39
1m muno de rmatology
1m mu no de rmatology
Comprehensive Immunology Series Editors: ROBERT A. GOOD and STACEY B. DAY
Memorial Sloan-Kettering Cancer Center New York, New York
1 2 3 4 5 6 7 8 9
Immunology and Aging
Edited by TAKAS HI MAKINODAN and EDMOND YUNIS
Biological Amplification Systems in Immunology Edited by NOORBIBI K. DAY and ROBERT A_ GOOD
Immunopharmacology Edited by JOHN W. HADDEN, RONALD G_ COFFEY, and FEDERICO SPREAFICO
The Immunopathology of Lymphoreticular Neoplasms Edited by J_ J. TWOMEY and ROBERT A. GOOD
Immunoglobulins Edited by GARY W. LITMAN and ROBERT A_ GOOD
Cellular, Molecular, and Clinical Aspects of Allergic Disorders Edited by SUDHIR GUPTA and ROBERT A. GOOD
Immunodermatology Edited by BIJAN SAFAI and ROBERT A. GOOD
Immunology of Human Infection, Part I: Bacteria, Mycoplasmae, Chlamydiae, and Fungi Edited by ANDRE J. NAHMIAS and RICHARD O'REILLY
Immunology of Human Infection, Part 2: Viruses and Parasites; Immunodiagnosis and Prevention of Infectious Diseases Edited by ANDRE J_ NAHMIAS and RICHARD J. O'REILLY
Immunodermatology
Edited by BIJAN SAFAI, M.D. and ROBERT A.GOOD, Ph.D., M.D.
Memorial Sloan-Kettering Cancer Center New York. New York
PLENUM MEDICAL BOOK COMPANY New York and London
Library of Congress Cataloging in Publication Data
Main entry under title:
Immunodermatology .
(Comprehensive Immunology ; 7) Includes index. 1. Skin-Diseases- Immunological aspects. 2. Immunopathology. I. Safai, Bijan, II. Good,
Robert A., 1922· III. Series. [DNLM: 1. Immunity. 2. Skin diseases. WI C04523 v. 7/WR140 133] RL72.I48 616.5 '079 80·15102 ISBN 978-1-4615-7230-5 ISBN 978-1-4615-7228-2 (eBook) DOI 10.1007/978-1-4615-7228-2
© 1981 Plenum Publishing Corporation Softcover reprint of the hardcover 1 st edition 1981 227 West 17th Street, New York, N.Y. 10011
Plenum Medical Book Company is an imprint of Plenum Publishing Corporation
All rights reserved
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
We dedicate this book to Marion B. Sulzberger, teacher, investigator and humane physician, in recognition of his fundamental contribu-tion to dermatology and immunology for more than fifty years.
MARION B. SULZBERGER, M.D., F.A.C.P.
Dr. Marion B. Sulzberger was born on March 12, 1895, in New York City. He attended Harvard and then went on to the University of Zurich where he received his medical degree in 1926. He was the first George Miller MacKee Professor of Dermatology and Syphilology at New York University (1955-1969), where he is still Professor Emeritus. He has been a Clinical Professor of Dermatology at the University of California at San Francisco since 1961 and is also President of the Institute for Dermatologic Communication and Education.
Dr. Sulzberger has had a long scientific career in which he contributed much original work. During this time he accomplished the following:
Described "Incontinentia pigmenti" with Dr. Bruno Bloch (1928). First demonstrated specific immune tolerance in laboratory animals (in guinea
pigs with neoarsphenamine) (1929). Introduced the patch test into the United States with Dr. Fred Wise (1931). Coined the term "atopic dermatitis" with Dr. Arthur Coca and delineated the
clinical and immunological aspects of the syndrome (1932).
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viii DEDICATION
Demonstrated that certain vascular ill effects of tobacco are based on allergic response rather than due to nicotine (1934).
Described the distinctive exudative, discoid, and lichenoid chronic dermatosis with Dr. William Garbe (1937).
Carried out the first experimental sensitization with DNCB of human skin in the United States, with Dr. A. Rostenberg (1939).
Demonstrated the connection between miliaria, the sweat retention syndrome, and tropical anhidrotic asthenia with Dr. Franz Hermann, Harry Zimmerman, and co-workers (1946).
Perfected the method of simultaneous, symmetrical, paired comparisons for as-saying the relative effects of topical agents (with collaborators) (1947).
Introduced the therapeutic efficiency of topical steroids in inflammatory dermato-sis with Dr. Victor H. Witten (1952).
Demonstrated the effectiveness of occlusive dressings (Saran Wrap) in enhancing therapeutic effects of topical medicaments with Dr. Victor H. Witten (1960).
Demonstrated the mechanism of friction blistering, its pathology, its physical and chemical changes, and methods of prevention and management at Letterman Army Institute of Research with collaborators (1966-1969).
Contributors
J. Wesley Alexander Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Shriners Burns Institute, Cincinnati, Ohio
William M. Artis Department of Dermatology, Emory University, Atlanta, Georgia
K. Frank Austen Departments of Dermatology and Medicine, Harvard Medical School; and the Divisions of Dermatology, Departments of Medicine, Robert B. Brigham and Peter Bent Brigham Divisions of the Affiliated Hospitals Center, Boston, Massachusetts
F. C. Austin The National Cancer Institute, Bethesda, Maryland Rudolf L. Baer Department of Dermatology, New York University School of
Medicine, New York, New York Brian Berman Department of Dermatology, New York University School of
Medicine, New York, New York David R. Bickers Department of Dermatology, Case Western Reserve Univer-
sity, Cleveland, Ohio C. W. Boone The National Cancer Institute, Bethesda, Maryland R. W. Case The Roswell Park Memorial Institute, Buffalo, New York K. Lynn Cates Department of Pediatrics, University of Minnesota School of
Medicine, Minneapolis, Minnesota J. A. Cavins St. Vincent's Hospital Department of Oncology, Indianapolis,
Indiana Charlotte Cunningham-Rundles Immunobiology and Medicine, Memorial Sloan-
Kettering Cancer Center, New York, New York Susanna Cunningham-Rundles Clinical Immunology and Tissue Typing Labora-
tories, Sloan-Kettering Institute for Cancer Research, New York, New York Mark V. Dahl Department of Dermatology, University of Minnesota School of
Medicine, Minneapolis, Minnesota 1. Djerassi The Mercy Catholic Medical Center, Philadelphia, Pennsylvania Bo Dupont Tissue Typing Laboratory, Sloan-Kettering Institute for Cancer Re-
search, New York, New York Ervin H. Epstein, Jr. Dermatology Unit of the Medical Service, San Francisco
General Hospital Medical Center; and Department of Dermatology, Univer-sity of California, San Francisco, California
John H. Epstein Department of Dermatology, University of California School of Medicine, San Francisco, California
Roderick M. Farb Department of Medicine, Division of Dermatology, Duke University Medical Center, Durham, North Carolina
Michael J. Fellner Department of Dermatology, New York Medical College, New York, New York
Irma Gigli Department of Dermatology and Medicine, New York University Medical Center and Irvington House Institute, New York, New York
ix
X CONTRIBUTORS
James N. Gilliam Department of Dermatology, University of Texas Health Science Center, Dallas, Texas
Edmond A. Goidl Department of Medicine, Cornell University Medical College, New York, New York
Robert A. Good Memorial Sloan-Kettering Cancer Center, New York, New York
John W. Hadden Laboratory of Immunopharmacology, Memorial Sloan-Ketter-ing Cancer Center, New York, New York
G. Hahn The Roswell Park Memorial Institute, Buffalo, New York Jon M. Hanifin Department of Dermatology, University of Oregon Health
Sciences Center, Portland, Oregon John A. Hansen Puget Sound Blood Center, Fred Hutchinson Cancer Research
Center; and University of Washington, Seattle, Washington Yashar Hirshaut Memorial Sloan-Kettering Cancer Center, New York, New
York O. A. Holtermann The Roswell Park Memorial Institute, Buffalo, New York Alan N. Houghton Memorial Sloan-Kettering Cancer Center, New York, New
York Henry E. Jones Department of Dermatology, Emory University, Atlanta,
Georgia Robert E. Jordon Research Service, Veterans Administration Center, Wood
(Milwaukee), Wisconsin; and Dermatology Section, Department of Medi-cine, The Medical College of Wisconsin, Milwaukee, Wisconsin
Lawrence J. Kagen Hospital for Special Surgery, Cornell University Medical College, New York, New York
Stephen 1. Katz Dermatology Branch, National Cancer Institute, National Insti-tutes of Health, Bethesda, Maryland
Charles H. Kirkpatrick Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
E. Klein The Roswell Park Memorial Institute, Buffalo, New York L. Klein The Roswell Park Memorial Institute, Buffalo, New York Gerald S. Lazarus Department of Medicine, Division of Dermatology, Duke
University Medical Center, Durham, North Carolina Michael D. Lockshin Hospital for Special Surgery, Cornell University Medical
College, New York, New York Carlos Lopez Laboratory of Herpesvirus Infections, Memorial Sloan-Kettering
Cancer Center, New York, New York Frederic C. McDuffie Arthritis Foundation, Atlanta, Georgia; and Department of
Medicine, Emory University, Atlanta, Georgia H. Milgram The Roswell Park Memorial Institute, Buffalo, New York Michael E. Miller Department of Pediatrics, Harbor/UCLA Medical Center,
UCLA School of Medicine, Torrance, California E. J. Moynahan Department of Dermatology, Guy's Hospital, London, England Mark A. Nir State University of New York, Downstate Medical Center, Brook-
lyn, New York Herbert F. Oettgen Memorial Sloan-Kettering Cancer Center, New York, New
York Lloyd J. Old Memorial Sloan-Kettering Cancer Center, New York, New York Elliott F. Osserman College of Physicians and Surgeons of Columbia Univer-
sity, New York, New York Rajendra N. Pahwa Memorial Sloan-Kettering Cancer Center, New York, New
York Marilyn C. Pike The Laboratory of Immune Effector Function of the Howard
Hughes Medical Institute in the Division of Rheumatic and Genetic Diseases, Departments of Medicine and Immunology and Microbiology, Duke Univer-sitv Medical Center, Durham, North Carolina
CONTRIBUTORS xi
Thomas T. Provost Department of Dermatology, State University of New York, Buffalo, New York
Paul G. Quie Department of Pediatrics, University of Minnesota School of Med-icine, Minneapolis, Minnesota
Peter W. Ramwell Department of Physiology and Biophysics, Georgetown Uni-versity Medical Center, Washington D.C.
