Table Of ContentMonographs on Endocrinology
Volume 20
Edited by
F. Gross, Heidelberg· M. M. Grumbach, San Francisco
A. Labhart, ZUrich . M. B. Lipsett, Bethesda
T. Mann, Cambridge' L. T. Samuels (t), Salt Lake City
J. Zander, MUnchen
Robert Volpe
Auto-immunity
in the
Endocrine System
With 32 Figures and 15 Tables
Springer-Verlag
Berlin Heidelberg New York 1981
Robert Volpe, M. D., F.R.C.P. (C), F.A.C.P.
Professor, Department of Medicine,
University of Toronto;
Physician-in-Chief,
The Wellesley Hospital,
Toronto, Ontario M4Y 113,
Canada
ISBN-13:978-3-642-81626-0 e-ISBN-13:978-3-642-81624-6
DOl: 10.1007/978-3-642-81624-6
Library of Congress Cataloging in Publication Data.
Volpe, Robert, 1926- . Auto-immunity in the endocrine system.
(Monographs on endocrinology; v. 20) Includes bibliographies and index.
1. Endocrine glands - Diseases - Immunological aspects. 2. Autoimmune diseases. 1. Title. I I. Series.
[DNLM: I. Autoimmune diseases. 2. Endocrine diseases-Etiology. 3. Endocrine diseases-Immunology.
WL MOS7 v. 20/ WK 100 A9396]
RC649.V64 616.4'079 81-9090
ISBN-13:978-3-642-81626-0 (U.S.) AACR2
This work is subject to copyright. All rights arc reserved, whether the whole or part of the material is
concerned, specifically those of translation, reprinting, fe-use of illustrations, broadcasting, reproduction
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'Verwertungsgesellschaft Wort', Munich.
© Springer-Verlag Berlin, Heidelberg 1981
Softeover reprint of the hardcover t st edition t 981
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a
specific statement, that such names are exempt from the relevant protective laws and regulations and
therefore free for general use.
2125/3020-543210
Preface
The present monograph will concern itself with those disorders of the endocrine
system, either associated with destruction, interference with function or hyper
function, which are considered to be due to auto-immune processes.
Endocrinopathies Non-endocrine auto-immune
disorders associated with the endocrinopathies
Graves' (Basedow's, Parry's) disease Pernicious anaemia
Hashimoto's thyroiditis Vitiligo
Idiopathic Addison's disease Myaesthenia gravis
Insulinopenic diabetes mellitus Sjogren's syndrome
Auto-immune oophoritis and orchitis Rheumatoid arthritis
Auto-immune hypoparathyroidism Idiopathic thrombocytopenic purpura
Auto-immune hypophysitis Chronic active hepatitis
Possibly some cases of infertility Primary biliary cirrhosis
due to anti-sperm antibodies
Reproduced with permission from Volpe (1977)
The above table indicates those organ-specific endocrinopathies considered to
be due to auto-immune factors, as well as those non-endocrine, organ-specific
auto-immune disorders which may be associated with them (Volpe 1977). It is
evident that such disorders, occurring without any obvious external cause, raise the
very elementary question of how immune processes directed against self
constituents could be initiated. Generally, of course, the immune system acts as a
regulatory and defence mechanism, and disorders of auto-immunity represent
breakdowns in this regulatory system. The following chapters will be concerned
with the individual components ofthe endocrine system so affected by auto-immune
processes; it will first be necessary to provide an initial chapter for the purpose of
summarizing some general principles of immunology, in order to place the immune
disorders of the endocrine system in context.
It is commonplace to observe that the field of immunology is of very great'
magnitude and is evolving very rapidly. The chapter on general principles therefore
will not be all-embracing, but will select those elements which will be necessary for a
comprehension of the disorders to be discussed later. Moreover, the chapters which
follow will not offer comprehensive citations of the literature, but rather references
will be made to studies considered most appropriate, most important or repre
sentative or to many of the extensive and excellent reviews which have recently
appeared on topics appropriate to this text.
