARD D. BERMAN • Laboratory Service, Boston Veterans Administration Medical Center, and Department of Pathology and Hubert H. Humphrey Cancer Center, Boston University School of Medicine, Boston, Massachu­setts

TIBOR BORSOS • Laboratory of Immunobiology, National Cancer Institute, Na­tional Institutes of Health, Bethesda, Maryland

MICHAEL D. P. BOYLE • Laboratory of Immunobiology, National Cancer In­stitute, National Institutes of Health, Bethesda, Maryland. Present address: Department of Immunology and Medical Microbiology, College of Medi­cine, University of Florida, Gainesville, Florida 32610

MARIO R. ESCOBAR • Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

M. D. KAZATCHKINE • Clinique Medicale et INSE RM U 28,H6pital Broussais, Paris, France

H. LAMBERT • WHO Immunology Research and Training Center, Geneva Blood Center, and Department of Medicine, University of Geneva, Switzerland

MAURICE J. LEFFORD • Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan

BRIAN LEIBOVITZ • Division of Immunology, Department of Medicine, Univer­sity of Oregon Health Sciences Center, Portland, Oregon

P. A. MIESCHER • WHO Immunology Research and Training Center, Geneva Blood Center, and Department of Medicine, University of Geneva, Switzerland

RICHARD D. MOORE • Department of Pathology, University of Oregon Health Sciences Center, Portland, Oregon

JANE I. MORTON • Division of Immunology, Department of Medicine, Univer­sity of Oregon Health Sciences Center, Portland, Oregon

RUTH NETA • Department of Microbiology, University of Notre Dame, Notre Dame, Indiana

U. E. NYDEGGER • Central Laboratory of the Swiss Red Cross Blood Transfusion Service, Bern, Switzerland

ARNOLD E. REIF • Department of Pathology, Boston University School of Medi~ cine, and Experimental Cancer Immunotherapy Laboratory, Mallory In­stitute of Pathology, Boston City Hospital, Boston, Massachusetts

NOEL R. ROSE • Department of Immunology and Infectious Diseases, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland

v

vi CONTRIBUTORS

S. B. SALVIN • Department of Microbiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

BENJAMIN V. SIEGEL • Department of Pathology, University of Oregon Health Sciences Center, Portland, Oregon

GRAHAM O. SOLLEY • Department of Internal Medicine (Division of Allergic Diseases), Mayo Clinic and Mayo Foundation, The Mayo Medical School, Rochester, Minnesota

MATSUNOBU SUKO • Department of Pathology, University of Connecticut Health Center, Farmington, Connecticut

PAUL D. SWENSON • Division of Infectious Diseases, Department of Medicine, North Shore University Hospital, Manhasset, New York

DANIEL E. TRACEY • Hypersensitivity Diseases Research, The UpJohn Com­pany, Kalamazoo, Michigan

TAKES HI YOSHIDA • Department of Pathology, University of Connecticut Health Center, Farmington, Connecticut

Foreword

This comprehensive treatise on the reticuloendothelial system is a project jointly shared by individual members of the Reticuloendothelial (RE) Society and bio­medical scientists in general who are interested in the intricate system of cells and molecular moieties derived from these cells which constitute the RES. It may now be more fashionable in some quarters to consider these cells as part of what is called the mononuclear phagocytic system or the lymphoreticular system. Nevertheless, because of historical developments and current interest in the subject by investigators from many diverse areas, it seems advantageous to present in one comprehensive treatise current information and knowledge con­cerning basic aspects of the RES, such as morphology, biochemistry, phylogeny and ontogeny, physiology, and pharmacology as well as clinical areas including immunopathology, cancer, infectious diseases, allergy, and hypersensitivity. It is anticipated that by presenting information concerning these apparently heterogeneous topics under the unifying umbrella of the RES attention will be focused on the similarities as well as interactions among the cell types constitut­ing the RES from the viewpoint of various disciplines. The treatise editors and their editorial board, consisting predominantly of the editors of individual vol­umes, are extremely grateful for the enthusiastic cooperation and enormous task undertaken by members of the biomedical community in general and especially by members of the American as well as European and Japanese Reticuloendothe­lial Societies. The assistance, cooperation, and great support from the editorial staff of Plenum Press are also valued greatly. It is hoped that this unique treatise, the first to offer a fully comprehensive treatment of our knowledge concerning the RES, will provide a unified framework for evaluating what is known and what still has to be investigated in this actively growing field. The various vol­umes of this treatise provide extensive in-depth and integrated information on classical as well as experimental aspects of the RES. It is expected that these volumes will serve as a major reference for day-to-day examination of various subjects dealing with the RES from many different viewpoints.

