The Immunity of the Human Foetus and Newborn Infant

257 Pages·1983·14.684 MB·English

by  Ivo Miler M. D., C. Sc. (Ph. D.) (auth.)

THE IMMUNITY OF THE HUMAN FOETUS
AND NEWBORN INFANT
DEVELOPMENTS IN PERINATAL
MEDICINE
VOLUME 3
1 Meyer R de (ed.): Metabolic Adaptation to Extrauterine Life.
ISBN 90-247-2484-8
2 Ledger W J (ed.): Antibiotics in Obstetrics and Gynecology.
ISBN 90-247-2529-1
Series ISBN 90-247-2443-0
The Immunity
of the Human Foetus
and Newborn Infant
IVO MILER, M. D., C. Sc. (Ph. D.)
Institute for the Care of Mother and Child~ Prague
•
1983
MARTINUS NI]HOFF PUBLISHERS
THE HAGUE/BOSTON/LONDON
Distributors:
for the United States and Canada
Kluwer Boston, Inc.
190 Old Derby Street
Hingham, MA 02043 U.S.A.
for all other countries
Kluwer Academic Publishers Group
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The Netherlands
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Cuba, Czechoslovakia,
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of Korea, Mongolia, Poland,
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and Yugoslavia
AVICENUM,
Czechoslovak Medical Press,
Prague
Library of Congress Cataloging in Publication Data
Miler, Ivo.
The immunity of the foetus and newborn infant.
(Developments in perinatal medicine ; v. 3)
Bibliography: _p.
1. Fetus--Physiology. 2. Immunology, Develop
mental. 3. Infants-(Newborn)--Physiology.
4. Infants .(Newborn)--D.iseases--Immunological
aspects. I. Title. II. Series. [DNLM: 1. Fetus-
Immunology. 2. Infant, Newborn. -3. Immunit~--
In infancy and childhood. Wl DE998NI v. 3 / WS
420 M642iJ
RG6l0.M5413 618.92'01 81-22312
ISBN -13:978-94-009-6777-9 AACR2
ISBN·13:978·94·009·6777·9 e· ISBN ·13:978·94·009·6775·5
DOl: 10.1007/978·94·009·6775·5
© Translation M. Schierlova
Copyright © 1982 by Martinus Nijho./f Publishers, The Hague.
Softeover reprint of the hardcover 1st edition 1982
All rights reserved. No part of this publication may be reproduced, stored in retrieval ~vstem, or transmitted
in any form or by any means, mechanical, photocopying, recording, or otherwise, without the prior written.
permission of the publisher.
Martinus Nijho./f Publishers, P.O. Box 566, 2501 CN The Hague, The Netherlands.
Preface 7
Introduction - what is ontogenesis? 9
Ontogenesis of immunity of the human foetus 12
Development of the cellular substrate of the immune system . . . . . .. 13
Development of the lymphatic system ................ 14
Synthesis of immunologically active proteins - the complement components and
immunoglobulins - in the foetal period 18
Complement components. . . . . . . . . . . . . 18
Immunoglobulin synthesis ... . . . . . . . . . 23
B lymphocytes with surface membrane immunoglobulins 26
Transmission of antibodies ami immunoglobulins from mother to foetus 29
Transplacental transmission of specific antibodies .......• 29
Transplacental transmission of immunoglobulins . . . . . . . . . 33
Physiological conditions for the transmission of immunoglobulins from
mother to foetus . . . . . . . . . . . . . . . . . . . . . . . . . 36
Mechanism of transplacental transmission of IgG .......... 39
Role of the Fc fragment of the IgG molecule and of cell receptors in the
transplacental transmission of IgG . . . . . 42
Antibacterial mechanisms of the amniotic fluid ............ 45
Ontogenesis of the foetus's cellular immunity ............ 47
Incidence in the foetus of T lymphocytes forming spontaneous E rosettes 48
Functional activity of the T cell system . . . . . . . . . . . . . . . 49
Response offoetallymphocytes to phytohaemagglutinin (PHA) stimulation
in vitro ............................ 49
Proliferative response of foetal lymphocytes to stimulation by allogenic
cells in mi.xed lymphocyte cultures . . . . . . . . . . . . . . .. 51
Effector activity of foetal lymphocytes - cytotoxicity . . . . . . .. 52
Chronological survey of the commencement of foetal immunocompetence 53
Immunity of the physiological neonate
Natural (nonspecific) neonatal immunity ., . . . . . . . . . . . . . 61
Cellular factors of natural neonatal immunity. The function ofp olym orpho-
nuclear (PMN) leucocytes - the inflammatory reaction ..... 62
Migratory activity of the PMN leucocytes of newborn infants in vivo 63
In vitro migration of the PMN leucocytes of neonates (chemotaxis) 66
Chemotactic activity of neonatal monocytes . . . . . . . . . . . 74
The neonatal phagocytic system . . . . . . . . . . . . . . . . 75
Ingestion of particles by neonatal phagocytes. Neonatal serum opsonins 76
Antibacterial (bactericidal) activity of neonatalleucocytes . . . . . 89
Activity of the complement system in neonatal serum . . . . . . . 97
Alternative pathway of activation of complement in neonatal serum 104
Cell-mediated immunity in newborn infants . 109
Delayed hypersensitivity in newborn infants . . 110
Activity of the neonatal T cell system .... 112