While the reviews of the endocrinopathies which follow the introductory chapter
will cite the views of many workers, the perspectives will not be neutral. The author
VI Preface
will infuse his own interpretations on the various observations collated herein, in an
effort to derive a unitary hypothesis which will then encompass most, ifnot all, of the
auto-immune organ-specific endocrinopathies (and those non-endocrine, organ
specific auto-immune disorders associated with them). These views have evolved
from consideration of studies in the author's laboratory and of many others, as
distilled through innumerable discussions between the present writer and many
colleagues. Particular gratitude is expressed to Vas V. Row, my research associate,
and many previous research fellows: Drs. Jean Dussault, Eric Laryea, Joseph
McConnon, Lamk Lamki, Peter Clarke, Robert Munro, John O'Donnell, Andrew
Knox, Merrill Edmonds, Christian von Westarp, Jay Silverberg, Akira Sugenoya,
Krinos Trokoudes, Arthur Kidd, Nobumitsu Ok ita, Mark Lewis, Jacques How,
and Duncan Topliss. These young men have been a source of constant stimulation
over the years, for which the author is greatly indebted.
It is important also to express gratitude to the unsung heroes of this monograph;
to my secretaries, Mrs. Sarah McLaughlin and Mrs. Ursula Besteman, for their
efforts in typing, arranging and organizing this work; to Mrs. V. Empey, Medical
Librarian, Wellesley Hospital, and her stafffor their assistance with the background
references; to the Medical Art Department, Wellesley Hospital, for the diagrams;
and finally, to my wife and family, and my skiing and tennis partners for their
forbearance during the long months of preparation of this manuscript.
Toronto, July 1981 Robert Volpe
Contents
General Principles of Immunology
(as Related to Auto-immune Disease) . 1
1.1 Immunity and the Immune Response . . . . . . 1
1.1.1 The Role of Lymphocytes in the Immune Response 2
1.1.2 Types of Lymphocytes . . . . . . . . . 2
1.1.3 Processing of Antigen. . . . . . . . . . 5
1.1.4 Genetic Control of the Immune Response 6
1.1.5 Significance of HLA Disease Associations. 9
1.1.6 Cell Interactions and Immunoregulation 9
1.2 References. . . . . . . . . . . . 16
2 Auto-immunity in Thyroid Disease . 19
2.1 Introduction. . . . . . . . . . . . . . . . . . . . . 19
2.2 Studies of the Immunological Aspects of Thyroid Disease 22
2.2.1 Initial Observations . . . . . . . . . . . . . . . . . 22
2.2.2 Experimental and Spontaneous Animal Models in Auto-immune
Thyroid Disease. . . . . . . . . . . . . . . . 22
2.2.2.1 Experimental Auto-immune Thyroiditis . . . . . . . . . .. 23
2.2.2.2 Spontaneous Auto-immune Thyroiditis in Animals . . . . .. 26
2.2.2.3 Attempts to Produce Experimental Models for Graves' Disease. 28
2.2.3 Humoral Immunity in Human Thyroid Disease. 29
2.2.3.1 Thyroglobulin Antibodies. . . . . . . . . . . . . . . . . 29
2.2.3.2 Antimicrosomal Antibodies. . . . . . . . . . . . . . . . 32
2.2.3.3 Antibody to a Colloid Component Other than Thyroglobulin 33
2.2.3.4 Antibodies to the Thyroid Hormones . . . . . . . . . . . 33
2.2.3.5 Thyrotrophin (TSH) Receptor-Related Antigen and Cell Surface
Antigens and Their Relationship to Thyroid-Stimulating
Immunoglobulin. . . . . . . . . . . . . . . . . . . . .. 33
2.2.3.6 Immune Complexes, Rheumatoid Factors and Other Antibodies 40
2.2.3.7 Production of Thyroid Antibodies and Thyroid-Stimulating
Immunoglobulin In Vitro. . . . . . . . . . . . . . 41
2.2.4 Cellular Aspects of Graves' and Hashimoto's Diseases. 42
2.2.4.1 Thyroid Lymphocytes . . . . 42
2.2.4.2 Peripheral Blood Lymphocytes . . . . 44
2.2.4.3 Cytotoxic Lymphocytes. . . . . . . . 46
2.2.4.4 Migration Inhibition Factor Procedures 46
2.2.4.5 Evidence for a Defect in Suppressor T-Iymphocytes 49
2.2.4.6 Other Cellular Mechanisms. . . . . . . . . . . 55
2.2.5 The Role of the Antigen: Is There Antigenic Stimulation? 55
VIII Contents
2.2.6 The Genetics of Graves' and Hashimoto's Diseases . . . 59
2.2.6.1 Observations in Twins . . . . . . . . . . . . . . . . 59
