Neonatal Immunology

Robert L. Schelonka and Anthony J. Infante

The neonate, whether premature or of normal gestational age, is a unique host from an immunologic
perspective. Many components of the immune system function less well in neonates compared with
adults, giving rise to the concept of an "immunodeficiency o f immaturity." The adaptive significance
of these alterations for neonatal survival remains obscure. This review highlights some of the most
prominent quantitative and qualitative differences between neonatal and adult immune systems.
From a clinical standpoint, the most important differences appear to be (1) reduction in the available
bone marrow reserve of granulocyte precursors, (2) reduction in serum complement activity, (3)
decreased ability to produce antibodies against bacterial polysaccharide antigens, and (4) increased
percentage of T lymphocytes bearing an antigenically "naive" cell surface phenotype and a corre-
spondingly naive functional program.
Copyright 9 1998 by W.B. Saunders Company

ewborn infants are at increased risk for seri-
N ous viral and fungal infection. Neonates
poorly localize certain bacterial infections, and
there is a predilection to systemic dissemination.
As a result, infectious diseases are a leading cause
of major morbidity and mortality, 1'2 especially in
very low birth weight infants. Certain features of
the newborn i m m u n e system appear immature,
while other aspects are fully functional at the
time of birth, even in very premature infants.
The purpose of this report is to review key ele-
ments of innate and acquired immunity, and to
describe the current understanding of the cellu-
lar and molecular basis for differences in im-
m u n e function between the newborn child and
adult.
Neutrophils
Neutrophils (polymorphonuclear leukocytes)
are poised to respond quickly and in vast num-
bers to sites of injury and infection, comprising
a key c o m p o n e n t of innate immunity. A popula-
From the Division of Neonatology, Department of Pediatrics, Wilford
Hall USAFMedical Center, Lackland AFB, TX; and the Department
of Pediatrics, Division of Hematolog3/Oncology/Immunology , Uni-
versity of Texas Health Science Centerat San Antonio, San Antonio,
TX.
Address reprints requests to Anthony J. Infante, MD, PhD, Depart-
ment of Pediatrics, Division of Hematology/Oncology/Immunology ,
University of Texas Health Science Center at San Antonio, 7703
Floyd Curl Dr, San Antonio, TX 78284-7810.
Copyright 9 1998 by W.B. Saunders Company
0146-0005/98/2201-0002508. 00/0
tion of essentially identical cells, neutrophils en-
gulf foreign matter such as bacteria and degrade
inflammatory debris. This is accomplished in a
nonspecific manner; it is not necessary to have
e n c o u n t e r e d the foreign material previously for
effective phagocytosis and degradation.
The c o m m o n progenitor cell for granulocytes
is the granulocyte-monocyte colony-forming
unit. These progenitor cells differentiate in the
bone marrow u n d e r the influence of glycopro-
rein h o r m o n e s called colony-stimulating factors.
Progeny of the granulocyte-macrophage colony-
forming unit are committed stern cells that give
rise to myeloblasts followed by myelocytes, meta-
myelocytes, bands, and, finally, segmented neu-
trophils.
Neutrophils populate several compartments
within the body. These include the bone marrow
storage pool, the circulating and marginated
pools, and the tissue pool. O f the neutrophils
that reside in the blood stream, approximately
half associate with the vascular endothelium,
comprising the so-called marginated pool. Infec-
tion, corticosteroids, and epinephrine demargi-
nate and release neutrophils into the circulating
pool, leading to a dramatic elevation in the abso-
lute neutrophil count. The total white blood cell
count is quite high during the first hours of life
and is probably due to demargination from the
"stress" of birth. 3 Circulating neutrophils sur-
vive approximately 8 hours. Those that migrate
into the tissues may live for an additional 24
hours.
Several features of neutrophil function are

2 Seminars in Perinatology, Vol 22, No 1 (February), 1998: pp 2-14

 Neonatal Immunology
critical to the appropriate response to microbial
invasion and inflammation. These include che-
motaxis, adherence, phagocytosis, and microbial
killing.