K. MuraU Krishna Rao Department of Pediatrics and Communicable Diseases, The University of Michigan, Ann Arbor, Michigan
Roy S. Rogers III Department of Dermatology, Mayo Medical School, Roches-ter, Minnesota
Paul Rosenstock Memorial Sloan-Kettering Cancer Center, New York, New York
Bijan Safai Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, New York
W. Mitchell Sams, Jr. Department of bermatology, North Carolina Memorial Hospital, University of North Carolina School of Medicine, Chapel Hill, North Carolina
R. A. Schwartz The Roswell Park Memorial Institute, Buffalo, New York. Pre-sent affiliation: Department of Dermatology, University of California School of Medicine, San Francisco, California
Stanley A. Schwartz Department of Pediatrics and Communicable Diseases, The University of Michigan, Ann Arbor, Michigan
Anthony M. Smithyman Laboratory of Cell Ecology, Memorial Sloan-Kettering Cancer Center, New York, New York
Ralph Snyderman The Laboratory of Immune Effector Function of the Howard Hughes Medical Institute in the Division of Rheumatic and Genetic Diseases, Departments of Medicine and Immunology and Microbiology, Duke Univer-sity Medical Center, Durham, North Carolina
Peter G. Sohnle Department of Medicine, The Medical College of Wisconsin, Milwaukee, Wisconsin
J. A. Solomon The Roswell Park Memorial Institute, Buffalo, New York Nicholas A. Soter Departments of Dermatology and Medicine, Harvard Medical
School; and the Divisions of Dermatology, Departments of Medicine, Robert B. Brigham and Peter Bent Brigham Divisions of the Affiliated Hospitals Center, Boston, Massachusetts
Charlotte A. Thomas Department of Medicine, Division of Dermatology, Duke University Medical Center, Durham, North Carolina
J. L. Turk Department of Pathology, Royal College of Surgeons of England, London, England
John J. Voorhees Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan
Alwin H. Warfel Laboratory of Immunopharmacology, Memorial Sloan-Ketter-ing Cancer Center, New York, New York
Marc E. Weksler Department of Medicine, Cornell University Medical College, New York, New York
Anne West Memorial Sloan-Kettering Cancer Center, New York, New York James M. Woodruff Memorial Sloan-Kettering Cancer Center, New York, New
York Kirk D. Wuepper Department of Dermatology, School of Medicine, University
of Oregon Health Science Center, Portland, Oregon D. Zucker-Franklin Department of Medicine, New York University Medical
School, New York, New York Robert B. Zurier Department of Medicine/Rheumatic Diseases, University of
Connecticut School of Medicine, Farmington, Connecticut
Foreword
By 1940, immunological mechanisms had been proved to have fundamental influ-ences on a great number and variety of skin reactions, and skin diseases had brought to light a great number of fundamental immunological mechanisms that were basic to a wide range of different diseases, dermatological and nondermato-logical. The preeminence of dermatological research in the advancement of immu-nological knowledge should not astonish anyone. For the skin is not only the most easily accessible tissue for producing and studying immunological reactions, it is also the great organ of protection that meets the first onslaughts of inimical environmental forces and agents-potential enemies, both living and dead. And protection is in essence what immunology is all about.
To get an idea of the long-established role that testing the skin and the study of its many reactions has played in advancing general immunology, one need recall only smallpox vaccination; tuberculin testing; testing with fungal extracts; skin testing in hay fever, asthma, and serum sickness; skin tests with toxins and toxoids; the patch test; the passive transfer of skin-adhering antibodies (reagins); skin sensitization by simple chemicals; and similar dermatological procedures that have exerted their influence on medical and scientific disciplines far beyond dermatology.
But these older tests and observations were only the forerunners of the present complexities of immunodermatology-the permutations of the interactions be-tween different varieties of T cells and B cells; the Langerhans cell; the transfer factor; the immunodeficiencies; the complement cascade and complement defi-ciencies; the opsonins; the phagocytic mechanisms; the autoantibodies; the en-zymes and chemical mediators; and the legion of other immunological phenomena that play their parts in skin reactions and diseases.
The speed at which knowledge about the immunology of the skin has grown in the past few decades is such that a practitioner of medicine can hardly be success-ful and a research worker in immunology can hardly be productive without ac-quaintance with the advances in immunodermatology. Therefore, this text on immunodermatology, encompassing the latest advances in this branch of science, satisfies an absolute need of both practitioners and investigators.
Over 300 years ago, Hermann van Boerhaave, the great physician of Leyden, made the following pronouncement: "Simplicitas sigillum veritatis" (Simplicity is the sign of truth). Nothing could be further from the truth in regard to immunoder-matology today. For such are the complexity and scope of modern knowledge about the immunology of the skin that the present textbook has achieved its remarkable comprehensiveness by drawing on the special expertise of over 60 authorities on particular subdivisions of immunodermatology.
There is about as much resemblance between the dermatological allergy* of 1940 and dermatological allergy today as there is between a newborn baby and a
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xiv ~REWORD
healthy youth of 18 years. Yet an 18-year-old youth still has a long way to go to achieve the full realization of his promise.
I feel that this is true of the immunodermatology of today. It is like a vigorous youth. For it is just beginning to feel and to exercise its powers. If I am not mistaken, immunological investigations of the skin have before them an era of productivity that will lead to as yet undreamed of successes in the prevention and management of disease. The editors and authors of the present text will have contributed in no small measure to many of these successes.
Marion B. Sulzberger
*I use "dermatological allergy" as a synonym for "dermatological immunology" and for "immu-nodermatology, " also. For me, the term "allergy" means what von Pirquet intended it to mean when he coined it. Allergy covers all acquired specific alterations in the capacity to react in whatever manner and in whatever direction-toward increased sensitivity or susceptibility, or toward de-creased sensitivity, decreased susceptibility, or immunity. This makes the science of allergy the equivalent of the science of immunology, in today's usage.
Foreword
The dawn of immunology in dermatology is traceable to 1940, when Sulzberger published his volume of didactic lectures on Dermatologic Allergy. In the preface to that classic book Sulzberger begged his readers' 'to remember that the study of allergy is very young, and that the careful analysis of any series of facts must lead one almost immediately to the borders of the unknown. It is therefore not aston-ishing that this new and stimulating brand of medicine should be characterized by rapid progress and by the consequent conflict between old concepts and new findings." Reading this statement today, one realizes its prophecy: never before in the history of medicine has so much information come to light in the short span of 40 years. And no other specialty is so important to dermatology today as immunology.
Skin is a uniquely practical organ for studies on allergic events. It is easily accessible and technically expedient, and has long been favored by clinicians and scientists for investigations ranging from allergic diseases to homografts. Because of gross differences in the timing and the qualitative appearance of test responses to various allergens, skin is a convenient indicator of allergic states and essential in the classification of allergies.
Many allergic diseases that do not normally express themselves in skin can be detected by skin test responses; others produce pathological changes or lesions in the skin secondarily. Still other allergic conditions whose expression is restricted to skin can actually be initiated by normal or altered components of the skin acting as antigens.
