Table Of ContentTHE
AUTOIMMUNE DISEASES
Edited by
NOEL R. ROSE
Department of Immunology and Infectious Diseases
and Department of Medicine
The Johns Hopkins Medical Institutions
Baltimore, Maryland
IAN R. MACKAY
Clinical Research Unit
of The Walter and Eliza Hall Institute of Medical Research
and the Royal Melbourne Hospital
Melbourne, Victoria, Australia
1985
ACADEMIC PRESS, INC.
Harcourt Brace Jovanovich, Publishers
Orlando San Diego New York Austin
London Montreal Sydney Tokyo Toronto
COPYRIGHT © 1985 BY ACADEMIC PRESS, INC.
ALL RIGHTS RESERVED.
NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR
TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC
OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR
ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT
PERMISSION IN WRITING FROM THE PUBLISHER.
ACADEMIC PRESS, INC.
Orlando, Florida 32887
United Kingdom Edition published by
ACADEMIC PRESS INC. (LONDON) LTD.
24-28 Oval Road, London NW1 7DX
LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA
Main entry under title:
The Autoimmune diseases.
Includes index.
1. Autoimmune diseases. I. Rose, Noel R.
II. Mackay, Ian R. [DNLM: 1. Autoimmune Diseases.
WD 305 A9375]
RC600.A83 1985 616.97 85-1406
ISBN 0-12-596920-1 (alk. paper)
ISBN 0-12-596921-X (paperback)
PRINTED IN THE UNITED STATES OF AMERICA
85 86 87 88 987654321
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Donato Alarcon-Segovia (119), Department of Immunology and Rheuma
tology, Instituto Nacional de la Nutricion "Salvador Zubiran," Mex
ico City, Distrito Federal 14000, Mexico
Giuseppe A. Andres (339), Department of Microbiology, Department of
Pathology, and Department of Medicine, School of Medicine, State
University of New York at Buffalo, Buffalo, New York 14214
Grant J. Anhalt (443), Department of Dermatology, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205
Barry G. W. Arnason (399), Department of Neurology, The University of
Chicago, Chicago, Illinois 60637
Richard H. Aster (493), The Blood Center of Southeastern Wisconsin,
Inc., and Medical College of Wisconsin, Milwaukee, Wisconsin
53233
Pierluigi E. Bigazzi (161), Department of Pathology, University of Con
necticut Health Center School of Medicine, Farmington, Connecticut
06032
Robert M. Blizzard (201), Department of Pediatrics, University of Vir
ginia Medical Center, Charlottesville, Virginia 22908
Gian Franco Bottazzo (227), Department of Immunology, The Middlesex
Hospital Medical School, London W1P 9PG, England
Jan R. Brentjens (339), Department of Pathology, Department of Microbi
ology, and Department of Medicine, School of Medicine, State Uni
versity of New York at Buffalo, Buffalo, New York 14214
Roger L. Dawkins (591, 669), Departments of Clinical Immunology,
Royal Perth Hospital, and The Queen Elizabeth II Medical Centre,
Perth, 6001, Australia
Luis A. Diaz (443), Department of Dermatology, The Johns Hopkins Uni
versity School of Medicine, Baltimore, Maryland 21205
xiii
xiv CONTRIBUTORS
Deborah Doniach (227), Department of Immunology, The Middlesex
Hospital Medical School, London W1P 9PG, England
P. Brent Ferrell1 (29), George Washington University School of Medicine,
Washington, D.C. 20037
Michael J. Garlepp (591), Departments of Clinical Immunology, Royal
Perth Hospital, and The Queen Elizabeth II Medical Centre, Perth,
Western Australia 6001, Australia
Stephen B. Hanauer (267), Department of Medicine, The University of
Chicago, Chicago, Illinois 60637
Leonard C. Harrison (617), Department of Diabetes and Endocrinology,
The Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia
Sumner C. Kraft (267), Department of Medicine, The University of Chi
cago, Chicago, Illinois 60637
Parviz Lalezari (523), Division of Immunohematology, Department of
Medicine, Montefiore Hospital, and Albert Einstein College of Medi
cine, The Bronx, New York 10467
lan R. Mackay (1, 243, 291), Clinical Research Unit of The Walter and
Eliza Hall Institute of Medical Research and The Royal Melbourne
Hospital, Melbourne, Victoria 3050, Australia
Noel K. Maclaren (201), Department of Pathology, and Department of
Pediatrics, College of Medicine, University of Florida, Gainesville,
Florida 32610
Alan C. Menge (537), Department of Obstetrics and Gynecology, The
University of Michigan Medical Center, Ann Arbor, Michigan 48104
Bernice Noble (339), Department of Microbiology and Department of
Pathology, School of Medicine, State University of New York at
Buffalo, Buffalo, New York 14214
Sir Gustav Nossal (695), The Walter and Eliza Hall Institute of Medical
Research, Melbourne, Victoria 3050, Australia
Robert B. Nussenblatt (371), Clinical Ophthalmic Immunology Section,
National Eye Institute, National Institutes of Health, Bethesda,
Maryland 20205
Harish P. Patel (443), Department of Dermatology, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205
Bernard Pirofsky (469), Division of Immunology, Allergy, and Rheuma
tology, Department of Medicine, The Oregon Health Sciences Uni
versity, Portland, Oregon 97201
Thomas T. Provost (443), Department of Dermatology, The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205