Chemotaxis
Chemotaxis is the directed migration of a cell
toward a chemoattractant along a concentration
gradient. Potent neutrophil chemoattractants in-
clude complement fragments, interleukin-8, leu-
kotriene B4, and platelet activating factor. 4 After
stimulation with chemotactic factors, neutro-
phils undergo cytoskeletal changes involving the
rapid polymerization of monomeric G-acfin to
filamentous F-actin. This change in conforma-
tion then serves as a framework to generate the
force necessary for shape change and motile be-
havior. 6'6 Cytoskeletal changes drive modifica-
tions in cell shape, such as the formation of a
pseudopod and uropod. The cell migrates by
repetitive extension of the pseudopod in the di-
rection of the gradient and retraction of the uro-
pod toward the body of the cell. 7
Adherence
After receiving appropriate signals from chemo-
attractants, the phagocyte adheres to the en-
dothelium of small blood vessels. Exposure to
bacterial cell wall components such as lipopoly-
saccharide, thrombin, or other factors liberated
from injured tissue upregulates expression of a
family of membrane glycoproteins called selec-
tins. Selectin proteins are found on cell mem-
branes of neutrophils and vascular endothelium,
and initiate reversible attachment of neutrophils
to the vascular endothelium, a process described
as cell "rolling. ''s L-selectin (CD62L) is ex-
pressed on the surface of neutrophils, and is crit-
ically involved in the initial adhesion and subse-
quent migration of the phagocyte to the site of
inflammation or infection.
When the rolling neutrophil senses the pres-
ence of inflammatory signals, another receptor-
ligand interaction causes tight adhesion to the
endothelium. Leukocyte functional antigen type
1, a/32 integrin, serves as a neutrophil receptor
for intercellular adhesion molecule type 1 on
endothelial cells. ~ The adherent neutrophil flat-
tens and undergoes transmigration from the vas-
cular lumen to the tissue site of inflammation.
3
Phagocytosis and Microbial Killing
At a site of injury or infection, neutrophils engulf
bacteria, cellular debris, or foreign matter. This
is accomplished by nonspecific receptors that
recognize oligosaccharides or other chemical
moieties. Many particles, including encapsulated
bacteria, do not interact with neutrophil cellular
receptors and cannot be phagocytized directly.
Encapsulated bacteria are essentially "invisible"
to the neutrophil until the microorganism has
been "labeled" by host-derived proteins called
opsonins. Of the many opsonins present in the
human, the most important are complement
fragments and irnmunoglobulins. Specific com-
plement and immunoglobulin receptors on the
neutrophil cell surface recognize opsonized bac-
teria, and they are eliminated by phagocytosis.
Particles engulfed by the phagocyte are first
encircled by membrane-bound vacuoles called
phagolysosomes. Cytoplasmic granules con-
raining potent degradative enzymes fuse and
empty their contents into the phagolysosome.
Known enzymes that are used in this process
include lysozyme, proteases, lactoferrin, and de-
fensins.
Cytokines and components of bacterial cell
walls activate neutrophils to undergo a burst of
oxygen consumption and produce several highly
reactive antibacterial oxygen-containing moie-
ties. The respiratory burst generates superoxide
(O2-), hydrogen peroxide, and hydroxyl radicals
(OH) that are toxic to ingested bacteria. Oxygen
radicals are short-lived. Singlet oxygen spontane-
ously dismutates to form hydrogen peroxide and
combines with chloride ions to form hypochlo-
rous acid, a potent oxidizing agent. Hypochlo-
rous acid oxidizes proteins, amines, and other
biomolecules to form organic chloramines,
which are longer-lived oxidizing agents. 1~
Deficiencies of Neonatal Neutrophil
Production
Fetal and neonatal bone marrow contain ex-
panded precursor cell populations, H'~2 and the
basal proliferative rate of these cells is nearly
maximal. ~s The neutrophil storage pool in hu-
man neonatal bone marrow is considerably
smaller than that of the adult t4 and in the face
of sepsis may be rapidly exhausted. An infant
with a serious infection rapidly consumes the
4 Schelonka and Infante
limited neutrophil stores, and diminished capac-
ity to accelerate proliferation leads to neutro-
penia. 15
Survival of animals infected with Escherichia
coli and group B Streptococcus improves after ad-
ministration of hematopoietic growth fac-
tors. 16A7 In addition, colony-stimulating factors
may augment certain neutrophil functions, such
as surface m e m b r a n e receptor expression, che-
motaxis, and phagocytosis, is To date, one ran-
domized controlled trial of granulocyte colony-
stimulating factor administration to infants with
presumed sepsis has been u n d e r t a k e n / 9 T h e r e
was rapid induction of peripheral and bone mar-
row neutrophilia in treated infants but no im-
p r o v e m e n t in survival, perhaps because there
were very few deaths in the untreated group.