A monograph on immunodermatology is timely. An earlier attempt was pub-lished in 1969 as Volume XI of the Advances in Biology of Skin. At that time, immunologists, dermatologists, and biologists reviewed ahd discussed the status of knowledge of the "roles" played by the skin in the genesis and expression of immunological phenomena. An attempt was made to distinguish between roles unique to skin because of its position, anatomy, and biological constitution and roles that can be or are undertaken by other tissues but that may escape notice.
The present volume is testimony to the great strides made in the science of immunodermatology: our knowledge of the immunopathogenic mechanisms in-volved in many cutaneous disorders has suddenly exploded. The many chapters in this volume show that the cutaneous system is unique among other organs in that, as a field of study, it represents an ideal union of clinical and academic research.
This publication is the result of the efforts of B. Safai and R. A. Good, two of today's outstanding investigators of clinical and experimental immunology. The book, a thorough review and analysis of skin immunology today, leaves out nothing important, from historical highlights to current understanding, from un-solved problems to the way to future explorations. All of its contributors have
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xvi FOREWORD
distinguished careers in experimental and clinical dermatoimmunology. Many of them are young enough to have developed pari passu with this new science.
This book is unique in its completeness and timeliness. Anyone wishing to be informed on the subject, whether clinician or experimenter, will want a personal copy. For the practicing clinical dermatologist, it is a must.
William Montagna
Preface
If one could relive history, surely no moment would be more thrilling than when Edward Jenner connected prior exposure to cowpox, among the English milk-maids, with their safety from the smallpox which was scarring, blinding, and killing people throughout eighteenth-century Europe. At that moment, the smooth, healthy complexions of these women became eloquent statements of a saving truth. If Jenner's insight can be said to mark the birth of immunology as a modern medical science, it surely establishes the vital link between immunologi-cal changes and the organ which is quickest to reveal them: the skin.
In return for the contributions of the skin to the development of immunological analysis, immunological analysis has radically altered the nature of dermatology, creating a powerful new focus on disease processes which have long been ob-scure. In recent years, technological advances have made this reciprocal relation-ship an ever closer one.
The purpose of this book is to present a range of information-basic scientific and clinical, historic perspectives, and sharply defined recent studies-which maps out the present state of immunodermatology. The first chapters establish the overall scientific context in which our work takes place. A second group describes the systems-cellular, genetic, physiological-which furnish the microenviron-ment for immune processes. The mechanisms of inflammation, as they manifest a wide range of immunodermatological events, are then explored in some depth. Next, three articles on autoimmune disorders introduce a series of papers on specific disease entities, involving the skin, in which the immune system is com-promised. Herpes infections, malignancies, and immunodeficiencies are among other diseases examined. The roles of trace metals in cellular and serologic anom-alies are among the leads being followed toward greater biological understanding of these processes. The concluding chapters consider the problem of environmen-tal influences and possibilities of broad-based therapeutic approaches.
We hope that this volume will serve as a resource, offering comprehensive background as well as important case studies, and providing a useful tool for the new surge of work in immunodermatology which we have seen to be already in vigorous progress.
Bijan Safai Robert A. Good
xvii
Introduction
BIJAN SAFAI and ROBERT A. GOOD
Ancient records show that the relationship between the skin and immunological events has been understood for centuries: long before inoculation was performed in England, standard medical practice in China and Turkey featured the inhalation of particles from crusts of healing smallpox skin lesions. Since Edward Jenner's time, the remarkable advances of immunology as a discipline have been consis-tently marked by use of the skin as a resource. Patch tests and subcutaneous or intradermal tuberculin tests have been in use since the late nineteenth century, and inhalant antigens had been shown to cause immediate urticarial skin reactions as early as the 1860's (Baer, 1976). The potential of an immunogen either to increase or decrease sensitivity, or both-the seeming paradox which was to bring inoculation to the world-was described by Von Pirquet after his brilliant studies of skin reactions (Von Pirquet, 1911). Prausnitz and Kiistner's bold experiments, utilizing the concept of passive immunization, made use of Prausnitz's own skin, which gave an urticarial reaction to boiled fish protein after an injection of serum from the originally hypersensitive Kiistner (Prausnitz and Kiistner, 1921). In their extraordinary studies interpreting this beautiful experiment of Nature, these early clinical investigators discovered desensitization, perhaps today better considered immunization against immunity. They also discovered that certain antibodies, later to be called reagens, adhere firmly to cells in the skin. In the past two to three decades innumerable experimental skin grafts, revealing host-versus-graft reac-tions, have clarified the role of genetics in allograft rejection and immunological tolerance. As a constant reminder of the association which has brought such benefits to humanity in this century, every summer we see the faint circles left by the tuberculin vaccination on the skin of people's upper arms. And meanwhile, Jenner's work has been completed: the scourge of smallpox has been virtually eliminated from the globe.
We have also found that the association between skin and immunology is recip-rocal; studies and discoveries in immunology have greatly affected the state of dermatology. Atopic dermatitis was associated with reagenic hypersensitivity as early as 1923 (Coca and Cooke, 1923) but the lack of distinct diagnostic indicators hindered both research and treatment (Hanifin, this volume). Today we can iden-tify several immunological changes which correlate with the degree of skin in-volvement in this disease. IgE production is elevated in over 80% of patients with atopic dermatitis, and the highest levels occur in patients with the most severe disease. This imbalance may be due to impaired T-cell regulation (Tada et aI., 1973). Increased susceptibility to cutaneous viral, fungal, and bacterial infections poses a serious problem for these patients. The exact nature of the impairment in cell-mediated immunity which underlies this troublesome disorder-whether a
xix
XX INTRODUCTION
local breakdown in cellular performance or a more general defect of immune cells -has not yet been established.
In Sezary syndrome, an exfoliative dermatitis with intense pruritis, characteris-tic abnormal T lymphocytes with highly convoluted nuclei which are present in peripheral blood infiltrate the skin (Zucker-Franklin, 1976). Recently it has also been discovered that both this disease and the closely related mycosis fungoides feature increased levels of circulating factors similar to those secreted by thymic epithelial cells (Safai et al., 1979). Evidence that the abnormal T cells of Sezary syndrome preferentially infiltrate the skin, possibly conferring a thymus-like func-tion on the skin itself, suggest a unique relationship between these two organs in this disorder.
Components of the complement system are now known to participate in immu-nological injury when this system is activated in the skin, producing skin manifes-tations in the bullous dermatoses certain forms of vasculitis and erythema multi-forme (Gigli, this volume). Skin lesions are also frequent in several profound immunodeficiency disorders that primarily involve the complement system (Day and Good, 1977). Acquired deficiencies of the complement system are manifested in many diseases, including systemic lupus erythematosus and lupus-like syn-dromes. Inherited isolated deficiencies of CIs, Clr, C2, C4, C5, or other comple-ment components may also lead in some way to the development of lupus or lupus-like disease. Angioneurotic edema, and sometimes lupus as well, feature a deficiency of Cl esterase inhibitor. Patients with Clr deficiency suffer from infec-tions which produce severe necrotizing skin lesions and destructive vasculitis, or sometimes lupus-like syndrome with similar skin rashes. C3 deficiency has also been linked with skin rash and skin infections, as well as severe pneumonia and susceptibility to pyogenic infections. C5 dysfunction is associated with Leiner's disease and susceptibility to gram-negative, bacterial, and yeast infections of skin and gut. C8 deficiency may occur in xeroderma pigmentosum, while C2 deficiency is complicated by a host of skin diseases including anaphylactoid purpura, derma-titis herpetiformis, several lupus-like illnesses, and fatal dermatomyositis. The skin lesions of pemphigus and bullous pemphigoid refled the injurious influences of autoantibodies directed at particular components of the skin, as well as the capacity of these antibodies to reactivate complement components. Circulating immune complexes and complement system activation are regularly found in erythema multiforme, erythema multiforme bullosum, dermatitis herpetiformis, and severe bullous dermatitis of childhood. Several of these diseases are now known to be related to the At, Bs haplotype or the Bs antigen of the HLA supergene.
"Cold" abscesses of the skin, remarkable for their lack of inflammatory cells, have led to the characterization of Job's syndrome, in which a defective phagocy-tic response leaves the patient vulnerable to chronic pyogenic bacterial infections. Phagocyte dysfunction (Dahl et al., this volume) has also been identified as one basis for several primary immunodeficiency diseases, all of which present with characteristic skin disorders. The granulomas of the skin and pyogenic derma-toses in· patients with chronic granulomatous disease of childhood (Berendes et aI., 1957; Holmes et aI., 1966) are visible signs of an immunological dysfunction in which phagocytic cells fail to generate the oxidative burst leading to production of bactericidal H2H02, singlet oxygen 02, superoxide 02 and OH-radical. The skin lesions of the Chediak-Higashi anomaly, of which oculocutaneous albinism and susceptibility to several forms of cancer are both regular features, are appar-ently caused by abnormal packaging of pigment (Baehner and Nathan, 1967; Boxer et al., 1976). This abnormality is associated with poor chemotactic and
INTRODUCTION xxi
phagocytic function based at least in part on defects of the leukocytes' microtu-bule structure: a dramatic instance of how increased susceptibility to both infec-tion and cancer is signaled by characteristic skin manifestations.