1 Present address: Shelby Medical Associates, Shelby, North Carolina 28150.
CONTRIBUTORS XV
Noel R. Rose (1, 161), Department of Immunology and Infectious Dis
eases, and Department of Medicine, The Johns Hopkins Medical
Institutions, Baltimore, Maryland 21205
Gordon C. Sharp (81), Division of Immunology and Rheumatology, De
partment of Medicine, University of Missouri-Columbia School of
Medicine, Columbia, Missouri 65212
Arthur M. Silverstein (371), The Wilmer Ophthalmological Institute, The
Johns Hopkins University School of Medicine, Baltimore, Maryland
21205
Bernhard H. Singsen (81), Departments of Child Health, Medicine, and
Pathology, University of Missouri Health Sciences Center, Colum
bia, Missouri 65212
Kate M. Spencer (227), Department of Diabetes and Immunology, St.
Batholomew's Hospital, London, England
Norman Talal (145), Division of Clinical Immunology, Department of
Medicine, The University of Texas Health Science Center at San
Antonio, and Clinical Immunology Section, Audie L. Murphy Me
morial Veterans Administration Hospital, San Antonio, Texas 78284
Eng M. Tan (29), W. M. Keck Foundation Autoimmune Disease Center,
Research Institute of Scripps Clinic, Scripps Clinic and Research
Foundation, La Jolla, California 92037
Kenneth S. K. Tung (537), Department of Pathology, University of New
Mexico School of Medicine, Albuquerque, New Mexico 87131
Mathew A. Vadas2 (429), Institute for Medical and Veterinary Science,
Adelaide 5000, Australia
Senga Whittingham (243), Clinical Research Unit, The Walter and Eliza
Hall Institute of Medical Research, The Royal Melbourne Hospital,
Melbourne 3050, Australia
Mathew A. Vadas2 (429), Clinical Research Unit of The Walter and Eliza
Hall Institute of Medical Research and The Royal Melbourne Hospi
tal, Melbourne, Victoria 3050, Australia
Senga Whittingham (243), Clinical Research Unit of The Walter and Eliza
Hall Institute of Medical Research and The Royal Melbourne Hospi
tal, Melbourne, Victoria 3050, Australia
Morris Ziff (59), Department of Internal Medicine, The University of
Texas Health Science Center at Dallas, Dallas, Texas 75235
2 Present address: Institute for Medical and Veterinary Science, Adelaide, South Australia
5000, Australia.
Foreword
Like many other medical scientists I first became aware of autoimmune
disease as a clinical entity from the work of Dameshek and Schwartz in
1937, and I have been interested in it ever since although always mainly
from its bearing on immunological theory. During 1962 I collaborated on
the theoretical side with Dr. Mackay in writing one of the earlier texts in
English, which was published in 1963. In the ensuing 20 years experimen
tal and clinical research has enriched the field immensely and widened the
range of diseases attributable wholly or in part to autoimmunity. At least
we were thinking along the right lines, and I am happy to contribute a
foreword to the present volume.
To one who has been away from active research in immunology since
1965, the dominant impression of what has happened since is the daunting
complexity of the genetic and biochemical processes that are concerned
with the regulation of the immune system. Almost all recent experimental
work designed to elucidate basic immunology has centered on the use of
mouse strains of known genetic composition. As a result, a much more
precise understanding of the structural chemistry and genetic control of
the diversity of specific patterns in antibodies is now available. This holds
also for the nature and developmental sequence of the several species of
immunoglobulins and their respective functions. Many other relevant
substances, particularly cell surface antigens and receptors, lymphokines,
and other cell secretions, have also been effectively studied. All of these
body components concerned in immune responses are proteins directly or
indirectly coded for by germ line structural genes. In the case of antibod
ies at least, diversity is achieved by modification at some stage of differen
tiation, within the lines of somatic stem cells, of one or more germ line
genes by transposition or recombination, or by somatic mutation.