More definitive clinical trials aimed at improving
survival in overwhelming bacterial sepsis and
neutropenia with the use of recombinant h u m a n
granulocyte colony-stimulating factor have not
yet been completed.
Neonatal Neutrophil Functional Deficiencies
Although L-selectin achieves adult levels in the
fetus and immature newborn, 2~ at full term its
expression is downregulated. Low expression of
this adhesion molecule persists for years, and
adult levels are not achieved until 15 years of
age. 21 L-selectin is further diminished during
acute bacterial infection. 2~ T h e explanation for
this paradoxical downregulation may be that in-
creased numbers of immature neutrophils,
which have lower levels of selectin expression, 22
are released from the bone marrow.
Neonatal neutrophils generate less filamen-
tous actin, a cytoskeletal contractile element es-
sential for locomotion, than adult neutrophils. 23
Sepsis depresses chemotaxis, but the mechanism
does not involve further reduction of F-actin. 24
Chemotactic deficiencies in newborn infants can
be further explained by increased fluidity of the
neutropbil cell membrane. Rigidification of cell
membranes with cholesteryl hemisuccinate
markedly improves chemotaxis in vitro. 25 After
birth, chemotaxis improves rapidly and healthy
infants born at full term have adult levels of che-
motactic function by 10 days of age. 21 The natu-
ral history of chemotactic function in infants
born prematurely is less well characterized, and
the mechanisms underlying the postnatal im-
provements in chemotaxis are still unclear.
In summary, the newborn has limited neutro-
phil reserves and a diminished ability to acceler-
ate production during times of rapid consump-
tion. Granulocytes from newborns are also
deficient in their ability to accumulate at sites
of infection. The capacity of neutrophils from
healthy neonates to engulf and kill bacteria is
similar to the adult; however, sepsis and the res-
piratory distress syndrome decrease the bacteri-
cidal capabilities of these c e l l s . 26-28 These defi-
ciencies together compromise neonatal innate
immunity.
The Complement System
The c o m p l e m e n t system generates multiple
products with anti-infective properties. It consists
of more than 19 unique serum proteins and re-
quires sequential activation of multiple soluble
factors. T h e r e are two activation pathways for the
c o m p l e m e n t system. The "classical" pathway is
initiated by cross-linking subunits of the first
c o m p l e m e n t protein (C1) by an antigen-anti-
body complex. The "alternative" pathway is acti-
vated nonspecifically by contact with certain cell
surface components, including polysaccharides
and endotoxin, shared by multiple bacterial spe-
cies. Both classical and alternative c o m p l e m e n t
activation pathways converge at the third com-
plement protein, C3, and subsequently generate
a m e m b r a n e attack complex comprised of the
terminal c o m p l e m e n t proteins, C5b6789. The
m e m b r a n e attack complex produces a channel
in biological membranes and is capable of lysing
certain bacteria, fungi, and erythrocytes.
In addition to the m e m b r a n e attack complex,
c o m p l e m e n t activation generates a n u m b e r of
enzymatic intermediates and cleavage products
that influence the i m m u n e response. 29 For ex-
ample, the cleavage product C5a is a potent che-
motactic stimulus for neutrophils, and C3b is an
efficient opsonin for bacterial cell membranes.
Complement in the Newborn
C o m p l e m e n t components are detectable early
in gestation, but levels of these proteins remain
low until the third trimester. Since c o m p l e m e n t
proteins do not cross the placenta, all compo-
 Neonatal Immunology
nents are derived from the fetus, s~ Late in gesta-
tion a rapid increase of the serum concentration
of C3 occurs; 60% to 80% of adult values are
achieved by the end of the pregnancy. Terminal
c o m p l e m e n t components, however, may achieve
only 10% of maternal levels. Despite this quanti-
tative "deficiency," the functional capacity at
full term, as measured by the total hemolytic
c o m p l e m e n t activity (CHs0) assay, approaches
adult values. Alternative pathway components in
newborn infants reach 35% to 70% of adult lev-
els. Premature infants generally have lower com-
plement levels, and C3, C4, and CH~0 levels in-
crease with advancing gestational a g e ) 1 By 3
months of postnatal age, most infants have adult
levels of c o m p l e m e n t components.