Both humoral and cell-mediated immunity functions are compromised in the Wiskott-Aldrich syndrome (Cooper et al., 1968, Blaese et al., 1974), which fea-tures hemorrhagic skin lesions, a peculiar form of eczema, and many skin infec-tions. Ataxia telangiectasia is a disastrous illness which presents with a clinical tetrad including ataxia, cutaneous telangiectases, profound immunodeficiency, and susceptibility to many cancers (Boder, 1974). Extensive cutaneous moniliasis is the most common presenting symptom in infants with thymic aplasia (Rosen, 1976). An array of truly scourge-like dermatologic conditions may accompany all types of agammaglobulinemia: pyoderma with severe cicatrization of the skin, recurrent and severe furunculosis, eczema, verruca vulgaris, cutaneous granulo-mas, dermatomyositis-like syndrome with violaceous rash, and edema and indura-tion of the subcutaneous tissues and even subcutaneous nodules (Good and Varco, 1955; Rosen, 1976). All this: and yet these miserable children cannot mount a wheal-and-flare reaction, so severe is their immunodeficiency.
As we continue to uncover the intricate mechanisms of the immune system, we can anticipate finding specific immune defects close to the source of other di-seases which involve the skin. Immunologically-based therapy may then provide relief for illnesses which have defeated other forms of treatment. We have seen that the ancient affliction of leprosy may benefit from a form of immunologic engineering in which a transient T-cell reaction, stimulated by injections of alloge-neic lymphocytes, generated enough cell-mediated immune activity for striking resolution of many of the patients' skin lesions (Lim et al., 1974). Lymphokines, the immunological substances which appear to mediate many skin disorders, may also prove to be a highly potent therapeutic resource in the future, when basic science has achieved sufficient understanding of their mechanisms and the means to produce them in substantial quantities. We have learned that skin cancer, the most common neoplasm in the United States, is correlated with decreased immun-ity. The unusual immunopathology which accompanies head and neck carcinomas (Berlinger and Good, 1976) may yield more insights into the nature of this relation-ship. And it will surely be through immunological manipulation that we ultimately halt the courses of lupus erythematosus and scleroderma, pemphigus, erythema nodosum, and other autoimmune diseases.
While studies in these two disciplines have historically aided each other's pur-poses-the Gell and Coombs classification system, for example, has long demon-strated the importance of skin reactions as a medium for studying immunological injury-recent technical advances have associated the basic methods of immu-nology and dermatology more closely than ever before. Fluorescence micro-scopy, providing the means to observe and quantify the binding of immuno-globulins and complement to tissue, has been a major tool for studying the cutaneous and vascular immunopathology. Electron-microscopic studies have re-vealed striking histologic and inflammatory changes in bullous skin lesions. Our ability to detect histocompatibility antigens, besides enabling us to perform a variety of cell and organ transplantations, has helped us to define the gene-con-trolled aspects of several cutaneous disorders, including dermatitis herpetiformis, where the skin disease is inextricably linked to the alleles of the HLA supergene. Cyclic nucleotides are among the molecular factors of special interest to derma-tologists, because they seem to be linked to the abnormal cell proliferation in psoriatic tissue, and could also underlie the immune dysfunctions in atopic derma-titis (Voorhees, this volume).
xxii INTRODUCTION
References
Baer, R. L., 1976, Cutaneous immunology-then and now, Arch. Dermatol. 112:1661. Baehner, R. L., and Nathan, D. G., 1%7, Leukocyte oxidase: Defective activity in chronic granulo-
matous disease, Science 155:835. Berendes, H., Bridges, R. A., and Good, R. A., 1957, Fatal granulomatous disease of childhood:
Clinical study of a new syndrome, Minn. Med. 40:309. Berlinger, N. T., and Good, R. A., 1976, Concomitant immunopathology with squamous cell carcino-
mas of the head and neck regions, Trans. Am. Acad. Opthalmol. Otolaryngol. 82:588. Blaese, R. M., Strober, W., and Waldmann, T. S., 1974, Immunodeficiency in the Wiskott-Aldrich
syndrome, in: Immunodeficiency in Man and Animals (D. Bergsma, ed.), Birth Defects: Original Article Series, Vol. XI, No.1, p. 250, Sunderland, Mass., Sinauer Associates.
Boder, E., 1974, Ataxia-telangiectasia: Some historic, clinical, and pathologic observations, in: Immu-nodeficiency in Man and Animals (D. Bergsma, ed.), Birth Defects: Original Article Series, Vol. XI, No.1, p. 255, Sunderland, Mass., Sinauer Associates.
Boxer, L. A., Watanabe, A. M., Rister, M., Besch, H. R., Allen, J., and Baehner, R. L., 1976, Correction of leukocyte function in Chediak-Higashi syndrome by ascorbate, N. Engl. J. Med. 295:1041.
Coca, A. F., and Cooke, R. A., 1923, On the classification of the phenomenon of hypersensitiveness, J. Immunol. 8:163.
Cooper, M. D., Chase, H. P., Lowman, J. T., Krivit, W., and Good, R. A., 1968, Wiskott-Aldrich syndrome: An immunologic deficiency disease involving the afferent limb of immunity, Am. J. Med. 44:499.
Day, N. K., and Good, R. A. (eds.), 1977, Comprehensive Immunology, Vol. 2, Biological Amplifica-tion Systems in Immunology, Plenum Press, New York.
Good, R. A., and Varco, L., 1955, A clinical and experimental study of agamma-globulinemia, Lancet 75:245.
Holmes, B., Quie, P. G., Windhorst, D. B., and Good, R. A., 1%6, Fatal granulomatous disease of childhood, an inborn abnormality of phagocytic function, Lancet 1: 1225.
Lim, S. D., Kiszkiss, D. F., Choi, Y. S., Gajl-Peczalska, K., and Good, R. A., Immunodeficiency in leprosy, in: Immunodeficiency in Man and Animals (D. Bergsma, ed.), Birth Defects: Original Article Series, Vol. XI, No.1, p. 244, Sunderland, Mass., Sinauer Associates, 1974.
Prausnitz, C., and Kiistner, H., 1921, Studien iiber die Uberempfindlichkeit, Zentralbl. Bakteriol. Parasitol. Infekt. Hyg. 86:160.
Rosen, F. S., 1976, The primary immunodeficiencies: Dermatologic manifestations, J. Invest. Derma-tol.67:457.
Safai, B., Dardenne, M., Incefy, G. S., Bach, J. F., and Good, R. A., 1979, Circulating thymic factor, facteur thymique serique, in mycosis fungoides and Sezary syndrome, Clin. Immunol. Immuno-pathol. 13:402-406.
Tada, T., Okumura, K., and Taniguchi, M., 1973, Cellular and humoral controls of reagenic antibody synthesis in the rat, in: Mechanisms in Allergy L. Goodfriend, A. H. Sehon, and R. P. Orange, eds.), pp. 43-61, Marcel Dekker, New York.
Zucker-Franklin, D., 1976, Thymus-dependent lymphocytes in Iymphoproliferative disorders of the skin (Sezary syndrome and mycosis fungoides), J. Invest. Dermatol. 67:412.