Herman Friedman Mario R. Escobar

Sherwood M. Reichard

vii

Introduction

From the evolutionary point of view, phagocytosis in vertebrates is the descen­dent of the demands upon single-celled animals to seek out food. As Metchnikoff (1905) pointed out many years ago, the process by which the pha­gocytic cells of multicellular animals ingest invading microorganisms calls to mind the engulfment of particulates by amebas. The reticuloendothelial system, in a real sense, is the child of the digestive system.

In a similar way, the immunological response may be thought of as the evolutionary descendent of primitive cellular recognition. The immunological system is the specialized organ for carrying out that function. It belongs to that great family of organ systems devoted to maintaining internal homeostasis by means of adaptation to external stimuli. It has a close working relationship to the nervous and endocrine systems, and each has significant impact on the other.

Like other specialized organs, the immunological function depends upon the cooperative interactions of a conglomerate of cells, each with special proper­ties and capabilities. The immunological organ is not anatomically localized; it is dispersed throughout the body. It comprises several different cell types and their soluble effector products such as antibodies and lymphokines as well as numerous humoral mediators and modifiers. All of the cells of the immunologi­cal system arise from a single population of pluripotential stem cells. In early embryonic life, they are found in the liver but later the stem cells are located in the bone marrow. Interestingly, the same stem cell generates the other cellular elements of the blood. Arising from this pluripotential cell, then, are precursors of the erythrocytes and megakaryocytes along with the myelocytic-monocytic precursor. The cell central to immunological recognition, the lymphocyte, is one of the descendents of the same pluripotential stem cell. Recognition of foreign molecules is a property of all living cells, but in vertebrates has become the particular responsibility of the lymphocyte.

The development of the lymphoid precursor into functional cells is reflected in a series of changes in their surfaces. Physiologically, these changes determine the pattern of migration of lymphocytes throughout the body. For example, T cells are the predominant population of mature lymphocytes in the lymphatics and in peripheral blood, as well as comprising most of the lymphocytes in the para cortical areas of lymph nodes and the periarteriolar sheaths of the spleen, the so-called T-dependent areas. B cells make up most of the lymphocyte popu­lation in the medulla and remaining areas of lymph node cortex, and the white

ix

X INTRODUCTION

pulp of the spleen. Lymphocyte maturation is also accompanied by the ap­pearance of characteristic antigenic determinants on the cell surface. Often, these markers are the basis of practical laboratory tests for the enumeration of the different populations of lymphocytes. The availability of highly specific monoclonal antibodies to these determinants now provides reagents for pre­cisely defining the status of the various populations and even subpopulations of lymphocytes.

The most important change the lymphocyte undergoes during development is the appearance of antigen-specific receptors on the cell surface. Each lympho­cyte is endowed with an individual recognition site. Correspondingly, there are lymphocytes intrinsically capable of recognizing and responding to any anti­genic determinant, whether naturally occurring or synthetic. On encountering its specific antigen, the lymphocyte is triggered to enlarge and divide, giving rise to a family or clone of lymphocytes endowed with that particular specificity. The eventual product secreted by stimulated B lymphocytes is the antigen-specific immunoglobulin, the antibody which provides the most accessible tool for mea­suring a particular immunological response. Stimulated T cells produce soluble lymphokines that influence the actions of a broad array of other cells. T cells may also act directly as cytotoxic effectors against particular targets, including tumor cells, transplanted cells, or sometimes the host's own virus-infected cells.

