Introduction to Clinical Immunology

136 Pages·1985·18.28 MB·English

by  Mansel Haeney (Auth.)

To Kay,
James, Owen and Bethan
Introduction to Clinical Immunology
Mansel Haeney,
MSc, MB, BCh, MRCP, MRCPath
Consultant Immunologist, Clinical Sciences Building, Hope Hospital, Salford
Butterworths Update Publications
London Boston Durban Singapore Sydney London
Toronto Wellington
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First published, 1985
© Update, 1985
British Library Cataloguing in Publication Data
Haeney, Mansel
An introduction to clinical immunology.
1: Immunology
I. Title
616.079 QR181
ISBN 0-407-00362-2
Library of Congress Cataloging in Publication Data
Haeney, Mansel.
An introduction to clinical immunology.
Rev. and expanded articles originally
published in Hospital update.
Includes index.
1. Immunologie diseases. 2. Immunopathology.
I. Title. II. Hospital update. [DNLM: 1. Autoimmune
Diseases. 2. Immunity. 3. Immunologie Deficiency
Syndromes. QW 504 H135i]
RC582.H341984 616.079 84-9564
ISBN 0-407-00362-2
Photoset by Butterworths Litho Preparation Department
Printed by Cambus Litho Ltd, Scotland
Bound by Anchor Brendon, Tiptree, Essex
Preface
Clinical immunology is the application of immunological doctors who had minimal immunology teaching during
principles to achieving a better understanding of the their undergraduate or postgraduate years: many have little
mechanisms of human diseases, more appropriate labora idea where to begin in familiarizing themselves with the
tory investigations and so more rational and effective scope of clinical immunology.
therapy. This book is based on series of articles commissioned by
Immunologically mediated diseases permeate all the Hospital Update. Each chapter has been revised and three
traditional clinical specialities but the fact that clinical new chapters added. This is not a textbook: it is neither
immunology has so far achieved only a limited impact on comprehensive nor balanced, and is thus not intended to
patient management underlines the progress yet to be supplant those existing, larger volumes of clinical im
made in fully appreciating the complexities of the human munology which use an organ-based approach. Instead, I
immune system. Nevertheless, at moments of optimism, have tried to provide an introduction to clinical immunolo
clinical immunologists believe they are on the verge of a gy for junior doctors in training, but I hope it will also be of
new era - a time when immunology will make major value to more senior clinical investigators in all disciplines
contributions to health care. who find themselves reluctantly obliged to acquire the
Immunology is a flourishing discipline. In recent years, rudiments of immunology in order to interpret important
basic immunologists have generated a formidable literature new developments in their own fields.
of scientific observations, sometimes so rapidly that even
workers in this field have difficulty in keeping pace with M. Haeney
developments. The situation is even more perplexing for
Acknowledgements
It is a pleasure to acknowledge my debt to the Staff of the ability to convert my hesitant drawings into superb colour
Department of Immunology, University of Birmingham illustrations. I would like to express my appreciation to Mrs
and the Regional Immunology Laboratory, East Birming Eileen Walker, who skilfully interpreted so many corrected
ham Hospital, who first stimulated and fed my interest in typescripts.
clinical immunology. I also want to thank Mrs Anne Finally, to my wife and children I can only express my
Patterson of Update and Mr Charles Fry of Butterworths for deepest appreciation for their patience because, without
their unfailing help and advice. The Staff of the Illustration their loving support and encouragement, this book would
Department at Update deserve a special mention for their never have been possible.