Contents
Chapter 1 Cell-Mediated Immunity
Susanna Cunningham-Rundles
1. Introduction 2. Cellular Immune Function 2
2.1. T-Cell Immunity 2 2.2. The Primary Response 3 2.3. The Secondary Response 3 2.4. Lymphocyte Subpopulations 6
12 12 13
3. Lymphocyte Activation in Vitro 3.1. Parameters of Activation 3.2. Lymphocyte Stimulators 3.3. Process of Activation 15
17 3.4. Lymphocyte Mediators 4. References 23
Chapter 2 Antigens and Immunogens
Frederic C. McDuffie
1. Introduction 35 2. Properties of Antigenic Determinants 35
2.1. Size 36 2.2. Specificity 37 2.3. Forces Binding Antigen to Antibody 39 2.4. Conformation 39 2.5. Cross-Reactions 40
3. Immunogens 42 3.1. Foreignness 42 3.2. Size 42 3.3. Requirement for Multivalence 42 3.4. Genetic Control 43
4. Allergens 43 5. Autoantigens 44 6. References 44
1
35
xxiii
xxiv CONTENTS
Chapter 3 Humoral Immunity in Comprehensive Immunology
Charlotte Cunningham-Rundles
1. Introduction 47 2. Antibody Structure and Function 47
2.1. General Characteristics 47 2.2. Conformation of Immunoglobulins 47
3. Structure and Biological Function of the Antibodies 3.1. Immunoglobulin G 49 3.2. Immunoglobulin M 51 3.3. Immunoglobulin A 52 3.4. Immunoglobulin D 55 3.5. Immunoglobulin E 56
4. The B-Cell System 56 5. B-Cell Activation 58 6. Immunoglobulin Synthesis and Secretion 58 7. Evolution of the Immunoglobulins 59 8. References 60
Chapter 4
49
The Complement System: Mechanisms of Action, Biology, and Participation in
47
Dermatological Diseases 65 Irma Gigli
1. Introduction 65 2. Biochemistry of Complement: Activation Mechanisms 65
2.1. Classical Complement Reaction 65 2.2. Alternative and Amplification Pathways of Complement
Activation 70 3. Roles of "Control" Proteins in the Complement System 72
3.1. Inhibitor of the Activated First Component (Cl) of Complement (CIINH) 72
3.2. The C3b Inactivator (C3bINA)-Control Protein of C3b and C4b 72 3.3. An Inactivator of the C3a and C5a Anaphylatoxins (AI) 73
4. Biological Activity of Some Products of the Complement System 73 5. Evaluation of the Complement System 76 6. Laboratory Measurement of Complement 76
6.1. Collection of Samples 76 6.2. Functional Hemolytic Assays 76 6.3. Immunochemical Assays for Complement Proteins 77 6.4. Additional Complement Assays 77
7. Complement Abnormalities in Skin Diseases 77 8. Inborn Deficiencies of the Complement System 78
8.1. Deficiencies of Components 78 8.2. Deficiencies of Control Proteins 83
9. Acquired Abnormalities of the Complement System Associated with Skin Diseases 84 9.1. Angioedema and Urticaria 84 9.2. Complement Abnormalities in Cutaneous Vasculitis 86 9.3. Complement Abnormalities in Infectious Processes with Skin
Manifestations 87
CONTENTS XXV
9.4. Uncommon Cutaneous Disorders Associated with Complement Abnormalities 88
9.5. Autoimmune Processes Involving the Skin Associated with Complement Abnormalities 89
9.6. Inflammatory Processes Involving the Skin Associated with Complement Abnormalities 90
10. Conclusions 91 11. References 91
Chapter 5 Mechanisms of Nonspecific Host Resistance
Ralph Snyderman and Marilyn C. Pike
1. Introduction 101 2. Methods for Measurement of Inflammatory Cell Accumulation and
Chemotaxis 102 3. Chemotactic Factors 104
3.1. C-Derived Chemotactic Factors 104 3.2. Cell-Derived Chemotactic Factors 105 3.3. Bacterial Chemotactic Factors 106
4. Mechanisms of Chemotaxis 106 5. Phagocytosis 108 6. Summary 110 7. References 111
Chapter 6 The HLA System and Dermatological Diseases
BoDupont
1. Introduction 115 2. HLA System 116
2.1. HLA-A, -B, -C 116 2.2. HLA-Dand-DR 117
3. Genetics of HLA 120 4. HLA Genetic Linkage Group 121 5. HLA and Disease 121
5.1. Introduction 121 5.2. Statistical Considerations and Experimental Design 5.3. HLA and Dermatological Diseases 123 5.4. HLA-Linked Diseases 124
6. Conclusions 125 7. References 125
122
101
115
xxvi CONTENTS
Chapter 7 Natural Control over Immune Responses 129
Stanley A. Schwartz and K. Murali Krishna Rao
1. Introduction 129 2. Immunological Enhancement 129
2.1. Role of Lymphocytes 129 2.2. Role of Monocytes and Macrophages 130
3. Suppressor Cells and Activities 130 3.1. Animal Models 130 3.2. Studies in Man 131 3.3. Soluble Suppressor Factors 132
4. Lymphokines 132 5. Immunological Memory 133
5.1. B-Cell Memory 133 5.2. T-Cell Memory 134
6. Immune Tolerance 134 6.1. B-Cell Tolerance 135 6.2. T-Cell Tolerance 135 6.3. Role of Other Cells in Tolerance 135 6.4. Role of Antibody and Antigen-Antibody Complexes in Tolerance 136
7. Summary 136 8. References 136
Chapter 8 Mechanisms of Tissue Injuries and Repairs in Hypersensitivity 141
Michael E. Miller
1. Introduction 141 2. Type I Reactions 142
2.1. Receptor Binding Phase 143 2.2. Activation Phase 143 2.3. Release of Mediators 144 2.4. Clinical Signs 144
3. Type II Reactions 144 3.1. Classes of Antibody 145 3.2. Mechanisms of Activation 146 3.3. Effects on Sensitized Cells 146
4. Type III Reactions 146 4.1. Mechanisms of Reaction 146 4.2. Serum Sickness 146 4.3. Arthus Reactions 147 4.4. Massive Complement Activation 148
5. Type IV Reactions 148 6. Differential Diagnosis and Cautions 148 7. References 149
CONTENTS xxvii
Chapter 9 Cyclic Nucleotides, Arachidonic Acid, and Polyamines in the Pathophysiology of Inflammatory Proliferative Skin Diseases 151
John J. Voorhees
1. Introduction 151 2. Role of the Cyclic AMP System 151 3. Role of the Cyclic GMP System 153 4. Role of the Arachidonic Acid-Prostaglandin Transformation System 5. Role of the Cell Surface 156 6. Role of the Polyamines 157 7. Summary 157 8. References 157
Chapter 10 Prostaglandins and Other Arachidonate Metabolites
Robert B. Zurier and Peter W. Ramwell
1. Introduction 161 2. Biochemistry 161 3. Prostaglandins and Inflammation 163
3. 1. Induction of Inflammation 164 3.2. Release during Inflammation 164 3.3. Effects of Antiinflammatory Drugs 165 3.4. Prostaglandins as Modulators of Inflammation 166
4. Prostaglandins and Immune Responses 166 4.1. Humoral Immune Response 167 4.2. Cell-Mediated Responses 168
5. Prostaglandins and Cutaneous Pathophysiology 169 5.1. Prostaglandins and Vitamin A 170 5.2. Prostaglandins and Pigmentation 170
6. Concluding Remarks 171 7. References 171
Chapter 11
154
161
Role of Proteinases in Cutaneous Inflammation 177 Gerald S. Lazarus, Roderick M. Farb, and Charlotte A. Thomas
1. Introduction 177 2. Epidermal Proteinases 177
2.1. Cathepsin D 177 2.2. Cathepsin BI 178 2.3. Plasminogen Activator 178
3. Serine Proteinases Operable at Physiological pH 178 4. Role of Serine Proteinase as a Possible Messenger for Polymorphonuclear
Leukocyte Accumulation 179 5. Chemotactic Proteinase in Psoriasis 180 6. Role of Proteinase in Pemphigus Vulgaris 181 7. Conclusion 184 8. References 185
xxviii CONTENTS
Chapter 12 Collagen Biosynthesis and Connective Tissue Abnormalities
Ervin H. Epstein, Jr.
1. Introduction 189 2. Collagen Structure and Amino Acid Sequence 3. Intracellular Biosynthesis i91 4. Extracellular Modifications 192 5. Collagen Degradation 193 6. Collagen and the Immune System 194 7. Conclusions 195 8. References 195