Two cardinal properties of the immunological system are crucial for its function. The first is specificity and the second is diversity. Individuallympho­cytes must be tailored to fit any conceivable antigenic determinant or epitope, the bit of information read by a lymphocyte. A determinant depends upon the stereochemical configuration of a portion of a molecule, typically a few peptide or monosaccharide units projecting from the molecule.

An antigen-specific recognition site capable of combining with any particu­lar antigenic determinant is inherently present on some small number of lym­phocytes in the body. It is based on the amino acid sequence of a receptor molecule; the same sequence is probably carried over into the antibody molecule in the case of the immunoglobulin produced by the B cell. When it becomes an immunologically committed cell, the lymphocyte selects the DNA code for this particular amino acid sequence from the great variety of genes (called V genes) available to it.

This treasure house of information is carried from generation to generation in a relatively small number of germ-line genes. It seems that a combination of unique genetic mechanisms has been evolved to provide the required degree of diversity. The generation of diversity is best understood in relation to antibody formation.

Immunoglobulins are molecules comprising four peptide chains, one pair of heavy chains and one pair of light chains. On each chain can be distinguished two functional regions; the variable region is responsible for specific recognition of the antigenic determinant while the constant region determines other effector functions. The variable region contains four-subregions that vary only slightly among antibody molecules, known as framework residues, and three hyper­variable regions that fold into the diverse antigen-binding receptors. Light

INTRODUCTION xi

chains are coded by at least three genes, the V gene determining the hypervaria­ble sequences, C genes coding for the constant region, and J genes containing the amino acids at the junction of these two regions. Heavy chains require an additional 0 gene that codes the third hypervariable subregion. The differentiat­ing lymphocyte combines a particular V gene with J (and 0) genes at random to synthesize both light and heavy chains. In B cells, C genes are activated in temporal sequence to give various classes of immunoglobulins, IgM, IgO, IgG, and sometimes IgA and IgE.

The equivalents of C genes have not yet been defined in T cells, but very likely the same V genes are called upon to code for the antigen-specific receptor of the T cell.

Another requirement for proper function of the immunological system is regulation. A reaction as powerful as the immunological response may well become destructive if it goes on ungoverned. Regulation depends upon the production of T lymphocytes that can control antibody formation by B cells or T­cell-mediated immunity. Antibodies to the unique recognition sites (idiotype) also have been found to suppress immune response, perhaps directly or through the induction of suppressor lymphocytes. Many important diseases arise from abnormalities in regulation of the immunological response. Immu­nopathology, the study of immunological disorders, is the focus of this volume.

REFERENCE

Herman Friedman Mario R. Escobar

Sherwood M. Reichard

Metchnikoff, E., 1905, Immunity in Infective Diseases, Cambridge University Press, London.

Preface

Immunopathology, the fourth volume of a comprehensive treatise on the re­ticuloendothelial system (RES) brings together the new information that has emerged over the last several years concerning a variety of disorders that arise from either hereditary or acquired defects in regulation of the immunologic response. Although some immunologic diseases still remain hazy to our view as regards their pathogenesis, there are many others that have already been brought into sharp focus thanks to the rapidly growing knowledge of basic and clinical immunology in the last two decades. The editors of this book have succeeded in assembling an eminent group of active investigators in their re­spective fields in their efforts to integrate a series of relatively brief but critical reviews with emphasis on concepts and mechanisms fundamental to our under­standing of the immunopathology of the RES.

In the first group of chapters (1-4), Drs. Siegel, Leibovitz, and Morton pre­sent in their initial chapter a general review of the etiologic factors and mecha­nisms involved in the mediation of tissue injury by the RES followed by a second chapter dealing with the mechanism of activation and lytic activity of T lympho­cytes, with emphasis on the importance of cAMP/cGMP system, which appears to be dependent on the redox state of the cell. These authors illustrate in great detail their own work dealing with a disorder of hemopoietic regulation innate to the stem cell and its lymphocytic progeny in the New Zealand Black strain mouse model. Drs. Boyle and Borsos then discuss the mechanism for generation of the various complement factors and the direct and indirect role of comple­ment in immunopathology. To complete this section, Dr. Tracey reviews the multifunctional properties and central role of the macrophage in tissue damage.