Since c o m p l e m e n t activation is an amplifica-
tion cascade, minor deficiencies in early compo-
nents markedly diminish the formation of later
components. ~2 Individuals with congenital defi-
ciency of C3 are p r o n e to severe, often fatal in-
fections with gram-positive organisms at an early
age. This is in contradistinction to individuals
who are deficient in the late c o m p l e m e n t com-
ponents and subject to recurrent meningococcal
infections, which are rarely fatal) ~ Lower levels
of early c o m p l e m e n t components in the new-
born lead to deficiencies of c o m p l e m e n t activa-
tion products critical to chemotaxis and opsoni-
zation.
Acquired Immunity
T Lymphocytes
T lymphocytes are specialized i m m u n e cells with
diverse roles in the i m m u n e response. T cells
can be divided into a n u m b e r of subsets based
on developmental history, cell surface markers,
and cytokine production. Two major subpopula-
tions of primary importance to the specific im-
m u n e response are the CD4 + and CD8 + T lym-
phocytes. T h e CD4 + population has mostly
executive functions, such as macrophage-activat-
ing capacity and helper activity for B cells and
antibody production. To be recognized by CD4 +
T cells, antigens require uptake and processing
by specialized phagocytes called antigen-present-
ing cells (APCs), which include macrophages,
dendritic cells, and B lymphocytes. These "pro-
fessional" APCs constitutively express major his-
5
tocompatibility complex (MHC) class II mole-
cules, which bind peptide fragments of
exogenous antigens and display them on the
APC surface. Antigen-specific T-cell receptors
(TCRs) recognize the MHC-bound peptide and
initiate a cascade of cell signaling that activates
the cell's executive and effector functions. The
CD8 § population mediates the majority of cyto-
toxic activity against virally infected cells and tu-
mors. CD8 + cytotoxic T cells discern predomi-
nately intracytoplasmic antigens displayed in the
context of MHC class I molecules, which are
ubiquitous. Activation of cytotoxic T cells results
in lysis of the specific target cell.
T-Cell Receptors
The T-cell antigen recognition molecule, the
TCR, is comprised of two glycoprotein chains
(either a,/3 or y, 6). Similar to the immunoglob-
ulin paradigm, TCR molecules possess variable
and constant regions (Fig 1). The variable region
forms an antigen-binding domain while the con-
stant region links the TCR to the cell membrane.
T h e TCR is noncovalently linked to a complex of
signal-transducing molecules collectively called
CD3.
Molecular Basis of Diversity
T h e e n o r m o u s diversity of immunoglobulin and
TCR (Ig/TCR) molecules is based on recombi-
nation o f minigenes into a single functional ge-
netic unit. Genetic mechanisms responsible for
generation of I g / T C R receptors are similar. The
antigen-binding site of I g / T C R is generated by
variable (V), diversity (D), and joining (J) re-
gions. Random joining of these minigenes gen-
erates an estimated 109 unique Ig heavy chains
and slightly fewer TCRs. Additional diversity is
achieved by at least two other mechanisms. First,
splicing of V and J segments at their junction
sites is not precise. This leads to exclusion or
inclusion of germline-encoded nucleotides. Sec-
ond, nontemplated (N) nucleotides can be ran-
domly added by the enzyme terminal deoxy-
nucleotidyl transferase. 3s The potential I g / T C R
repertoire due to recombination,joining impre-
cision, and N-nucleotide addition is estimated to
be greater than 1013. 34
In addition to p r o g r a m m e d diversity by ge-
netic rearrangement, genes encoding Ig heavy
6 Schelonka and Infante
IgG Monomer T cell receptor complex
LC
CDR
,bv I
and light chains undergo point (somatic) muta-
tions in germinal centers during the i m m u n e
response. These gene mutations lead to amino
acid substitutions within Ig proteins that alter
the three-dimensional structure and the antigen-
binding characteristics. Many mutations lead to
self-reactive or low-affinity immunoglobulin.
These are eliminated. O t h e r mutations enhance
the antigen-binding capability of the Ig molecule
and are selected for expression, a process called
affinity maturation. Somatic point mutations oc-
cur rarely, or not at all, in TCR. These processes
provide a mechanism for maintaining i m m u n e
tolerance to self-antigens.