It must be remembered, however, that the mammalian genome contains
a great deal of DNA not demonstrably coding for specific protein and
presumably concerned with regulatory processes, including the timing
xvii
xviii FOREWORD
and correlation of activity of each structural gene during the processes of
growth, differentiation, and repair. Far less is known about the detailed
structure and function of regulatory DNA than about structural DNA and
the peptide sequences that it codes for. Biologically, however, it is proba
bly just as important as the protein-synthetic system, particularly in deter
mining the details of morphological and functional differentiation during
development. It is well known that the chemical and serological qualities
of the proteins of humans and chimpanzees are so extremely similar that
these can be regarded as sibling species. The differences to be found in
almost every detail of morphology, therefore, must be derived from muta
tional or other types of modification of the regulatory segments of the
genome of the common ancestral species.
Most experimental and theoretical immunologists now recognize that
the immune system is an immensely complex web of interactions that
evolved to deal with a wide variety of exceptional situations. Its regula
tion obviously requires a sophisticated system of communication, with
active responses and feedbacks involving either a proliferative response,
a step in differentiation, or an activation of secretory function, and, on the
negative side, inhibitory or destructive responses of corresponding type.
The concept of immune surveillance was introduced to account for a
variety of oncological phenomena but nowadays there is a growing opin
ion that it is principally concerned with, or is a by-product of, the internal
specific control of all types of lymphocytes and their derivatives. Katz has
summarized the position by saying that all populations of functioning
lymphocytes must be under positive and negative control coordinated to
optimize the survival of the individual exposed to infection or to some
internally induced change of "self" pattern. Jerne's concept of immune
regulation by antibody, or suppressor cells with specificity for idiotypes,
is one example of how this may be achieved.
In the absence of any accepted interpretation of immune regulatory
processes, I still prefer to think of them broadly as complex homeostatic
and self-monitoring functions. Very early in this century Ehrlich clearly
expressed the logical necessity that the vertebrate body must in some way
be inhibited from developing antibodies reactive against its own compo
nents, and this constraint has been more or less consciously recognized
ever since. It can be expressed broadly in the form that the function of the
immune system is to recognize the presence of substances or chemical
patterns foreign to the body and to eliminate them or nullify their harmful
actions.
At the risk of being too easily satisfied, one can still look at the problem
in general biological terms rather than at a molecular level and use terms
lore appropriate perhaps to the 1950s than to the 1980s. The immune
FOREWORD xix
system in my view exists primarily to maintain the structural and chemi
cal integrity of the body. The facts of infectious disease, of allergic com
plaints, and of the troubles that may follow injection or transplantation of
cells or tissues from other individuals all suggest that the entry of things
that are "not-self" parenterally is harmful and, at least in relation to
microbial infection, has needed the evolution of mechanisms to avoid or
deal with any such entry into the tissues. In broad terms what is needed is
for cells to recognize the foreign quality of the material, to counteract any
damaging quality, and in some way to segregate and to destroy or elimi
nate the offending particles or molecules.
From what we now know of the production and functioning of antibody
it is clear that what is needed is a repertoire of epitopes (immune specifici
ties) on immunoglobulins and immunocytes, sufficient to cover as many
types of foreign molecular groups as is physically possible but without
such action on all molecular groupings of body ("self") components that
are accessible to circulating cells or proteins in the blood or lymph. Pro
duction of such a repertoire demands a set of mechanisms by which a very
wide—virtually infinite—diversity of molecular patterns can be conferred
on immunoglobulins or the related cell receptors, and also that any of
those patterns reactive with self-components are in one way or another
effectively inhibited or eliminated from the repertoire or rendered incapa
ble of being stimulated to proliferation or other significant activity. If this
is to be accomplished without the general metabolism being disturbed, an
elaborate communications system is clearly needed. Much of the control
of the antibody system is at the genetic level. The random transposition of
alternative DNA segments within a well-ordered framework plus acceler
ated point mutation in the V gene segments indicates some of the subtlety
of the processes.
When we come to cellular aspects of immune responses, however,
experimental immunology is much less revealing. It is evident that many
classes of lymphocytes carry receptors of similar specificity to those
forming the variable regions of antibodies. The B-cell surface receptor
responsible for specific cellular activation after contact with antigen ap
pears to be monomeric IgM synthesized by the cell itself. Must less is
known of the specific T-cell receptor. There is considerable evidence,
which I find impressive, that points to the passive transfer of the whole or
part of B-cell receptors to Τ cells, which then take on the characteristic
specificity in their functional responses. Others consider that T-cell speci
ficity is autonomous to the cell concerned.