The next group of chapters (5-9) has as a central theme the subject of host-parasite interactions in the induction of immunopathology. In Chapter 5, Dr. Lefford deals in general with immunity to facultative intracellular parasites, discussing in depth genetic and immunologic attributes of the host as well as the immunogenic properties of the parasites.

In subsequent chapters, the immunopathology associated with different groups of microorganisms is covered. Mycotic infections are reviewed by Drs. Salvin and Neta, including both human and animal studies. Drs. Escobar and Swenson deal with mechanisms of viral immunopathology in general, while Drs. Berman and Reif discuss in separate chapters the immunopathology of virus-induced tumors in experimental animals and leukemia and lymphomas in mice, respectively.

xiii

xiv PREFACE

The last group of chapters in this volume (10-14) consists of a review by Dr. Moore on the immunopathology of malignant disease in humans, a discussion of autoimmune diseases by Dr. Rose, and of the immunopathology of immune complex disease by Drs. Nydegger, Kazatchkine, Lambert, and Miescher. Dr. Solley introduces briefly the concept of biphasic responses induced by 19E anti­bodies and then goes in greater depth into the late 19E-induced inflammatory reactions. Finally, in the last chapter, Drs. Yoshida and Suko discuss mainly the pathogenesis and histopathology of delayed hypersensitivity reactions, es­pecially focusing on their mediation mechanism by lymphokines, and including their induction by microorganisms as well as antigens other than infectious agents.

We are confident that the reader will join us in acknowledging the valuable contributions made by each of the authors.

Noel R. Rose Benjamin V. Siegel

Contents

1. The Reticuloendothelial System and Tissue Injury

BENJAMIN V. SIEGEL, BRIAN LEIBOVITZ, and JANE I. MORTON

1. Introduction 1 2. Autoimmune Disease 1 3. Pulmonary Injury 3

3.1. Silicosis and Asbestosis 3 3.2. Emphysema 7

4. Interactions of Prostaglandins with Macrophages 12 4.1. Prostaglandins and Inflammation 13 4.2. Anti-Inflammatory Drugs and Macrophage Prostaglandin

Synthesis 15 4.3. Lipid Peroxides and Prostaglandin Biosynthesis 15 4.4. Prostaglandins and Other Macrophage Functions 16

5. Reticuloendothelial System in Athymic Mice 17 References 18

2. T-Cell-Mediated Injury

BENJAMIN V. SIEGEL, BRIAN LEIBOVITZ, and JANE I. MORTON

1. Introduction 25 2. Cell-Mediated Cytolysis 25

2.1. Recognition 26 2.2. Lethal Hit Stage 27 2.3. Target Cell Disintegration 28 2.4. Possible Mechanisms of TSL 29

3. Oxidative Metabolism in Lymphocytes 30 4. T -Cell-Mediated Immunity in Disease 32 5. T-Cell Abnormalities in Autoimmunity 32 References 37

xv

XVI CONTENTS

3. Tissue Damage Caused by the Direct and Indirect Action of Complement

MICHAEL D. P. BOYLE and TIBOR BORSOS

1. Introduction 43 2. Studies of the Directly Cytolytic Action of C 43

2.1. The Direct Cytotoxic Action of C 46 2.2. Studies of C Lysis in Cell Targets Other Than

Erythrocytes 50 3. The Role of C in Disease 52

3.1. Hematological Diseases 54 3.2. Chronic Hypocomplement Membrane Proliferative

Glomerulonephritis 56 4. Biological Activities of C Fragments 56

4.1. Biological Activities of Bound C Components 59 4.2. Control of the Biologically Active Fragments 60 4.3. Role of C in Cell-Mediated Immune Reactions 61

5. Summary 63 6. Appendix: One-Hit Theory of Immune Hemolysis 63 References 66

4. Macrophage-Mediated Injury

DANIEL E. TRACEY

1. Introduction 77 1.1. Regulation of Immune Responses by Macrophages 77 1.2. Macrophages in Inflammatory Reactions 77 1.3. Macrophage Heterogeneity 78