T lymphocytes in the blood of newborn infants 112
Response of neonatal lymphocytes to stimulation by phytohaemagglutinin
(PHA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5
Antigenic stimulation of neonatal lymphocytes . . . . . 117
Production oflymphokines by neonatal lymphocytes 120
Cytotoxic activity of neonatallymphocytes . . . . 124
Transplacental transmission of antigen - sensitization of the foetus 126
Transplacental infiltration of lymphocytes. . . . . . . . . . . 128
Specific humoral immunity of the newborn infant and its postnatal deve-
lopment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Antibody formation and immunoglobulin synthesis . . . . . . . . . . 129
Effect of passively transmitted maternal antibodies on active antibody
synthesis by neonates and older infants . . . . . . . . . . . . . . . 134
B lymphocytes with surface membrane immunoglobulins in the blood of
newborn infants . . . . . . . . . . . . . . 136
Immunocompetence of neonatal B lymphocytes 142
Immunological significance of maternal milk 144
Humoral immunity factors in colostrum and milk 145
Immunoglo~u1ins . . . . . . . . . . . . . 145
Antibodies . . . . . . . . . . . . . . . . 147
Immunologica\ly active cells in colostrum and milk. 149
Nonspecific factors in maternal milk . . . . . . . 151
Immunity of the high risk, pathological neonate 163
Immunity disturbance of premature and small-for-dates neonates . 163
Cellular factors of natural (nonspecific) immunity 164
Humoral factors of natural immunity . 173
Cellular immunity. . . . . . . . . . . . . . 174
Immunoglobulins and antibodies ....... 177
Rh isoimmunization - the immunological basis of haemolytic disease of
the newborn. . . . . . . . . . . . . . . . . . . . . . . . .. 182
Formation of ant-Rh (anti-D) antibodies and their transmission to the
foetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Effect of hyperbilirubinaemia on the newborn infant's immunity and the
immunosuppressive effect of bilirubin in in vivo and in vitro experiments 186
Effect of hyperb ilirubinaemia on antibody formation and immunoglobu-
lin synthesis ......................... 187
Effect of exchange blood transfusion on the newborn infant's immune
system . . . . . . . . . . . . . . . . . . . . . . . . 190
Effect of hyperbilirubinaemia on specific cellular immunity 192
Effect of bilirubin on f"'ftors of natural, nonspecific immunity 194
Immunological aspects of perinatal infections . . . . . . . . . 197
The immunity of infants with Down's syndrome 204
Natural immunity factors . . . . 205
Cell-mediated immunity . . . . 206
Immunoglobulins and antibodies 208
References . . . . . . . . . . . 214
6
Preface
The birth of a human being is generally described as the most dramatic event
in an individual's life, which cannot be compared with any other physiological
process or change which may occur at any time during the whole of his
subsequent independent existence. Ethically, only death, the dissolution of the
individual, is invested with equal drama and emotion. In this respect the two
peaks of a human being's life are equal, but birth contains optimism, promise
and hope for the future, whereas death is the final culmination, the ultimate
and definitive reckoning and physical departure to "that bourne from whence
no traveller returns". It is specific for human existence that the physiological
termination of life does not mean the immediate destruction of working,
mental, cultural and other creative values which the individual, in accordance
with his abilities, is able to produce durin9 his lifetime and which "survive"
him as a large or small part of the ever-growing fund of values created by
human society over thousands of years. If considered from this aspect, death
is not entirely negative, not just man's sad lot, and physiological death can
be seen in a positive light, even if we do not believe in a life after death or
an immortal soul. Nevertheless, despite this philosophical comfort, birth will
always have the advantage over death; it will always be seen as something
unequivocally positive, it will comprise the virtues of the act of creation as
against the act of dissolution, it will be celebrated, awaited with breathless
anticipation and welcomed. This intensive ethical and emotional superstructure
imposed on birth probably has deepl yrooted biological foundations determined
by the simple elemental fact that procreation and birth are the key, the basic
condition of the maintenance of human existence and the future of mankind,
so that any potential menace to this basic reproductive property is perceived
very sharply by society (for example, deterioration of the environment and
the disquieting increase in negative environmental factors affecting man in
general and his reproductive capacity in particular).