Chapter 13 Vasculitis
W. Mitchell Sams, Jr.
1. Introduction 197
189
2. Leukocytoclastic Vasculitis (Hypersensitivity Angiitis or Allergic Vasculitis) 198 2.1. Leukocytoclastic Vasculitis 198 2.2. Hypocomplementemic (Urticarial) Vasculitis 200 2.3. Essential Mixed Cryoglobulinemia 201
3. Rheumatic Vasculitis 202 3.1. Systemic Lupus Erythematosus 202 3.2. Rheumatoid Vasculitis 202 3.3. Dermatomyositis 203 3.4. Progressive Systemic Sclerosis (Scleroderma) 204
4. Granulomatous Vasculitis 204 4.1. Allergic Granulomatous Angiitis (Churg-Strauss Syndrome) 204 4.2. Wegener's Granulomatosis 204 4.3. Lymphomatoid Granulomatosis 205 4.4. Granuloma Annulare, Necrobiosis Lipoidica Diabeticorum, and
Rheumatoid Nodules 206 5. Polyarteritis Nodosa 206
5.1. Classic Type 206 5.2. Cutaneous Type 206
6. Giant-Cell Arteritis 207 6.1. Temporal Arteritis 207 6.2. Polymyalgia Rheumatica 208 6.3. Takayasu's Disease 208
7. Immunological and Etiological Aspects 208 8. References 212
Chapter 14
189
197
Adverse Drug Reactions 217 Michael J. Fellner
1. Introduction 217 2. Anaphylaxis 217
CONTENTS xxix
3. Urticaria 217 4. Bullous Reactions 219
4.1. Toxic Epidermal Necrolysis 219 4.2. Erythema Multiforme 219 4.3. Bullous Pemphigoid 220 4.4. Systemic Lupus Erythematosus 220
5. Specific Drugs 220 5.1. Silicone 220 5.2. Penicillin 221 5.3. Parabens 221 5.4. Trichloroethylene 222 5.5. Ethylene Oxide 222 5.6. Phenylbutazone 222 5.7. Salicylanilides, Bithionol, and Other Photo sensitizers 222 5.8. Tetracycline 223 5.9. Dyes 224 5.10. Antihistamines 224 5.11. Phenothiazines 225 5.12. Sulfones 225 5.13. Neomycin 225 5.14. Gold 225 5.15. Isoniazid 226 5.16. Penicillamine 226
6. Treatment 226 7. References 226
Chapter 15 The Graft-vs.-Host Reaction in Man: Genetics, Clinical Features, and Immunopathology 229
John A. Hansen, James M. Woodruff, and Robert A. Good
1. Introduction 229 2. Clinical Spectrum 229
2.1. GVHR in Children with Immune Deficiency 229 2.2. GVHR in Immunosuppressed Patients 230 2.3. GVHR Following Marrow Transplantation 231
3. Genetics of Transplantation 231 3.1. Allograft Reaction 231 3.2. Determinants Controlling GVHR 232
4. GVHR in Bone Marrow Transplant Patients 232 4.1. Treatment of Children with Severe Combined Immune Deficiency
Disease 232 4.2. Patients with Aplastic Anemia and Leukemia 234
5. Pathogenesis of GVHR and Immunological Mechanisms 5.1. Experimental GVHR 234 5.2. Graft-vs.-Host Disease in Humans
6. Clinical Features of Graft-vs.-Host Disease 6.1. Acute GVHD 236 6.2. Chronic GVHD 237
7. Pathology of Cutaneous GVHD 7.1. Acute Cutaneous G VHR 7.2. Chronic Cutaneous GVHR
238 238
247
236 236
234
XXX CONTENTS
7.3. Pathogenesis and Results of Special Studies 248 8. Therapy of GVHD 250
8.1. A voidance of G VHR in Susceptible Individuals: Use of Irradiated Blood Products 250
8.2. Prophylactic Treatment of GVHR in Marrow Transplant Patients 251 8.3. Treatment of Established GVHD 251
9. References 252
Chapter 16 Allergic Contact Dermatitis, Photoallergic Contact Dermatitis, and Phototoxic Dermatitis 259
Rudolf L. BaerandDavid R. Bickers
1. Introduction 259 2. Allergic Eczematous Contact Dermatitis 259
2.1. Clinical Changes 259 2.2. Histological Changes 260 2.3. Immunological Mechanisms 260 2.4. Antigens 261 2.5. In Vivo and in Vitro Tests 263 2.6. Genetic Factors 263 2.7. Specific Immunological Tolerance 263 2.8. "Systemic" Effects of Contact Allergens 2.9. Hyposensitization and Desensitization
3. Photoallergic Contact Dermatitis 265 3.1. Introduction 265 3.2. Clinical Manifestations 265 3.3. Histological Changes 266 3.4. Immunological Mechanisms 266 3.5. Mechanism of Persistent Light Reactivity 3.6. Photopatch Tests 268
4. Phototoxic Dermatitis 268 5. References 270
Chapter 17
264 264
267
Urticaria/Angioedema: The Mast Cell, Its Diverse Mediators, and Its Role in Cutaneous Inflammation 273
Nicholas A. Soter and K. Frank Austen
1. Introduction and Definition 273 2. Epidemiology 273 3. Pathogenesis 274
3.1. The Mast Cell 274 3.2. Chemical Mediators 275 3.3. Mast Cell Activation in Vivo 277
4. Clinical Manifestations 278 4.1. IgE-Dependent Urticaria/Angioedema 278 4.2. Complement-Mediated Urticaria/Angioedema 280 4.3. Non immunological Urticaria/Angioedema 282 4.4. Idiopathic Urticaria/Angioedema 283
CONTENTS xxxi
5. Laboratory Findings 283 6. Pathology 283 7. Diagnosis and Differential Diagnosis 8. Prevention and Treatment 284 9. References 285
Chapter 18 Eosinophil in Skin Disorders
Dorothea Zucker-Franklin
1. Introduction 293 2. Morphology and Function 293 3. Specific Properties 295
284
4. Eosinophilia in Dermatological Disorders 5. Conclusion 298 6. References 298
Chapter 19 Atopic Dermatitis
Jon M. Hanifin
1. General Considerations 301 1.1. Definition 301 1.2. History 301 1.3. Natural Course 301 1.4. Epidemiology and Inheritance 301
2. Immunological Associations 302 2.1. Reagenic Hypersensitivity 302 2.2. IgE in Atopic Dermatitis 303
296
2.3. Other Immunoglobulin Studies in Atopic Dermatitis 304 2.4. Dysfunctional Cellular Immune Mechanisms 304 2.5. Relationship to Immunodeficiency Diseases 306
3. Altered Physiological and Pharmacological Reactivity 307 3. 1. Abnormal Cutaneous Responses 307 3.2. Investigations Relating to the I3-Adrenergic Blockade Theory
4. Canine Allergy: A Possible Animal Model of Atopic Dermatitis 5. References 308
Chapter 20 Autoimmunity
Edmond A. Goidl and Marc E. Weksler
1. Self-Tolerance and the Control of Autoimmune Reactions 313 2. Autoimmune Reactions in Man 314 3. Factors Which Influence the Expression of Autoimmunity 316
3.1. Genetic Constitution 316 3.2. Sex 317 3.3. Age 318
4. Innovative Therapeutic Approaches to Autoimmunity 319 5. References 320
307 307
293
301
313
xxxii CONTENTS
Chapter 21 Immunopathology and Pathogenesis of Cutaneous Lupus Erythematosus 323
James N. Gilliam
1. Introduction 323 2. LE-Specific Skin Disease: Classification and Clinical Features 323 3. Pathological Features of Cutaneous LE 325 4. Immunopathology of Cutaneous LE 326 5. Experimental Models of LE Skin Disease 326 6. Relationship between Cutaneous and Systemic LE 326 7. Proposed Immunopathogenic Mechanism of Cutaneous LE 330 8. Summary and Conclusions 331 9. References 331
Chapter 22 Other Disorders with Autoimmune Manifestations 333
Michael D. Lockshin and Lawrence J. Kagen
1. Introduction 333 2. Rheumatoid Arthritis 333 3. Juvenile Rheumatoid Arthritis 334 4. Polymyositis and Dermatomyositis 335 5. Scleroderma 337 6. Sjogren's Syndrome 338 7. "Mixed Connective Tissue Disease" 339 8. Relapsing Polychondritis 339 9. Lyme Arthritis 340
10. References 340
Chapter 23 Recurrent Aphthous Stomatitis and Beh-;et's Syndrome
Roy S. Rogers III
1. Historical Perspective 345 2. Recurrent Aphthous Stomatitis 345
2.1. Clinical Characteristics 345 2.2. Epidemiological Characteristics 345
3. Beh~et's Syndrome 346 3.1. Clinical Characteristics 346 3.2. Epidemiological Characteristics 347
4. Evidence for an Immunopathogenesis of RAS and BS 347 4.1. Introduction 347 4.2. Disease Associations 347 4.3. Histocompatibility Antigen Associations 348 4.4. Response to Therapy 348 4.5. Pathological Observations 349 4.6. Absence of a Defined Microbiological Agent 349 4.7. Streptococcal Antigens 349 4.8. Oral Mucosal Antigens 350
5. Conclusion 350 6. References 351
345
Chapter 24 Alopecia Areata
Bijan Safai
1. Introduction 355 2. Histopathology 355 3. Etiology and Pathogenesis 356 4. Association with Autoimmune Disorders 357 5. Association with Mongolism 357 6. Experimental Studies 358 7. Conclusion 359 8. References 359