2. Macrophage Activation 79 2.1. Resident Macrophages 79 2.2. Activation Stimuli 80 2.3. Generation and Properties of Stimulated Macrophages 81 2.4. Generation and Properties of Activated Macrophages 81

3. Direct Macrophage-Mediated Injury 84 3.1. Chronic Inflammation 84 3.2. Acute Inflammation 85 3.3. Cytotoxicity of Allogeneic Cells and Tumor Cells 86

4. Indirect Macrophage-Mediated Injury 90 4.1. Macrophages as Accessory Cells 91 4.2. Comparison of the Cytotoxic Activities of NK Cells and

Macrophages in Vivo 91

4.3. Macrophages as Suppressor Cells 95 5. Concluding Remarks 96 References 96

5. Immunity to Facultative Intracellular Parasites

MAURICE J. LEFFORD

1. Introduction 103 2. Genetic Factors in Host Susceptibility 104

2.1. Species Susceptibility 104 2.2. Intraspecies Susceptibility 105

3. Immediate Fate of Infecting Organisms 108 4. Pathology 111 5. Induction of Immunity 113 6. Characteristics of the Effector Lymphocytes 115 7. Relationship of Protective Immunity to Other Expressions of

CMI 120 8. Macrophage Activation 122 9. Specific, Cross-Reactive, and Nonspecific Immunity 125

10. Regulation of the Immune Response 128 11. Dependence of Immunity on Living Organisms 132 References 134

6. Immunopathology of Mycotic Infections

S. B. SALVIN and RUTH NETA

1. Introduction 145 2. Aspergillosis 146

2.1. Aspergillosis in Man 147 2.2. Pathogenesis in Experimental Disease 2.3. Allergic Bronchopulmonary Aspergillosis 2.4. Immunity 149 2.5. Toxins 150

3. North American Blastomycosis 150 3.1. The Disease in Animals and Man 150

147 148

3.2. Development of Immunity and Related Immunological Reactions 151

4. Candidiasis (Moniliasis, Candidosis) 153 4.1. Infection of Laboratory Animals 153 4.2. Internal Fungal Factors in Host Response 155

CONTENTS xvii

XVlll CONTENTS

4.3. Resistance 156 4.4. Cell-Mediated Immunity 157

5. Coccidioidomycosis 159 5.1. Infection in Animals and Man 160 5.2. Immunity 161 5.3. Live Vaccines 161 5.4. Dead Vaccines 162 5.5. Nature of Resistance 164 5.6. Immunotherapy 165

6. Cryptococcosis 165 6.1. Pathogenesis and Innate Resistance 166 6.2. Acquired Resistance 167

7. Dermatomycoses 169 7.1. Acquired Resistance in Animals 169 7.2. Acquired Resistance in Humans 170 7.3. Hypersensitivity 170 7.4. Dermatophytids ("ids") 172 7.5. Serum Factors 173

8. Histoplasmosis 173 8.1. Experimental Disease in Animals 174 8.2. Acquired Resistance after Primary Infection 176 8.3. Acquired Resistance after Vaccination with Dead Cells 177 8.4. Cell-Mediated Immunity 177 8.5. Antibodies 179

9. Phycomycosis (Mucormycosis) 180 9.1. Animal Studies 180 9.2. Resistance 181 9.3. Human Studies 182

10. Sporotrichosis 183 10.1. Animal Studies 183 10.2. Immunity in Animals 184 10.3. Human Studies 184

11. Summary and Conclusions 185 References 186

7. Mechanisms of Viral Immunopathology

MARIO R. ESCOBAR and PAUL D. SWENSON

1. Introduction 201 2. Immunogenetic Mechanisms in Viral Infections 202

2.1. Macrophage-Dependent Genetically Determined Resistance and the Effect of Interferon 202

CONTENTS xix

2.2. Association of the MHC with Viral Disease 204 2.3. MHC Restriction of Effector Cell-Target Cell Interactions

in Viral Infections 204 3. Virus-Associated or -Induced Immunologically Mediated Tissue