2.2.6.2 Age-specific Incidence Rates in Graves' and Hashimoto's
Diseases. . . . . . . . . . . . . . . . . . . . . . . 59
2.2.6.3 Thyroid Auto-antibodies and Chromosomal Abnormalities. 62
2.2.6.4 HLA Associations . . . . . . . . . . . . . . . . . . . 62
2.2.6.5 Studies of Relatives of Patients with Graves' and Hashimoto's
Diseases. . . . . . . . . . . . . . . . . . . . . . . . . 64
2.2.6.6 Other Auto-immune and Neoplastic Associations . . . . . . . . 66
2.2.7 Interrelationships Between Graves' and Hashimoto's Diseases . . 68
2.2.8 Relationship of Painless ("Silent") Subacute Lymphocytic Thyroiditis
to Chronic Auto-immune Thyroiditis. . . . . . . . . . . . 70
2.2.9 Auto-Immune Thyroid Disease in Pregnancy and the Neonate 71
2.2.9.1 Post-partum Auto-immune Thyroid Disease . . . . . . . 71
2.2.9.2 Passive Transfer of Antibodies to the Foetus . . . . . . . . 73
2.2.10 The Effect of Pharmacological Agents, Thyroidectomy and
Radioactive Iodine on the Immunological Stigmata of Graves'
and Hashimoto's Diseases. . 73
2.2.10.1 Excessive Iodine Intake. . . 73
2.2.10.2 Thyroid Hormone Therapy. 74
2.2.10.3 Corticosteroid Therapy. . . 74
e
2.2.10.4 Effects of Radioactive Iodine 311) Therapy for Graves' Disease 75
2.2.10.5 The Effect of Subtotal Thyroidectomy in Graves' Disease on the
Immunological Disturbance. . . . . . . . . . . . . 76
2.2.10.6 Antithyroid Drug Therapy: Effects on Immune System. 78
2.2.10.7 Propranolol or Other Beta Adrenergic-Blocking Agents 81
2.2.11 The Role of Stress in the Induction of Graves' Disease. 81
2.2.12 The Nature of the Remissions. . . . . . . . 83
2.2.13 The Pathogenesis of Ophthalmopathy . . . . 85
2.2.14 Pretibial Myxoedema (Localized Dermopathy) 90
2.3 Summary. 91
2.4 References. . . . . . . . . . . . . . . . . 93
3 Auto-immunity in Diabetes Mellitus 112
3.1 Introduction. . . . . . . . . . . 112
3.2 Genetics ........... . 113
3.3 HLA Antigens in Type I Diabetes . 114
3.4 Relationship to Other Organ-specific Auto-immune Diseases . 118
3.5 Immunologic Disturbances . 119
3.5.1 Morphological Observations . . 119
3.5.2 Humoral Antibodies ..... . 119
3.5.3 Antibodies to Insulil1 Receptors . 121
3.5.4 Evidence of CeU~niediated Immunity. 122
3.5.4.1 Migration Inhibition Tests . . . . . 122
3.5.4.2 Cytotoxic Assays. . . . . . . . . . 124
3.5.4.3 Evidence for a Defect in Immunosuppression . 125
3.5.5 Animal Experiments . . . . . . . . . . . . 126
Contents IX
3.5.6 Insulin as an Antigen. . . . . . . . . . . . . 128
3.6 The Possible Role of Viruses in the Induction of
Insulinopenic Diabetes. . . . . . 129
3.6.1 Clinical and Pathological Evidence. . . . . . . 129
3.6.2 Experimental Evidence. . . . . . . . . . . . 130
3.6.3 Seasonal Variation in Incidence of Diabetes Mellitus. 131
3.6.4 Immune Responses to Viruses in Diabetes . . . . . 132
3.7 The Role of Immunity in the Pathogenesis of Complications of
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . .. 135
3.8 Immunological Aspects of Islet and Pancreas Transplantation in
Diabetes . 137
3.9 Summary. 138
3.10 References. 139
4 Auto-immunity of the Anterior Pituitary 146
4.1 References.............. 147
5 Auto-immune Diseases of the Adrenals, Gonads and Parathyroids:
Auto-immune Polyendocrine Disease . . 149
5.1 Addison's Disease . . . . . . . . . . . 149
5.2 Experimental Auto-immune Adrenalitis. . 150
5.3 Pathology of Idiopathic Addison's Disease 152
5.4 Humoral Immunity in Human Addison's Disease 152
5.5 Cell-mediated Immunity in Addison's Disease. . 154
5.6 Genetic Aspects of Auto-immune Addison's Disease. 156
5.6.1 HLA Antigens Associated with Addison's Disease. . 156
5.6.2 Family Studies. . . . . . . . . . . . . . . . . . 156
5.7 Other Organ-specific Auto-immune Diseases Associated with
Idiopathic Addison's Disease 157
5.7.1 Thyroid Disease. . . . . . . . 157
5.7.2 Ovarian Failure. . . . . . . . 159
5.7.3 Auto-immune Testicular Failure. 161
5.7.4 Pernicious Anaemia . . . . . . 162
5.7.5 Diabetes Mellitus Associated with Addison's Disease. 162
5.7.6 Hypoparathyroidism........... 162