Even if we leave these social, moral and philosophical aspects of birth
completely aside, from the purely physiological aspect we can still regard the
birth of a new individual as a revolutionary event. Today, physiologists know
a whole series of parameters of the changes which occur ,in association with
delivery of the foetus from the uterus into the outside world, with the abrupt
termination of a life dependent on the maternal organism, with the sudden
transition to an independent existence associated with immediate bombardment
by stimuli from the new environment (thermic, photic, acoustic, mechanical
and chemical stimuli and no doubt a whole series of others which we are not
yet able to define exactly). The need for the immediate initiation of vital
functions like breathing, the development of metabolic processes essential to
independent nutrition and the triggering and rapid development of complex
reflex mechanisms of the nervous system, all require a coordinated adaptation
7
process, on whose success and effectiveness the newborn infant's further progre&s
is directly dependent. The above processes are obviously absolutely "normal",
i.e. physiological; their function has been verified phylogenetic ally, thoroughly
and many times over, and it also has firm ontogenetic foundations and pre
requisite conditions. None the less, even these historically verified functions
cannot always be taken for granted; contemporary knowledge of pathological
perinatal states shows just how vulnerable their mechanisms are and that it
would therefore be neither wise nor ethical in this respect to let nature take
its own course unaided. A detailed knowledge of both physiological mechanisms
and potential pathological factors enables modern medicine to regulate natural
development rationally and optimalize it and also, to some extent, to prevent
possible injury by ruling out known negative factors.
The rules for physiological development of the newborn infant as a whole
likewise apply to the function of its immune defence system. From the immuno
logical and microbiological aspect, from the very first instant of its separate
existence the infant is thrown into a world of microbes and antigens. "Inter
feaces et urinas nascitur homo" is the newborn infant's first welcome -
a welcome which contains millions of living and dead microorganisms and
their antigens. These microorganisms very soon colonize the infant's skin and
the surface of its mucous membranes (especially of the gastrointestinal tract)
in astronomical quantities, thereby initiating the development of very complex
interplay between the macroorganism and its "fifth column", i.e. its microflora.
This dynamic interaction of vital and physiological manifestations between
the host and its complement of microorganisms lasts the whole of the individual's
lifetime. The sudden invasion of the newborn infant by foreign living elements
establishing intimate contact with its tissues and cells makes further demands
on its adaptation processes and in this case the main burden of responsibility
falls on its immune system right from the outset. It is on the efficiency, prompt
reaction and capacity of this system for further development that the sub
sequent successful development of the whole organism, inter alia, depends.
In the first place, the immune system must assure natural coexistence between
"normal" microorganisms colonizing different parts of the body and see
to it that they remain "within bounds". It must further repulse attempted
invasions of the tissues by pathogenic microorganisms and react to a host of
diverse foreign substances, i. e. antigens (such as products of microbial meta
bolism, food antigens, etc.), some of which may be potentially harmful to the
organism. The function of the immune system is obviously of vital importance.
A review of the ontogenetic development of the foetus shows that a number
of immune functions are already established, to varying degrees, Qvring
intrauterine development and that the newborn infant, the instant it is born,
already possesses some immunological "equipment" capable of fulfilling the
above functions. What, then, is the "immunological statvs" of the foetus and
the newborn infant immediately after birth? The reader will find an - at
least partial - answer in this book.
8
Introduction - What is Ontogenesis?