Damage 206 3.1. Role of Macrophages 206 3.2. Role of Natural Killer Cells 208 3.3. Immediate-Type Hypersensitivity in Viral Diseases 210 3.4. Role of Viral Antigen-Antibody Complexes 212 3.5. Antiviral Antibody-Mediated Lysis of Virus-Infected Cells 214 3.6. Direct and Indirect T-Lymphocyte-Mediated Cytotoxicity 217

4. Modulation of Immune Responses by Viruses 221 4.1. Macrophage Function 221 4.2. Immunomodulation of Cellular Responses 222 4.3. Immunomodulation of Humoral Responses 225

5. Viral Vaccines in Immunopathology 227 5.1. Attributes of the Host and Cell-Virus Interactions 227 5.2. Adverse Effects Related to the Nature of the Viral Antigen or

Route of Administration 230 5.3. Protection against Reinfection 236

References 238

8. Immunopathology of Malignant Disease in Experimental Animals: Virus-Induced Tumors

LEONARD D. BERMAN

1. Introduction 255 2. The Primary in Vivo Systems 256 3. The Antigens 263 4. The Host Response 270

4.1. Cellular Aspects 270 4.2. Humoral Factors 275

5. Conclusions 279 References 280

9. Immunopathology of Malignant Disease in Mice: Leukemias and Lymphomas, Stalking-Horses for Human Counterparts

ARNOLD E. REIF

1. Introduction 295 2. General Concepts of Carcinogenesis 297

XX CONTENTS

3. Development of Thymic Lymphoma in AKR Mice 299 3.1. Discovery of Viral Etiology 300 3.2. Unicentric Origin 300 3.3. Thymus Architecture 300 3.4. Thymic Lymphoma Development 301 3.5. Excision or Depletion of Thymus 302 3.6. Conditions for Lymphoma Development 3.7. Thymic Factors and Hormones 303

4. Other Types of Lymphoreticular Tumors 304 5. Viral Carcinogens 307

5.1. Classes of Virus 308 5.2. Cell Surface Antigens 308 5.3. Preleukemic Cell Surface Changes 310 5.4. Surveillance against Tumor Development 5.5. Immunosuppression by Leukemia Viruses 5.6. Suppressor Cell Involvement 314

6. Genetic Susceptibility to Lymphoreticular Tumors 7. Chemical Carcinogenesis 316 8. Radiation Carcinogenesis 317

303

311 311

314

8.1. Evidence That Radiation Promotes Viral Leukemogenesis in Mice 317

8.2. Mechanism of Radiation Leukemogenesis 319 9. Immune Irritation: Carcinogen or Promoter? 320

10. Diagnosis 321 11. Therapy 323

11.1. Tumor Cell Kinetics 323 11.2. Chemotherapy 324 11.3. Nonspecific Immune Stimulation 324 11.4. Attempts to Change Cell Surface

Antigenicity 325 11.5. Serotherapy and Vaccination 325 11.6. Other Modes of Therapy 326

12. Summary and Applications to Man 326 References 327

10. Immunopathology of Malignant Disease in Humans

RICHARD D. MOORE

1. Introduction 335 2. Local Cellular Reaction to Neoplasms 335 3. Response of Lymph Nodes to Neoplasms 336 4. Antigens Associated with Malignant Neoplasms 337

4.1. Evidence from Measurements of Humoral Immunity 337 4.2. Evidence from Measurements of Cellular Immunity 339

5. Immune Response to Malignant Neoplasms 339 5.1. Immune Surveillance 339 5.2. Protection of the Neoplasm 340 5.3. Activities of Various Types of Lymphocytes 341

6. Macrophage Reactions 342 6.1. Accumulation 342 6.2. Effects of Humoral and Cellular Immunity 343 6.3. Activation and Tumoricidal Activity 344 6.4. Effect of Tumor on Macrophage Functions 344 6.5. Macrophage Products That May Impair the Response to

