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The Human IgG Subclasses:
Molecular analysis of structure,
function and regulation
Edited by
FAROUK SHAKIB
Department of Immunology,
Queen's Medical Centre, Nottingham
PERGAMON PRESS
Member of Maxwell Macmillan Pergamon Publishing Corporation
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Copyright © 1990 Pergamon Press pic
All Rights Reserved. No part of this publication may be
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First edition 1990
Library of Congress Cataloging-in-Publication Data
The Human IgG Subclasses: Molecular analysis of structure,
function and regulation / edited by Farouk Shakib.
p. cm.
1. Immunoglobulin G. 2. Immunoglobulin G—Classifica-
tion.
I. Shakib, F.
[DNLM: 1. IgG—analysis. 2. IgG—classification. 3.
IgG—physiology. QW 601 M7175]
QR186.8.G2M63 1990 616.07'9—dc20 90-7303
British Library Cataloguing in Publication Data
Shakib, F.
The Human IgG Subclasses: Molecular analysis of structure,
function and regulation
1. Man. Immunoglobulins. Molecular biology
I. Title
616.079
ISBN 0-08-037504-9
Printed in Great Britain by B.P.C.C. Wheatons Ltd, Exeter
Preface
IT IS NOW a quarter of a century since IgG subclasses were first recognised.
However, whilst we have known for most of those years that different
antigens elicit antibody responses in different subclasses and each subclass
has a characteristic profile of effector functions, we are still largely unaware
of what determines such selectivity. For instance, we urgently need to know,
in molecular detail, how a particular IgG subclass is selected during an
immune response and the precise locations and structures of sites responsible
for such biological activities as complement fixation and binding to membrane
Fc receptors. As this volume will demonstrate, an impressive range of
technologies has recently become available and these are currently being
applied to address these crucial questions. The ultimate aims of these efforts
would be to use protein engineering to produce antibodies with predetermined
biological functions for therapeutic applications and to be able to stimulate
or suppress, at will, a particular IgG subclass antibody response, to the
benefit of the host. These are precisely the sentiments which have initiated
this book and which will guide our future research in this fascinating area
of immunology.
Like most other multi-author books, this volume provides a rich forum
for views to be expressed and hypotheses to be explored, and as such the
reader will find the text informative and stimulating. The book is the
culmination of true teamwork and my thanks are due to Marion Jowett of
Pergamon Press for her guidance and to the authors who somehow managed
to find the time to write highly competent chapters. It is to them that I
dedicate this volume.
Nottingham FAROUK SHAKIB
vii
List of Contributors
D. E. BRILES Department of Microbiology, University of Ala-
bama, Birmingham, AL 35294, USA
M. BROGGEMANN AFRC Institute of Animal Physiology and Genetics
Research, Babraham, Cambridge CB2 4AT, UK
M. E. DEVEY Department of Clinical Sciences, London School
of Hygiene and Tropical Medicine, Keppel Street,
London WC1E7HT, UK
R. G. HAMILTON Division of Clinical Immunology, Department of
Medicine, Johns Hopkins University School of
Medicine, Baltimore, MD 21224, USA
L. HAMMARSTROM Department of Clinical Immunology, Karolinska
Institute at Huddinge Hospital, S-14186 Huddinge,
Sweden
R. JEFFERIS Department of Immunology, The Medical School,
University of Birmingham, Vincent Drive, Birm-
ingham B15 2TJ, UK
G. LEFRANC Laboratoire dTmmunogenetique Moleculaire,
URA CNRS 1191, Universite de Montpellier II,
Sciences et Techniques du Languedoc, Place
Eugene Bataillon, 34095 Montpellier Cedex 5,
France
M.-P. LEFRANC Laboratoire dTmmunogenetique Moleculaire,
URA CNRS 1191, Universite de Montpellier II,
Sciences et Techniques du Languedoc, Place
Eugene Bataillon, 34095 Montpellier Cedex 5,
France
ix
List of Contributors
T. E. MlCHAELSEN Department of Immunology, National Institute of
Public Health, Geitmyrsvegen 75, 0462 Oslo 4,
Norway
M. H. NAHM Department of Pathology, Division of Laboratory
Medicine, Washington University School of Medi-
cine, St Louis, MO 63110, USA
J. D. POUND Department of Immunology, The Medical School,
University of Birmingham, Vincent Drive, Birm-
ingham B15 2TJ, UK
R. S. H. PUMPHREY Regional Immunology Service, St Mary's Hospital,
Hathersage Road, Manchester M13 OJH, UK
M. G. SCOTT Department of Pathology, Division of Laboratory
Medicine, Washington University School of Medi-
cine, St Louis, MO 63110, USA
M. J. SIMS Department of Immunology, AFRC Institute of
Animal Physiology and Genetics Research, Babra-
ham, Cambridge CB24AT, UK
N. R. STC. SINCLAIR Department of Microbiology and Immunology,
University of Western Ontario, London, Ontario,
N6A5C1, Canada
C. I. E. SMITH Department of Clinical Immunology, Karolinska
Institute at Huddinge Hospital, S-14186 Huddinge,
Sweden
C. M. SNAPPER Department of Pathology, Uniformed Services
University of the Health Sciences, 4301 Jones Bridge
Road, Bethesda, MD 20814, USA
M. J. TAUSSIG Department of Immunology, AFRC Institute of
Animal Physiology and Genetics Research, Babra-
ham, Cambridge CB24AT, UK
List of Contributors xi
M. R. WALKER Department of Clinical Chemistry, University of
Birmingham, Wolfson Research Laboratories,
Queen Elizabeth Medical Centre, Birmingham
B15 2TH, UK
E. WIENER Department of Haematology, St Mary's Hospital
Medical School, London, UK
1.