T-Cell Activation
When the TCR engages a peptide fragment in
the antigen-binding groove of the MHC mole-
cule, a message is sent via CD3 that triggers cell
activation. T-lymphocyte activation also requires
a second, "costimulatory" signal delivered by
the antigen-presenting cell. Arguably the most
important of the multiple costimulatory interac-
tions that have been defined is that of the ligand
B7, expressed on the antigen-presenting cell,
with its receptor (CD28) on the T cell (Fig 2).
Absence of costimulation during TCR engage-
Figure 1. Immunoglobu-
lin G monomer and TCR
y 5 e~q complex. CDR, comple-
mentarity determining re-
gion; LC, light chain; HC,
heavy chain; V, variable re-
CD3 gion; C, constant region.
m e n t has been shown to result in antigen-spe-
cific unresponsiveness, known as anergy, 35 or
p r o g r a m m e d cell death, called apoptosis. The
activation cascade results in inositol phosphate
turnover, an increase in intracellular Ca ++, and
protein kinase activation. Ultimately, the tran-
scription of specific genes, such as the one for
interleukin-2 (IL-2), is induced.
One important consequence of T-cell activa-
tion is the production of signal molecules called
cytokines. Cytokines are a diverse group of small
peptide molecules that signal the growth, prolif-
eration, and activation of multiple cell types and
modulate the i m m u n e response (Table 1). More
than 20 cytokines of known function are either
p r o d u c e d by or influence T lymphocytes. 36 The
prototypic cytokine is IL-2, which drives clonal
expansion of T lymphocytes. Interleukin-2 is an
autocrine cytokine that is primarily p r o d u c e d by
activated CD4 + cells, which are in turn stimu-
lated by IL-2. Cytokines also have paracrine prop-
erties by influencing cells in close proximity to
the synthesizing cell.
Guided by specific cytokine messages, CD4 +
T cells may differentiate into one of two distinct
cell types, Thl or Th2. These T-cell subsets have
unique roles in the i m m u n e response. Thl cells,
sometimes referred to as "inflammatory" T cells,
 Neonatal Immunology 7

Figure 2. Cell-cell interac-

tions. (A) Antigen-present- B.
ing cell presents an MHC- SIg
bound peptide fragment
and is recognized by the
TCR. A second signal via B7
and CD28 is required for T-
cell activation. (B) TCR/
MHC and CD40L/CD40
recognition is necessary for C.
cognate T- and B-cell inter- ig / /
action. (C) B-cell differenti-
ates into plasma cell, which
produces Ig. Ag, antigen; T, // , //
T cell; B, B cell; SIg, Surface
immunoglobulin.

enhance cellular immunity via the secretion of
IL-2 and interferon-y (IFN-y). Th2 cells support
differentiation of B cells for antibody produc-
t i o n Y '38 in part by secreting IL-4. This paradigm
is illustrated in Fig 3.
Antigen-induced lymphocyte proliferation is
an important c o m p o n e n t of the host i m m u n e
response that leads to amplification and the de-
velopment of immunologic memory. Secondary
or m e m o r y i m m u n e responses are more vigor-
ous because e x p a n d e d populations of lympho-
cyte clones, each capable of recognizing a spe-
cific antigen, are poised for response. In
addition, antigen-specific activation leads to al-
terations in the m e m b r a n e signaling pathways.
As a result, m e m o r y cells are more easily trig-
gered than "virgin" lymphocytes that have not
yet e n c o u n t e r e d antigen.
Lymphocyte-Mediated Cytolysis
Recognition o f specific MHC-bound antigen by
the TCR of CD8 § lymphocytes results in direct
killing o f virus-infected cells, tumors, and allo-
grafts. These cytolytic T cells liberate mediators
stored in cytoplasmic granules, such as perforin,
which are capable o f disrupting the target cell

TaMe 1. Important Cytokines Involved in T- and B-Cell Cooperation

Source Activity Production*
IL-1 Macrophage T and B proliferation; Ig synthesis Normal
IL-2 T cell T and B proliferation; induction of IL-2 receptors Normal/low
IL-4 T cell B cell proliferation; Ig switch Low
IL-6 T and B cells, macrophage, T and B activation; Ig production Normal/low
endothelial
IL-10 T cell Inhibits T help, Ig production
IL-12 T and B cells, macrophage Promotes NK killing and antigen-dependent cytolysis Low
IFN-y T cell Inhibit IgE production, increases MHC class II expression, Low
promotes antigen presentation
Abbreviations: IL, interleukin; IFN = 3', interferon-y; Ig, immunoglobulin; NK, natural killer cell.