Neoplasms 344 7. Summary 345 References 346

11. The Autoimmune Diseases

NOEL R. ROSE

1. Mechanisms of Self Recognition 353 1.1. Clonal Deletion 353 1.2. Active Suppression 355

2. The Spectrum of Autoantigens 356 3. Mechanisms of Autoimmunization

3.1. Lens 358 3.2. Central Nervous System 358 3.3. Necrotic Antigens 359 3.4. Erythrocytes 359 3.5. Immunoconglutinin 359 3.6. Rheumatoid Factor 360 3.7. Nephritogenic Factor 3.8. Cross-Reactive Antigens

360 360

4. Defects in Immunoregulation 361 4.1. Thymectomy 361 4.2. Irradiation 362

357

4.3. "Suppressor" Determinants 362 5. Immunopathological Mechanisms 362

5.1. Antibody-Mediated Cytotoxicity 362 5.2. Antireceptor Antibody Activity 364 5.3. Antibody-Dependent Cell-Mediated Cytotoxicity 365 5.4. Cytotoxic T Cells 365 5.5. Macrophage-Mediated Cytotoxicity 365

CONTENTS xxi

XXll CONTENTS

5.6. Immune Complexes 366 References 366

12. Immunopathology of Immune Complex Disease

U. E. NYDEGGER, M. D. KAZATCHKINE, P. H. LAMBERT, and P. A. MIESCHER

1. Introduction 371 2. Antigen Requirements for Immune Complex Formation 373 3. Physiological and Pathogenic Role of Immune Complex

Formation 374 4. Reaction of Immune Complexes with Humoral Receptors 375 5. Methods for the Detection of Soluble Immune Complexes 379

5.1. Physiochemical Methods 379 5.2. Biological Methods 379

6. Critical Aspects of Immune Complex Detection 381 6.1. Sensitivity and Standardization 381 6.2. Reproducibility 381 6.3. Specificity 381 6.4. Characterization of Complexed Antigen or Antibody 382

7. Experimental Immune Complex Disease 383 8. Evaluation of the in Vivo Pathogenic Potential of Circulating

Immune Complexes 386 9. Spontaneous Immune Complex Disease in Animals 387 References 388

13. Late Inflammatory Reactions Induced by IgE Antibodies

GRAHAM O. SOLLEY

1. Introduction 391 2. Role of IgE and Pathogenesis of Late-Phase Response 391 3. Clinical Relevance of the Late-Phase Response 394 References 394

14. Immunopathology of Delayed Hypersensitivity

T AKESHI YOSHIDA and MA TSUNOBU SUKO

1. Introduction 397 2. Induction of Delayed Hypersensitivity 398

2.1. Infections with Microorganisms 398 2.2. Sensitization to Antigens Other Than Infectious Agents 2.3. Contact Sensitization 400

3. Histopathology of Delayed Hypersensitivity Reactions 3.1. Delayed-Type Skin Reactions (Tuberculin Reactions) 3.2. Contact Sensitivity 402 3.3. Jones-Mote Reactions (Cutaneous Basophil

Hypersensitivity) 402

400 401

3.4. The Specificity of Infiltrating Lymphocytes in Delayed Skin Reaction 403

4. Passive Transfer of Delayed Hypersensitivity 404 5. Specificity of Delayed Hypersensitivity 405 6. Cellular Regulation in Induction of Delayed Hypersensitivity 7. In Vitro Correlates of Delayed Hypersensitivity 407 8. Kinds of Lymphokine Activities 408

8.1. Inflammatory Lymphokines 408 8.2. Immunoregulatory Lymphokines 410

9. General Physicochemical Characteristics of Lymphokines 411 10. Cells that Produce Lymphokines 411

10.1. T Lymphocytes and B Lymphocytes 411 10.2. Lymphokinelike Substances (Cytokines) Produced by

Nonlymphoid Cells 413 11. The Role of Lymphokines in Vivo 413

CONTENTS

399

406

11.1. Detection of Lymphokine Activity in Delayed Hypersensitivity Reactions 414

11.2. Injection of Exogenous Lymphokines 11.3. Granulomatous Inflammation 416

415

11.4. Serum Lymphokine Activity in Man 417 11.5. The Use of Antilymphokine Antibodies 417 11.6. Desensitization of Delayed Hypersensitivity and Anergy

12. Concluding Remarks 421 References 422 '

Index 429

418

xxiii