The Antibody Enigma

280 Pages·1984·6.43 MB·English

by  Thomas J. Kindt

THE ANTIBODY
ENIGMA
THE ANTIBODY
ENIGMA
THOMAS J. KINDT
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Maryland
AND
J. DONALD CAPRA
University of Texas Health Science Center
Dallas, Texas
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Kindt Thomas L 1939-
The antibody enigma.
Includes bibliographical references and index.
1. Antibody diversity. I. Capra, J. Donald, 1937- . II. Title. [DNLM: 1. Anti-
body diversity. QW 575 K51aj
QR186.7.K56 1984 599'.0293 84-4761
ISBN -13: 978-1-4684-4678-4 e-ISBN-13: 978-1-4684-4676-0
DOl: 10.1007/978-1-4684-4676-0
©1984 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1984
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
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
This book is dedicated to our teachers, H. Edward Conrad,
Charles Todd, Richard Krause, Thomas B. Tomasi, Jr.,
Alan Peterkofsky, and Henry Kunkel, and to our many
graduate students and postdoctoral fellows. Both groups
have been a continuous source of inspiration and ideas.
The empirical basis of objective science has thus nothing "absolute"
about it. Science does not rest upon solid bedrock. The bold struc
ture of its theories rises, as it were, above swamp. It is like a
building erected on piles. The piles are driven down from above
into the swamp, but not down to any natural or "given" base; and if
we stop driving the piles deeper, it is not because we have reached
firm ground. We simply stop when we are satisfied that the piles are
firm enough to carry the structure, at least for the time being.
- KARL POPPER (The Logic of Scientific Discovery)
PREFACE
The Antibody Enigma is a somewhat personal view of the antibody
diversity question from two investigators who have spent the past 18
years trying to penetrate the enigma. It is not and was not meant to be
an all-embracing comprehensively referenced review of the subject of
antibody diversity. Because of the subjective viewpoint, there are un
doubtedly omissions of data that others consider to be seminal, and if
we have offended anyone by omitting their own contribution we sin
cerelyapologize.
We have lived with "The Enigma" on and off for the past two years.
It has been both hard work and good fun but, above all, it has been a
learning experience. There were several difficult decisions to make in
putting together the final text, but perhaps the most difficult was de
ciding upon a stopping point. The field of antibody diversity is presently
enjoying an unparalleled expansion of information, and because of this
it was very tempting to await further developments in hopes of tying
up as many loose ends as possible. This was decided against for several
reasons; the major factor was that the project was growing burdensome
for both of us. From a more objective point of view this appears to be
a reasonable time to stop our exposition. The questions that began to
take shape in the mid-1950s with the first serious genetic studies have
been answered and a new set of rules for antibody diversity generation
has been defined. New and different questions have replaced the old,
and while some of these will be answered by studies in progress, there
are other questions that will be with us for a much longer time. Although
we have not written solely from an historic point of view there is em
phasis in this volume on the development of concepts related to our
subject. It is our opinion that an understanding of this development will
help investigators to better understand what is happening today and
what may happen tomorrow in this field.
ix
x PREFACE
Another difficult decision concerned determination of the audience
to which the book is directed. Related to this decision was the choice of
a title that would reach this intended group. In this respect we must
admit defeat. It has been impossible for us to say exactly for whom the
book is intended and perhaps this uncertainty is further reflected in our
choice of a title. Certainly it remains impossible to write a book entitled
The Solution to the Question of Antibody Diversity. Numerous title formu
lations were tried and rejected on the basis of being either too amorphous
or too indicative that the problem has been solved.
There have been a number of persons who have put much time
and effort into this project. First of all, Richard Wasserman, Lisa Steiner,