Introduction
R. S. H. PUMPHREY
Regional Immunology Service, St Mary's Hospital, Hathersage Road,
Manchester M130JH, UK
PROLOGUE
Piece out our imperfections with your thoughts:
Into a thousand parts divide one man,
and make imaginary puissance;
Think, when we talk of horses, that you see them
Printing their proud hooves i' the receiving earth.
For 'tis your thoughts that now must deck our kings,
Carry them here and there; jumping o'er times,
turning the accomplishment of many years
Into an hour-glass: for the which supply,
Admit me Chorus to this history;
Who, prologue-like, your humble patience pray,
Gently to hear, kindly to judge, our play.
(Chorus in Henry K, prologue; Shakespeare)
It is very difficult to understand how antibody molecules behave in real
terms: the scale of distance and time are so foreign to us that any
attempt at a graphic description seems more difficult than that confronting
Shakespeare in Henry V. Instead of turning the accomplishment of years
into an hour-glass, and portraying the battle of Agincourt on a small stage,
we have to magnify the molecular world by 10,000,000, both in time and
distance. The result, I hope, will be a kind of allegorical understanding of
the immunoglobulin subclasses that will be treated in more scientific detail
in the rest of this book. Like Chorus, I am only too aware of the imperfections
of my approach, and I would repeat the last two lines of his speech to you.
Dramatis personae (Fig. 1.1)
IgGl Usually the commonest immunoglobulin in serum, these antibodies
are mostly produced in the secondary response to protein antigens.
IgG2 The next most common immunoglobulin; at least a proportion of its
3
4 R. S. H. Pumphrey
antibody activity comes from responses to neutral polysaccharide
antigens.
IgG3 Like IgGl, most IgG3 antibodies are against protein antigens. The
extraordinary hinge of this subclass is found only in man and his
very closest primate relatives.
IgG4 Antibody activity in this subclass may come from prolonged antigenic
stimulation. Our model has to try to explain the apparent univalence
of this two-armed immunoglobulin.
Extras
Water, ions, small organic molecules, and other proteins will be needed to
complete the picture of this magnified world.
ANIMATING THE MODELS
The low-resolution models in Fig. 1.1 give an idea of the shape, but not of
the strength or flexibility of the molecules. How strong is the hinge, or the
binding site interaction with antigen? How flexible is the hinge, how rigid
each domain? Most of the questions we might want to ask can be answered
from familiar data, and though the answers will be for our magnified model
world, I think they give some insight into how real antibodies might behave.
Antibodies are of the order of 100 A tall. To create a model within the
realms of our experience we must magnify the world of antibodies 10
million times, so that 100 A becomes 10 cm. A natural consequence of this
magnification is that we must also slow down time by the same factor-and
when we do this, speed (linear velocity) returns to its original value, though
obviously spinning (angular velocity) has slowed down 10 million times. This
is entirely consistent with our everyday experience: imagine for instance a
mouse and an elephant. The scale factor here is only x 100, but the illustration
will serve. In principle all animals of the same shape can run as fast as each
other, no matter what their size, but the maximum angular velocity of the
mouse's femur when it is travelling the same speed as the elephant is 100
times that of the elephant's femur.
If we also keep density (mass per unit volume) constant, our antibody
molecule (let's say it's a human IgGl antibody) will weigh:
Molecular weight x volume scale
Avogadro's number
3
150,000 x (10,02300 ,000)
6 x 10
= 250g
Again, the result is naturally consistent with our experience. Now what about
strength and stiffness? Is our antibody molecule like a jellyfish out of water,
Introduction 5
FIG. 1.1.
IgG3
IgGl IgG2
IgG4
The coordinates for Fab (IgG NEW) and Fc (IgG Human) were taken from the
Brookhaven database. The a carbon atoms are represented by 5 A diameter spheres,
and are connected by 5A° diameter cylinders; each sugar is represented by a 6 A
sphere. Parts of the peptide chain with no coordinates in the database were
reconstructed - using the program IMMAM (P. Finn, A. Marsden and B. Robson)
to assemble peptide fragments. The crosslinked body of the hinge in IgG3 was
generated by assembling three repeating subunits whose atomic coordinates had
been calculated, using the program LUCIFER, by D. Ward and B. Robson. All the
illustrations here were only possible through the generous support of the Computer
Graphics Unit, University of Manchester Regional Computer Centre.
or harder than diamond? Intuitively one might expect it to retain the familiar
properties of proteins that we know, such as silk. The peptide backbone of
our model started out as 6 A diameter-is its tensile strength now comparable
to a silken thread 6 mm diameter after its 10 million times magnification?