The developmental, ontogenetic (and phylogenetic) approach is one of the most
important ways of studying biological and physiological phenomens. The
grounds for looking at biological and medical problems from this aspect are
simple, and today quite obvious. Any living system, from the single cell to the
highly organized organism, is a dynamic system characterized by a continuous
process of complexly determined changes. Consequently, if we want to have
a clear grasp of any living system - either whole or as separate components
- in dialectically determined associations, we cannot obtain a complete
picture unless we take into account one of its most important characteristics,
i.e. its continuous development. Biological interaction at molecular, cell and
system level thus takes place in a time-space vector, and from the gnosological
point of view this aspect is inseparable from the purely scientific view of living
matter. In the light of the present-day level of knowledge in biology and
medicine, this approach to biological processes becomes a matter of course
and it may even seem superfluous and unoriginal to keep on emphasizing
such a fundamental truth. Nevertheless, although this is not a book about the
history and philosophy of science, we should bear in mind that, historically
speaking, the acceptance of these now "matter-of-course" aspects was pre
ceded by a great deal of effort and by many conflicts between schools of
philosophy and science and between great scientific figures. In the realm of
philosophy, credit must go to the dialectic materialists for providing definitive
theoretical arguments refuting the metaphysical and idealistic approach to the
natural sciences, while in the biological sciences this approach was forced to
succumb to the logic of the facts in association with the rapid development
of the methodological, theoretical and applied foundations of science.
In the natural sciences, the developmental aspect not only has general,
philosophic grounds, which are after all an integral part of the far broader
conception of the materialistic outlook on the world, (nature and the motion
of matter) but its use is also warranted in the methodological approach to the
study of the laws governing living matter. When studying any process in the
human organism, whether physiological or pathologic.al, every single isolated
observation must be integrated with reference to the period (stage) of develop
ment at which the given organism or biological system happens to be at that
moment. Modern quantitative knowledge (which is constantly being brought
up to date) on the dynamics of cell populations in the body, the rate of meta
bolic processes, protein synthesis and catabolism, membrane processes, neuro
humoral regulative processes and'many others clearly show that, at the instant
of observation, the biological individual in question is literally not what he
was an hour, a week or a few years ago. The intensity, rate and quality of
9
biological changes in relation to time are naturally not the same in all phases
of the individual's development and do not apply to all cell and tissue systems
equally, but in toto they are continuous from the time the primary cell
primordium of the individual (zygote) is formed until he dies. In this context
our division of an individual's life into an embryonal period, a neonatal
period, infancy, childhood, adolescence, adulthood and old age is a mere
arbitrary convention. Some prominent biologists even go so far as to compre
hend ontogenesis as a compact, universal process of the individual's develop
ment throughout his entire existence and do not confine it simply to the early
phase of his development (which is the generally accepted use). This extreme
conception of ontogenesis, whose justification stems from the unified view of
the individual's development, cannot, of course, negate the scientifically and
practically warranted division of the individual's life into various stages
characterized by distinct, specific features. We should never dream of asking
a neonatologist to apply himself to gerontology on the grounds that in both
cases the same individual, at different stages of ontogenetic development, is
concerned. The purpose of this argument is simply to demonstrate that the
early stage of an individual's development (i.e. ontogenesis in the original,
normally used meaning of the term) both is and is not a separate, specific
stage. It is not separate in that it comprises all the essential attributes oflife,
i.e. a set of genes and a metabolic and neurological type - in short, all the
prospective genotype-determined potentials which will ineluctably accompany
the individual to the end of his life. We therefore· cannot say that a newborn
infant, for example, is qualitatively somebody completely different from what
he will be in a later phase of his individual life. And yet every one of us (especial
ly the child's mother), depending on our degree of knowledge and powers
of observation, can immediately think of dozens of differences, from superficial
characteristics such as size, weight, ability to walk and talk, etc, to differences
at subcellular level, which unequivocally differentiate the young individual
from his older fellows. In this respect, therefore, the early phase of development
is something special, unique and unrepeatable at individual level. The
differences which we can observe and define in this phase are both qualitative
and quantitative and are associated with the process of growth, maturation
and the development offu nctions and with the formation of phenotype charac
teristics. It is a phase in which anabolic processes dominate - although, as
we know, this does not mean that catabolism is absent. Destructive and
catabolic mechanisms already playa role in embryogenesis, in the removal
of developmentally osbolete structures. Ifwe were to define this point of view,
we could claim that a living individual begins to age the instant he comes
into being, since from then on, every moment brings him closer to his inevi
table end, i.e. to death. Here again, however, as in the discussion on the con
ception of ontogenesis, let us keep to the conventionals terms and retain the
term "aging" or "senescence" for the phase oflife characterized by degenerati
ve, regressive changes, either physiological or pathological. After weighing
10