and Edward Max deserve special mention for reading the draft of the
text, finding errors and inconsistencies, and pointing these out to us.
The enormous job of typing, correcting, and retyping was faithfully
carried out by Kathy van Egmond in Dallas and Virginia Shaw and
Lynette White in Bethesda. Their patience is to be commended. It was
a pleasure to work with the staff of Plenum Press, and we wish to thank
Kirk Jensen for his enormous contributions to this text. If all of the
abbreviations are finally consistent and all thats and whichs properly
sorted out, it is certainly due to the efforts of Jane Woolsey. We thank
numerous colleagues for prepublication information in various forms.
Finally we wish to thank our families for suffering with us through the
birth of this work.
T. J. Kindt
J. D. Capra
CONTENTS
1. THE NATURE OF THE PROBLEM
1.1. Introduction 1
1.2. Antibody Synthesis 2
1.3. Historical Roots 5
1.3.1. Introduction of the Germline Concept of
Immunologic Specificity 6
1.3.2. Introduction of the Somatic Concept of
Immunologic Specificity 7
1.4. Clonal Selection 9
1.5. Effector Functions 11
1.6. The Extent of Diversity-The Problem in a Nutshell 12
1.7. Scope of the Book 14
1.8. Precis 14
References and Bibliography 15
2. THE SEROLOGIST'S APPROACH TO THE PROBLEM
2.1. Introduction 17
2.2. Rabbit Allotypes 18
2.2.1. Discovery 18
2.2.2. Variable-Region Allotypes 21
2.3. Human Allotypes 27
2.3.1. Discovery 27
2.3.2. Allotypes and Isotypes 28
2.3.3. Haplogroups 29
2.4. Allotypes of the Mouse and the Rat 30
2.4.1. Mouse Allotypes 30
2.4.2. Allotypes of the Rat 32
xi
xii CONTENTS
2.5. Individual Antigenic Specificity and Idiotypy 32
2.5.1. Idiotypes of Human Immunoglobulins 33
2.5.2. Idiotypes of Rabbit Antibodies 35
2.5.3. Presence of Idiotypes on IgG and IgM 36
2.5.4. Idiotype versus lAS 38
2.6. Idiotypes as Markers for Antibody-Binding Regions 40
2.6.1. Idiotypic Cross-Specificity 40
2.6.2. Antigen Inhibition of Idiotype Reactions 42
2.6.3. Exceptions to the Correlation of Idiotypy and
Binding Site 43
2.7. The Inheritance of Idiotypes 44
2.7.1. Discovery 45
2.7.2. The Mouse Idiotype Systems 51
2.8. Conclusion 57
References and Bibliography 57
3. THE BIOCHEMIST'S APPROACH TO THE PROBLEM
3.1. Biochemical Studies on Heterogeneous Antibodies 61
3.2. Biochemical Studies on Homogeneous Antibodies 63
3.2.1. Human Myeloma 63
3.2.2. Mouse Myeloma 65
3.2.3. Other Homogeneous Antibodies 65
3.2.4. Hybridomas 67
3.3. Structural Features of Immunoglobulin Isotypes
and Allotypes 67
3.3.1. The Human Immunoglobulin Classes 68
3.3.2. The Carbohydrate Structures of Human
Immunoglobulins 71
3.3.3. Comparisons of Immunoglobulins from
Different Species 72
3.3.4. Immunoglobulin Allotypes 74
3.4. Structural Features of V Regions 76
3.4.1. V-Region Subgroups 76
3.4.2. Framework and Hypervariable Regions 79
3.4.3. The Antibody-Combining Site 82
3.5. Are the C Regions Really Constant? 86
3.6. Structural Analysis of Selected V Regions 86
3.6.1. Mouse VA 86
3.6.2. Mouse V K21 88
3.6.3. The Mouse V Ars Kappa Chains 90
CONTENTS xiii
3.7. Precis 92
References and Bibliography 92
4. UNIQUE FEATURES OF THE ANTIBODY PROBLEM
4.1. Introduction 95
4.2. Structural Variability of Antibodies 96
4.2.1. Immunoglobulins and Major Histocompatibility
Complex Proteins 96
4.2.2. Immunoglobulins and Hemoglobin 99
4.3. Two Genes-One Polypeptide Chain 100
4.3.1. The Todd Phenomenon 101
4.3.2. Structural Differentiation of V and C Regions 103
4.3.3. Statement of the Two-Gene Hypothesis 103
4.3.4. Cis or Trans Synthesis 107
4.3.5. Genetic Recombination between V- and C-Region
Allotypes 110
4.3.6. Biclonal Myeloma Proteins 110
4.3.7. Cross-overs between Idiotypes and C Regions 112
4.3.8. Theoretical Impact of the Two-Gene
Hypothesis 114
4.4. Allelic Exclusion 114
4.4.1. The Lyon Hypothesis 115
4.4.2. Selective Expression of Immunoglobulin Alleles 115
4.5. The Three Loci for Immunoglobulins 119
4.5.1. Kappa versus Lambda Light Chains 120
4.5.2. Expression of V-Region Subgroups 122
4.5.3. Allelic Selection of Immunoglobulin Genes 123
4.6. Conclusion 125
References and Bibliography 126
5. THE POLAR SOLUTIONS
5.1. Introduction 129
5.2. The Germline Theory 131
5.3. The Somatic Mutation Theory 132
5.4. Data Favoring Germline Theories 134
5.4.1. V-Region Subgroups 134
5.4.2. Evolutionary Divergence (Trees) 137
5.4.3. Inheritance of Idiotypes 139
5.5. Data Favoring Somatic Mutation Models 141
5.5.1. Phylogenetically Associated Residues 141