1 Immunoglobulins and disease
Basic immunoglobulin structure Immunoglobulin classes
All antibodies belong to the group of proteins called Although all immunoglobulins have a similar basic subunit
immunoglobulins. Every immunoglobulin molecule has a structure, five classes of heavy chain can be identified from
fundamentally similar structure made up of two identical structural differences in their CH regions: these are called a,
'heavy' polypeptide chains attached to a pair of identical
'light7 chains (Figure 1.1). Analysis of different myeloma
light chains shows that the amino acid sequences of the
N-terminal halves of these chains vary greatly: in contrast,
the C-terminal halves are almost identical. These two
segments are called the variable (V ) and constant (C )
L L
regions of the light chain. Heavy chain amino acid
sequences show a similar pattern: a variable region (V )
H /y J^ Light chain
occupies the N-terminal quarter of the chain and is of
similar length to the V region (110 amino acids), but the
L
heavy chain constant region (C ) is about three times %, S y
H
longer,
An antibody molecule has two characteristic functions:
(1) antigen recognition and (2) antigen elimination through
participation in effector mechanisms. These functions are
performed by different regions of the molecule. The Heavy chain (H)
proteolytic enzyme papain will split an immunoglobulin
into three parts of similar size (Figure 1.2). Two of the
fragments are identical, each containing one site capable of
specific combination with antigen. These antigen-binding
fragments (Fab) consist of the entire light chain, the V
H
region and part of the CH region. The third fragment is H2L·
composed of the C-terminal halves of the heavy chains but
does not combine with antigen. This crystaUizable fragment
Figure 1.1 Basic four-chain (HL) structure of immunoglobulins. The
(Fc) mediates the effector functions of an immunoglobulin 2 2
molecule is usually represented in the form of a Y with the amino (N-)
which has combined with specific antigen via its Fab termini of the four chains at the top and the carboxyl (C-) termini of the
regions. heavy chains at the bottom
γ, ò, ε and μ and define the corresponding immunoglobulin but the rest, and much of the IgA in secretions, consists of
classes IgA, IgG, IgD, IgE and IgM (Table 1.1). Some classes two subunits linked to an extra polypeptide chain
can be divided further into subclasses; for example, IgG is (secretory component) to form secretory IgA. Secretory
divisible into IgGj, IgG, IgG and IgG subclasses. There component is a product of intestinal epithelial cells and
2 3 4
are also two major types of light chain, designated kappa protects the molecule from proteolytic digestion in the
and lambda, associated with the heavy chains of all intestinal lumen. Serum IgM is a pentamer of five subunits
and therefore has 10 antigen-binding sites. Dimers and
pentamers are stabilized by a further polypeptide (J chain)
synthesized by plasma cells.
Antigen-binding site
*%^W^ · ' ■■·■" " -Jfa'
Immunoglobulin structure versus function
^Λ^ 1 \ v ^r
^Fab
The B lymphocyte response to a single antigen may include
α
\5\ specific antibody molecules of all five immunoglobulin
l\JOr'' -
classes. Antibodies of different classes may show identical
antigen-binding specificities and thus presumably may
! ^ ~—1 "i '' ' fi ^1***"*******. possess identical variable (VH + VL) regions; however, the
CH regions mediate different secondary effector functions
Papain cleavage 1 (Table 1.2).
CM
Complement activation
^Ψο
The classical pathway of complement activation is initiated
by the binding of the Clq subcomponent to the IgM or IgG
component of an antigen-antibody complex. An alterna­
tive pathway of complement activation, triggered by cell
wall endotoxins in conjunction with a series of serum
factors, can bypass the need for antibody, Cl, C4 or C2
Figure 1.2 Immunoglobulin fragments produced by papain digestion. The complement components and allow direct cleavage of C3.
antigen-binding site is contained within the Fab region and formed by the IgM and IgG can also activate this alternative pathway
variable regions of one heavy and one light chain. Each monomeric under certain circumstances but it is unclear whether other
immunoglobulin possesses two antigen-binding sites per molecule
immunoglobulin classes do so in vivo (see Chapter 4).
immunoglobulins. In other words, the class of an im­
munoglobulin molecule depends on the constituent heavy Binding to cells
chain and is independent of the light chain type. A single
immunoglobulin molecule has identical light and identical Some immunoglobulins are bound to cell surfaces. Phago-
heavy chains. cytic cells (monocytes, macrophages and polymorphs) have
Immunoglobulin classes also differ in the number of basic receptors which recognize sites in the constant regions of
HL subunits in the molecule (Table 1.1). IgG, IgD and IgE IgG molecules. Foreign particles coated with IgG antibodies
2 2
are each made up of one subunit. Most of the IgA in normal are bound by these receptors, so triggering rapid phagocy­
serum is composed of a single subunit (monomeric IgA), tosis.
Table 1.1 Immunoglobulin classes
IgG Ig A IgM IgD IgE
Heavy chain class y oc μ δ ε
Heavy chain subclasses YlY2Y3Y4 «ια2 μφι - -
Light chain type ΧΟΐλ κοΓλ κοΐλ xorX ΧΟΓλ
Molecular formulae γ2κ2 a2x2 δ2κ2 ε2χ2
γ2λ2 α2λ2 (^2)5-J· δ2λ2 ε2λ2
(α2Χ2)2 .SCJ.
(αλ) .SC.J.
2 22
Percentage of total serum immunoglobulins 73 20 6 <1 <0.01
Half-life (days) 23 6 5 3 2
Some cells can interact with IgG-coated foreign cells to Placental transfer
produce contact lysis rather than phagocytosis: this process
is called antibody-dependent cell-mediated cytotoxicity The placental transfer of immunoglobulins provides the
(ADCC) and the effector cells are termed killer (K) cells. IgE newborn infant with an adequate repertoire of antibody
antibodies are bound to tissue-fixed mast cells via sites in specificities. In humans, only IgG antibodies cross the
their Fc regions. If an antigen combines with two adjacent placenta: this is a property of the Fc region which interacts
IgE molecules, the resulting configurational change is with receptors on placental syncytiotrophoblast. The Fab
believed to expose a further Fc site that initiates mast cell fragment, although one-third the size of the whole
degranulation and the release of vasoactive amines (see molecule, is not transferred.