5.8 Polyendocrine Auto-immune Disease. . . . 163
5.8.1 Relative Incidence of Auto-immune Disease. 163
5.8.2 Mechanism of Cellular Destruction . . . . 165
5.8.3 Association with Various Non-Endocrine Auto-immune
Disorders. . . . . . . . . . . . . . . . . . 165
5.8.4 Defect in Immunoregulation . . . . . . . . . 166
5.9 Other Possible Auto-immune Endocrinopathies. 169
5.10 Summary. 169
5.11 References............... 171
6 Immunological Aspects of Male Infertility. 176
6.1 References............... 177
x
Contents
7 Epilogue ........ . 178
7.1 Introduction. . . . . . . . 178
7.1.1 Genetics and Epidemiology. 178
7.1.2 Histocompatibility Antigens. 178
7.1.3 Definition of the Role of the Antigen. 178
7.1.4 T-Lymphocyte Studies ...... . 179
7.1.5 Studies of Antibodies. . . . . . . . 179
7.1.6 Non-Specific Cellular and Chemical Elements. 180
7.1.7 Sex Incidence . . . . . . . . . 180
7.1.8 Tolerance .......... . 180
7.1.9 Future Therapeutic Possibilities . 180
7.1.10 Radio-immunoassay 180
Subject Index . . . . . . . 181
1 General Principles of Immunology
(as Related to Auto-immune Disease)
1.1 Immunity and the Immune Response
The term "immunity" may be defined as those physiological mechanisms which
endow the organism with the capacity to recognize substances as foreign, and to
neutralize, eliminate or metabolize them without injury to its own tissues.
Responses to such foreign substances may be divided into two types, i.e. those which
are non-specific, and those which are specific immunological responses. N on
specific responses may occur following the initial and even subsequent exposure to
foreign antigen, and are not dependent on specific recognition. A non-specific
response involves the participation of cellular and chemical mediators, such as
macrophages, lysozymes, properdin, interferon, prostaglandins and complement
(Playfair 1975).
Although the term "complement" was originally designated to imply. an auxiliary
factor in serum that, acting upon an antibody-coated cell, would lead to lysis of the
cell, the complement system is now known to be a complex cascade of interacting
proteins. It is evident that the complement sequence consists of nine functional
entities or eleven discrete proteins. These have a variety of different molecular
weights and properties. The terms applied to these components include Clq, Clr,
CIs, C2, C3, C4, C5, C6, C7, C8 and C9. The components of complement cause the
accumulation of neutrophils from the circulation (chemotaxis). Complement
products are capable of neutralizing viruses, producing kinin-like substances which
contract smooth muscle and cause increased vascular permeability, producing
immune adherence, intensifying an inflammatory reaction, and perhaps affecting
cell surfaces, thus resulting in cell damage or death. The phenomenon of rapid red
cell destruction may be closely related to that of immune adherence.
Specific immunological response (also called adaptive immunity) is restricted
primarily to chordates (Hildemann and Reddy 1973). In this form of immune
response, the organism demonstrates its ability to select from the entire spectrum of
possible foreign substances those to which it is actually exposed, and to react against
them in a specific manner. Moreover, this specific response can then be expanded,
either to combat a continuing invasion, or for subsequent use, by means of
immunological memory (Bellanti 1978). The specific response is mediated by
lymphocytes; the crucial role of lymphocytes in the immune response will be
discussed below.
Terminology to be employed in this chapter and monograph is of importance. A
substance giving rise to antibody is called an antigen. A determinant not antigenic
on its own, but against which antibody can be formed, is called a hapten. The
additional determinant required to convert a hapten into an antigen (usually by
stimulating a T-Iymphocyte) is called a carrier. The term "immunogen" refers to
substances capable of giving rise to actual immunity or protection. A substance