Chapter 25
CONTENTS xxxiii
355
Vesiculobullous Skin Diseases 361 Robert E. Jordon and Thomas T. Provost
1. Introduction 361 2. Pemphigus 361 3. Bullous Pemphigoid 364 4. Herpes Gestationis 368 5. Cicatricial Pemphigoid 371 6. Erythema Multiforme 371 7. Benign Chronic Bullous Dermatosis of Childhood 8. References 373
Chapter 26 Dermatitis Herpetiformis
Stephen I. Katz
1. Introduction 377
372
2. Immunoglobulin and Complement Deposition in DH Skin 377 3. Serum Factors 381 4. Gastrointestinal Lesion in Dermatitis Herpetiformis 382 5. Effect of Gluten Withdrawal on the Skin Disease 383 6. Immunogenetic Aspects of Dermatitis Herpetiformis 385 7. Conclusions 386 8. References 387
Chapter 27
377
Syndromes Resembling Scalding of the Skin 389 Kirk D. Wuepper
1. Introduction 389 2. Staphylococcal Epidermolytic Toxin Syndrome (SETS; Ritter von
Rittershain) 389 2.1. Clinical Observations 389 2.2. Histopathological Observations 390 2.3. Experimental SETS 391
xxxiv CONTENTS
2.4. Immunology of SETS 392 2.5. Epidermolysin in Bullous Impetigo 392
3. Toxic Epidermal Necrolysis (TEN; Lyell Syndrome) 393 3. 1. Clinical Observations of TEN 393 3.2. Histopathological Observations of TEN 393 3.3. Relation to Gv H Disease 394 3.4. Relation to Erythema Multiforme 394
4. Conclusion 395 5. References 395
Chapter 28 Primary Immunodeficiency Diseases of Man 399
Robert A. Good, Rajendra N. Pahwa, and Anne West
1. Introduction 399 2. X-Linked Infantile Agammaglobulinemia 399 3. DiGeorge's Syndrome 404 4. Severe Combined Immunodeficiencies (SCID, Swiss-Type
Immunodeficiencies) 406 5. Severe Combined Immunodeficiencies with Adenosine Deaminase
Deficiency 408 6. Thymoma with Immunodeficiency 408 7. Common Variable Immunodeficiency (CVI) 409 8. Selective Immunoglobulin Deficiency-Isolated Absence of IgA 411 9. Immunodeficiency with Wiskott-Aldrich and Ataxia-Telangiectasia
Syndromes 411 10. Other Primary Immunodeficiencies 412
10.1. Deficiencies of Components of the Complement System 413 10.2. Deficiencies of Phagocytic Cells 414 10.3. Chronic Mucocutaneous Candidiasis 414 10.4. Other Manifestations of Primary Immunodeficiency 415
11. Conclusion 415 12. References 416
Chapter 29 Deficiency of Phagocyte Function and Related Disorders
Mark V. Dahl, K. Lynn Cates, and Paul G. Quie
1. Introduction 425 2. Impaired Chemotaxis 425
2.1. Hyperimmunoglobulinemia E Syndrome 425 2.2. Atopic Dermatitis 426 2.3. Lazy Leukocyte Syndrome 427 2.4. Acrodermatitis Enteropathica 427 2.5. Ichthyosis 427 2.6. Mucocutaneous Candidiasis 427 2.7. Wiskott-Aldrich Syndrome 427 2.8. Measles 428 2.9. Mycosis Fungoides 428
2.10. Inhibitors of Chemotaxis 428
425
CONfENTS XXXV
2.11. Impaired Generation of Chemotactic Factors 428 2.12. Augmented Chemotaxis 429
3. Impaired Phagocytic Microbial Killing 429 3.1. Chronic Granulomatous Disease 429 3.2. Chediak-Higashi Syndrome 431 3.3. Myeloperoxidase Deficiency 432 3.4. Glucose-6-Phosphate Dehydrogenase Deficiency 432 3.5. Leukocyte Alkaline Phosphatase Deficiency 432
4. Conclusion 432 5. References 433
Chapter 30 Acrodermatitis Enteropathica and the Immunological Role of Zinc
E. J. Moynahan
1. Introduction 437 2. The Human Disorder 437 3. The Bovine Disease 438 4. Symptomatology 439 5. Biogeochemistry of Zinc 439 6. Sources of Zinc 439 7. Biochemistry of Zinc 440 8. Zinc and Nucleic Acids 441 9. Bioavailability and Biological Antagonism of Trace Metals 441
10. Zinc and Protein Metabolism 441 11. Zinc and Glutathione 441 12. Superoxide Dismutase 441 13. Physiology of Zinc 441
13.1. Absorption 441 13.2. Excretion 442 13.3. Loss in Hair, Nails, Sweat, and Sebum 442 13.4. Loss of Endogenous Zinc in Pancreatic Juice and Bile 442 13.5. Zinc and the Liver 442 13.6. Zinc and the Skin 442 13.7. Zinc and Wound Healing 443 13.8. Zinc in Bone and Teeth 443 13.9. Zinc and the Eye 443
13.10. Zinc and the Nervous System 443 13 .11. Zinc and Reproduction 443 13.12. Zinc and Pregnancy 444 13.13. Milk 444 13.14. Zinc in Inflammation and Infection 444 13.15. Leukocyte Endogenous Mediator (LEM) 444 13.16. Coricosteroids and Zinc 444 13 .17. Zinc and Lymphocytes 444 13.18. Zinc and Platelets 444
14. Zinc and Immunity 444 14.1. Nutritional Aspects 444 14.2. Zinc and the Immune Response 445
15. Cellular Immunodeficiency in Hereditary Parakeratosis of Calves and Acrodermatitis Enteropathica 445
16. Conclusion 446 17. References 446
437
xxxvi CONfENTS
Chapter 31 Mechanisms of Granuloma Formation 449
John W. Hadden, Anthony M. Smithyman, and Alwin H. Warfel
1. Introduction 449 2. Definitions of Granuloma 449 3, Relation of Granuloma Formation to Inflammation and Immunity 451 4. Cellular Aspects of Granuloma Formation in Vivo 453
4.1. Macrophage Proliferation 453 4.2. Macrophage Proliferation in Association with Cellular Immunity 453 4.3. Metabolic Activity of Macrophages in Granulomas 454 4.4. Macrophage Activation 454 4.5. Fate of Immigrant Macrophages 455
5. Role of Lymphocytes in Granuloma Formation 456 5.1. Role of T Lymphocytes in Granuloma Formation 456 5.2. Role of B Lymphocytes in Granuloma Formation 457 5.3. Other Cell Types 457
6. Molecular Aspects of Granuloma Formation 457 6.1. Macrophage Recruitment 457 6.2. Macrophage and Lymphocyte Localization 458 6.3. Inflammatory Responses of the Macrophage 458 6.4. Immunological Responses of the Macrophage 458 6.5. Multinucleated Giant-Cell Formation 460
7. Speculations and Conclusions 462 8. References 462
Chapter 32 Role of Langerhans Cells in Cutaneous Immunological Reactions
Rudolf L. Baer and Brian Berman
1. Introduction 467 2. Identification of Langerhans Cells 467 3. Derivation of Langerhans Cells 468 4. Distribution of Langerhans Cells 469 5. Uptake of Small and Large Molecules 469 6. Observations on Langerhans Cells in Contact Allergic Reactions 469 7. Comparison of Langerhans Cells and Monocytic Phagocytes 473 8. Effects of Immune Complexes on Langerhans Cells 474 9. Functions of Langerhans Cells in Contact Allergy 477
10. Findings Regarding Langerhans Cells in Other Dermatoses 479 11. Future Studies of Langerhans Cells 480 12. References 480
Chapter 33 Sarcoidosis
Yashar Hirshaut and Paul Rosenstock
1. Introduction 483 2. Humoral Immunity 483 3. Cell-Dependent Immunity 486
467
483
CONTENTS xxxvii
4. Specific Immunity 490 5. References 491
Chapter 34 Chronic Mucocutaneous Candidiasis 495
Charles H. Kirkpatrick and Peter G. Sohnle
1. Introduction 495 2. Etiology 495 3. Clinical Features 496
3.1. Syndromes of Mucocutaneous Candidiasis 496 3.2. Genetic Features 499 3.3. Clinical Course 500 3.4. Associated Disorders 500
4. Host Defenses 502 4.1. Lymphocyte-Mediated Functions 502 4.2. Antibody Production 504 4.3. Plasma Factors 505 4.4. Phagocytic Cell Function 505 4.5. Complement 505
5. Mechanisms of Cutaneous Inflammation 506 6. Therapy 506
6.1. Antibiotics 506 6.2. Immunological Therapy 508 6.3. Combination Therapy 509
7. Summary and Conclusions 510 8. References 511
Chapter 35 Dermatophytosis 515
Henry E. Jones and William M. Artis
1. Introduction 515 2. Pathogenesis and Clinical Manifestations 515
2.1. Colonization and Inflammation 515 2.2. Dermatopathology 516 2.3. Secondary Allergic Eruptions 516
3. Immunology 516 3.1. Antigens 516 3.2. Antibody Response 518 3.3. Cell-Mediated Immunity 518
4. Experimental Infection 519 5. Host Defense Mechanisms 520
5.1. Unsaturated Transferrin 521 5.2. Cell-Mediated Immunity 521 5.3. Epidermal Desquamation 522