Chapter 3).
Primary and secondary antibody responses
Table 1.2 Biological properties of the Fc region of immunoglobu­
lin molecules
When a normal individual is first exposed to a foreign
antigen, there is a lag phase lasting up to 10-12 days before
IgG* IgA IgM IgD Φ
antibodies appear in serum or body fluids (Figure 1.3). This
primary antibody response is typically IgM. The time
Complement fixation:
needed to reach maximal antibody levels and the duration
Classical pathway + + + + -
Alternative pathway + (+?) + (+?) of the peak titre varies with the nature of the antigen and
the method of immunization. Subsequent encounter with
Binding to mononuclear cells + - - -
the same antigen usually evokes an enhanced secondary
Binding to (or memory) response characterized by:
mast cells/basophils - - _ +
(1) a lower threshold dose of antigen;
Placental transfer + - - - (2) a shorter lag phase;
Control of catabolic rate + + + + + (3) higher titres of antibody;
(4) persistence of antibody synthesis;
*Some subclasses only (5) predominant synthesis of IgG antibodies.
10-1 Primary antibody response Secondary antibody response
m
ο
co
9
•β H
I0·1·
O
Φa
a)
- Lag phase- -*— Lag-
X
First exposure Second exposure
Time (days)
Figure 1.3 Primary and secondary antibody responses to an immunogenic stimulus. Specific antibody concentration is shown on a logarithmic scale
Immune response genes given vaccine in the population and those instances of
diseases showing strong association with a particular
In inbred experimental animals, specific responsiveness to histocompatibility type (for example, ankylosing spondyli-
some antigens is known to be under the control of tisandHLA-B27).
autosomal dominant genes inherited in strict mendelian
fashion and linked to the major histocompatibility complex
(MHC). Immune response (Ir) genes usually have been Immunoglobulin levels and age
defined by measuring the amount of antibody synthesized
in response to a restricted antigenic challenge. Mice with Serum immunoglobulin levels are fairly constant in healthy
different Ir alleles can be grouped into high or low adults but the development of adult levels from birth shows
responder strains but mice that are high responders to a characteristic trend for each immunoglobulin (Figure 1.4).
some antigens may be low responders to others. Ir genes Only IgG can cross the placenta; although transfer of
do not therefore control general immune responsiveness maternal IgG to the fetus begins as early as the thirteenth
but show antigen specificity. Genetic control of the immune week of pregnancy, maximum transfer takes place in the
response has now been demonstrated in mice, rats, guinea last trimester. Premature infants therefore have low IgG
pigs, chickens and monkeys. The existence of Ir genes in levels and show marked susceptibility to infection. At birth,
man could explain the variable nature of the response to a the serum IgG is wholly maternal in origin: catabolism of
Serum immunoglobulin levels f
(per cent of adult levels) I
Maternally
transferred IgG-- - - -
Total IgG-·—·-
IgG
IgM
IgA
//
20
Gestation (weeks) Age (years)
Figure 1.4 Serum immunoglobulin levels and age. Maternally transmitted IgG has mostly disappeared by 6 months. As the neonate actively synthesizes
IgG the level slowly rises, but a physiological trough of serum IgG is characteristically seen between 3 and 6 months
this transferred IgG produces a fall in serum levels which is similar course to IgA, adult levels being reached at between
only partly compensated by endogenous IgG synthesis 7 and 9 years.
stimulated by exposure to environmental antigens.
Although adult levels are reached by the age of 2 years the
period between 3 and 6 months is a phase of relative
Abnormalities of immunoglobulins
antibody deficiency ('physiological trough').
Placental transfer of IgM is negligible, but fetal produc Concept of polyclonality and monoclonality
tion of specific IgM rises to very high levels in intrauterine
infection and may be of diagnostic significance. In normal Each immunoglobulin is the product of a single family or
infants, the serum IgM level rises rapidly in the first few clone of plasma cells. Many different clones are involved in
months of life, reaching the adult range at between 6 the specific antibody response but only one clone will
months and 1 year. synthesize and secrete a particular V and V region.
H L
IgA is not detectable in cord blood. Its appearance in The malignant proliferation of a clone of plasma cells
serum and secretions is more gradual than IgG or IgM and results in the increased production of immunoglobulin
adult levels are not achieved until adolescence. molecules of identical class, subclass, V and V regions.
H L
IgE does not cross the placenta. Serum levels follow a Such monoclonal immunoglobulins have a unique amino