The activities of higher cells, suppressor cells, cytotoxic and nonspe
cific killer cells among the Τ cells have not yet been fully defined. The
implication is that within the immune system there must be means by
XX FOREWORD
which the numbers and distribution of every recognizably different type
of circulating cell can be monitored and, if necessary, be stimulated to
proliferate, functionally inhibited, or destroyed. In its own way communi
cation and control of the immune system may be as complex as its social
analogs, the control of crime and delinquency or the economics of an
industrial society. Autoimmune disease has often been likened to the
revolutionary violence of a rebellious section of the national police force,
and there may be just as many possible reasons for the conflict to become
clinically overt.
Immune tolerance to self-components is mediated through more than
one mechanism, but when antibody production is being considered I be
lieve that clonal deletion is the dominant process. If a precursor Β cell at
its first surface expression of the specific antibody receptor makes contact
with the corresponding antigenic determinant in adequate concentration,
the precursor cell is lethally damaged. As the clone matures, its cells
become less susceptible to damage and are more likely to show a prolifer
ative response to the same specific stimulus.
Autoimmune disease is not easy to define or to interpret. For fairly
obvious reasons the original hallmark of autoimmune disease was the
presence of autoantibodies, that is, antibodies reactive with normal con
stituents of the body. The prototype was "warm-type" autoimmune he
molytic anemia as described by Dameshek and Schwartz in 1950. Virtu
ally all the generally recognized autoimmune diseases have shown one or
more types of autoantibody not always directly related to the symptoms
of the condition. In healthy subjects the appearance of any of the common
autoantibodies tested for in clinical laboratories is quite unusual, but there
is a distinct increase in their incidence in old age.
In some ways the simplest interpretation of the appearance of an active
clone of Β cells producing autoantibody is that a mutation (germ line or
somatic) has significantly increased its resistance to tolerization by the
corresponding autoantigen. In view of the complexities, known in detail
or recognized in principle, that are needed for a normally functioning
immune system, it is only to be expected that a wide range of somatic
genetic errors may be needed for the appearance of an autoimmune clone.
The mutations or other type of change in DNA pattern may involve either
germ line cells or somatic cells at various stages of differentiation; and,
for overt manifestations of the clone, appropriate functional states of the
internal environment will be necessary.
Autoimmune disease has many resemblances to a conditioned malig
nancy and modern thinking on the initiation of malignancy may well be
relevant. There is a general agreement that the final step in the develop
ment of at least one important group of cancers is the undue activity of the
FOREWORD xxi
product of an oncogene, itself derived from a normal gene which is pre
sumably concerned with cell proliferation in development and repair and
which is referred to as a proto-oncogene. According to work in Wein
berg's laboratory, the change in structure associated with the proto-onco
gene to oncogene change is located in a single nucleotide, the codon GGC
being changed by a point mutation to GTC, corresponding to a glycine-
valine change in the gene product. Scolnick's group, however, has pub
lished evidence that a regulatory change, by which abnormally large
amounts of the gene product are synthesized, can produce the same cell-
transforming effect.
The eventual interpretation of the appearance of autoimmune clones of
Β or Τ cells will almost certainly be expressed in molecular terms that
may involve a sequence of point mutations, anomalous transpositions, or
some other intragenomic change, functionally equivalent to somatic mu
tation. It remains to be seen whether, when such investigations have been
successfully completed in mouse model systems of autoimmune disease,
the results can be usefully applied to autoimmune conditions in humans.
Perhaps the main lesson to be learned from the modern elucidation of
the mammalian immune system is that of the extraordinary complexity of
its regulatory mechanisms at both genetic and physiological levels. Clini
cal experience suggests that every case of serious autoimmune disease
has its own individual peculiarities, and it will probably always be imprac
ticable to provide a complete picture of the primary and secondary pro
cesses responsible for the patient's condition. In a work which must be
firmly directed toward the clinical realities of diagnosis and treatment in
the various manifestations of autoimmune disease, theoretical studies in
immunology and immunopathology have only a very limited place. The
handling of individual patients must conform to the current consensus of
clinical opinion. Basic research in immunopathology will continue, and if
past experience is any guide such research will provide at intervals ideas
that will modify the clinical approach. Equally important is the potential
of clinical and epidemiological studies in human disease to influence gen
eral thinking on the nature of autoimmune disease. The distribution of
HLA types in relation to clinical conditions, particularly of immunopatho-
logical character, is one of the most important findings of this sort.
Every chapter of this book represents a fusion of acts and ideas from
both the clinical and experimental fields. It is both inevitable and essential
that this cooperation go on indefinitely.
Sir Macfarlane Burnet
Canterbury, Victoria
Australia