6. Susceptibility Factors 522 6.1. Immune Disorders 522 6.2. Endocrine Relationships 522 6.3. Genetics and Other Factors 522
7. Immunotherapy 523 8. References 523
xxxviii CONTENTS
Chapter 36 Immunology of Leprosy and Related Chronic Infections of the Skin
J. L. Turk
1. Introduction 525 2. Mechanisms of Survival of Microorganisms in the Infected Host
2.1. Antigenic Variation 526 2.2. Intracellular Residence of Microorganisms 526
525
526
3. Possible Causes of Failure of Cellular Immunity in Certain Chronic Infectious Diseases 527
4. Immunological Spectra in Chronic Infectious Disease 5. Genetic Susceptibility in Chronic Infectious Disease 6. Mycobacterial Infections 528
6.1. Leprosy 528 6.2. Immunotherapy in Leprosy
7. Leishmaniasis 532 8. Syphilis-A Vertical Spectrum 9. Conclusion 536
10. References 537
Chapter 37 Herpesvirus Infections
Carlos Lopez
1. Introduction 539
532
534
2. Primary Herpes Simplex Virus Infections 539 2.1. Herpes Simplex Virus Type 1 540 2.2. Herpes Simplex Virus Type 2 540
3. Latent Virus Infections 540 4. Reactivation of Latent Infections 541
4.1. Association of Reactivation with Disease 541 4.2. Factors Associated with Reactivation 541
527 527
5. Herpes Infections of the Immunocompromised Host 541 5.1. Cancer Patients and Renal and Bone Marrow Transplant
Recipients 541 5.2. Newborns 542
6. Immunity to Herpesvirus Infections 542 6.1. Humoral Immunity 542 6.2. Cell-Mediated Immunity 542 6.3. The Macrophage in Resistance 543 6.4. Interferon in Resistance 543 6.5. Marrow-Dependent (M)-Cell Function in Natural Resistance 543
7. The Immune Response and Recurrent Infections 543 7.1. Resistance to Development of Latent Infection 544 7.2. A Cell-Mediated Immune Deficit Associated with Recurrent
Infections 544 7.3. Immunopathology Associated with Recurrent Infections 544 7.4. Association of Histocompatibility Antigen HLA-Al with Recurrent
Infections 545 8. Future Studies 546 9. References 546
539
Chapter 38 Kaposi's Sarcoma
Bijan Safai and Robert A. Good
1. Introduction 549 2. Geographical Distribution 549 3. Classification 550 4. Etiology 551 5. Role of the Immune System 551 6. Association with Other Malignancies 552 7. Cell Type of Origin 553 8. Conclusion 553 9. References 554
Chapter 39 Malignant Melanoma: Current Status of the Search for Melanoma-Specific Antigens
CONTENTS
Alan N. Houghton, Herbert F. Oettgen, and Lloyd 1. Old
1. Introduction 557 2. Selected Clinical and Biological Features of Malignant Melanoma 3. Cell Surface Antigens of Tumors in Experimental Animals and Man
3.1. Tumors of Experimental Animals 559 3.2. Human Tumors 560
xxxix
549
557
557 559
4. Serological Definition of Cell Surface Antigens of Malignant Melanomas by Autologous Typing 561
5. Changes in Autologous Serological Reactivity during the Clinical Course of Malignant Melanoma 566
6. Biochemical Aspects of Melanoma Cell Surface Antigens 567 7. Additional Approaches to the Detection and Characterization of Melanoma
Cell Surface Antigens 568 8. Cell-Mediated Immune Reaction to Melanoma Surface Antigens 9. Development of a Maximally Immunogenic Melanoma Vaccine
10. Concluding Remarks 573 11. References 573
Chapter 40 The Cutaneous Plasma Cell Dyscrasias
Mark A. Nir and Elliot F. Osserman
1. Introduction 577 2. Cutaneous Plasma Cell Dyscrasias 577
2.1. Immunopathic Dermal Mucinosis (Papular Mucinosis) 577 2.2. Xanthomatosis and Plasma Cell Dyscrasia 582 2.3. Cold Urticaria Associated with PCD 585 2.4. The Mixed Cryoglobulinemia Syndrome 585
569 570
3. Dermatoses with Immunological Aberrations and Occasional Plasma Cell Dyscrasia 586 3.1. Pyoderma Gangrenosum 586 3.2. Kaposi's Sarcoma 586
577
xl CONTENTS
3.3. Others 586 4. Cutaneous Manifestations of MUltiple Myeloma and Waldenstrom's
Macroglobulinemia 587 4.1. Cutaneous Plasmacytoma 587 4.2. Amyloidosis 587 4.3. Nonspecific Changes 588
5. References 589
Chapter 41 The Cutaneous Amyloidoses
MarkA. Nir
1. Definition, Composition, and Classification of the Systemic Amyloidoses 595
2. Classification of the Cutaneous Amyloidoses 596 3. The Cutaneous Amyloidoses 596
3.1. Papillary Amyloidoses 596 3.2. Reticular Amyloidoses 600
4. Conclusions 602 5. References 603
Chapter 42
595
Cutaneous T-Cell Lymphomas 607 B. Sa/ai and D. Zucker-Franklin
1. Introduction 607 2. Clinical Manifestations of Cutaneous T-Cell Lymphomas 607 3. Lymphomatoid Papulosis 609 4. Histopathology of Cutaneous T-Cell Lymphomas 609 5. Ultrastructural Features 610 6. Cytogenetic Studies 611 7. Immunological and Functional Studies 612 8. Staging Classification 618 9. Therapeutic Approaches to Cutaneous T-Cell Lymphoma 618
10. Summary of Current Concepts 618 11. References 619
Chapter 43 Transplantation Immunology 623
J. Wesley Alexander
1. Introduction 623 2. History of Skin Grafting 623 3. Healing of Skin Grafts 624 4. Immunological Rejection 625
4.1. Acute Rejection 625 4.2. Chronic Rejection 625 4.3. Hyperacute Rejection and White Grafts 625
CONTENTS xli
5. Mechanisms of Immunological Injury during Rejection 626 5.1. Injury Associated with Antigen-Antibody Reactions 626 5.2. Direct Cytotoxicity of T Lymphocytes 626 5.3. Cytotoxicity by T-Lymphocyte-Activating Macrophages 627
6. Protective Immunological Reactions 627 7. Effect of Histocompatibility 628 8. Individual Responsiveness 629 9. Modification of Graft Rejection: Treatment of the Graft 629
10. Conclusions 629 11. References 630
Chapter 44 Immunotherapy of Skin Cancer and Other Neoplasms Involving the Skin 633
E. Klein, G. Hahn, R. W. Case, 1.A. Solomon, R.A. Schwartz, C. W. Boone, F.e. Austin, L. Klein, 1. Djerassi, I.A. Cavins, H. Milgrom, and O.A. Holtermann
1. Introduction 633 2. Therapeutic Approaches Using Delayed-Hypersensitivity Reactions 634
2.1. Method of Inducing Delayed Hypersensitivity to Primary Antigens 634
2.2. Use of Immunological Memory 639 3. Premalignant Keratoses 640 4. Squamous Cell Carcinoma of the Skin 640 5. Multiple Superficial Basal Cell Carcinomas 641 6. Applications of Immunotherapy to the Treatment of Nonepidermal
Tumors 642 6.1. Mycosis Fungoides 642 6.2. Malignant Melanoma 644 6.3. Olner Tumors 645
7. Clinical Studies of Antimitotic Agents in the Regulation of the Immune System 645
8. Studies on Cellular and Noncellular Mediators of Delayed Hypersensitivity 647
9. Studies in the Viral Augmentation of Tumor-Specific Antigens 648
10. Implications of Immunotherapy 649 11. References 651
Chapter 45 Immunological Parameters in Photocarcinogenesis 655
lohn H. Epstein
1. Introduction 655 2. Tumor Antigens 655
2.1. Tumor-Specific Antigens 655 2.2. Antigen Deletion 656
3. Immunological Control 657 4. Influence of UV on UV -Induced Cancer Rejection 658 5. Conclusion 658 6. References 659
xlii CONTENTS
Chapter 46 Therapeutic Approaches to Immunological Diseases 661
Robert A. Good, Rajendra N. Pahwa, and Anne West
1. Introduction 661 2. Disorders of the Lymphoid System 661
2.1. Transplantation of Bone Marrow 662 2.2. Total Lymphoid Irradiation 667 2.3. Transplantation of Fetal Liver, Fetal Thymus, and Cultured Thymic
Epithelium for Treatment of SCID 668 3. Defects of the Complement System 669 4. Diseases of the Phagocytic System 670 5. Aplastic Anemia 672 6. Anticipating the Future 673
6.1. Thymic Hormones 673 6.2. Transfer Factor 674 6.3. Lymphokines 674 6.4. Cellular Therapy for Leprosy 675 6.5. Enzymes 677 6.6. Nutrition and Aging 677 6.7. Trace Metals 679 6.8. Y-Globulin and Plasma 680 6.9. Suppressor Cells 681
7. Conclusion 682 8. References 682
Index 697