8 Schelonka and Infante
IFNy
/
~ IL 4
IL-2/~,r ~ T-Cell Repertoire
0 IL-4 IFN7 0
IL-4
IFNy IL-5
IL-2 IL-6
TNFI3
IL-10
O IP
Cellular immunity/cytotoxicity Antibody production
Figure 3. Cytoldne-driven differentiation of Thl and
Th2 cells and functional capacity. CTL, cytotoxic T
lymphocyte; B, B cell.
membrane. Perforin-mediated cytolysis leads to
cell necrosis. An alternative mechanism of cyto-
toxic T-lymphocyte killing requires binding to a
molecule on the target cell known as Fas. This
interaction initiates a series of molecular events
ultimately resulting in "suicide" of the target
cell, a process known as apoptosis. ~9 Interleukin-
12 has a central role in the regulation of cytolytic
lymphocyte activity by promoting activation and
differentiation of effector cells and expression
of other cytokines important for the induction
of cell-mediated immunity, such as IFN-T. 4~
Natural killer (NK) cells are a population o f
nonspecific cytotoxic cells that are important in
the early response to viral infection. Their activa-
tion is also u n d e r the control of the cytokines
IL-12 and IFN-y.
Functional Response of Neonatal T Cells
Evidence of T-cell dysfunction in the newborn
comes from several observations. Infants have
an unusual predilection to serious infection with
certain viruses, such as herpes simplex and ru-
bella. Delayed hypersensitivity reactions are
markedly diminished. Following infection, ac-
quisition of antigen-specific antibody is delayed.
Research has focused on the repertoire of T-
c e l l - b i n d i n g capacity for a variety of antigens
and the ability of neonatal T cells to be activated
and perform specialized effector functions.
Previous analyses in early gestation fetal tissue
have demonstrated that the TCR repertoire is
limited and expands in a controlled, stepwise
fashion. 41 Mechanisms responsible for restric-
tion of the fetal repertoire include n o n r a n d o m
usage of TCR D and J elements 42 and limited
nucleotide additions to V-D and D-J joining sites.
This results in shorter antigen-binding sites and
diminished diversity of the TCR r e p e r t o i r e Y
Although the genetic mechanisms of reper-
toire diversification appear intact as early as 24
weeks' gestation, the expressed repertoire differs
from that of the adult. Short fetal CDR3 regions
may result in flat antigen-binding sites, 44 which
may provide an explanation for the frequent
presence of low affinity polyreactive specificities
in the fetal i m m u n e system. 45 The clinical impli-
cations of these findings await further clarifica-
tion.
Given these observations in early fetal tissue,
we questioned whether TCR repertoire restric-
tion persists in the latter half of h u m a n gestation.
By 24 weeks' gestation there were no limitations
in TCRBV family usage. However, the antigen-
binding sites were shorter for all families earlier
in gestation and increased in size until full term.
Oligloclonal expansion of specific T cells was
frequently observed. Interestingly, when oli-
goclonal expansion was detected in the newborn
infant, there was limited diversity within that
TCRBV family (unpublished observations). This
suggests that the fetus commonly encounters
and responds to antigens in utero. T h e r e is no
evidence that the genetic composition of neona-
tal TCRs is responsible for diminished T-cell
function and relative immunodeficiency.
Activation Signals
Neonatal T lymphocytes have different signaling
requirements than their adult cell counterparts.
Stimulation of adult lymphocytes with anti-CD2
elicits a vigorous proliferative response and sig-
nificant IL-2 production. The same stimulus of
neonatal T cells leads to minimal proliferation
and minimal IL-2 mRNA and IL-2 production.
These deficiencies are overcome in neonatal
 Neonatal Immunology
cells by engaging a costimulatory signaling mole-
cule, CD28. Signaling of neonatal T cells by
CD28 reverses the hyporesponsiveness to anti-
CD2 antibodies and may play an important role
in the expansion and generation of the neonatal
i m m u n e response. 46 T h e production of IL-2 is
probably diminished in activated newborn T
cells, 47'4s although discrepancies exist. 49'5~ Neo-
natal T cells appear to have a greater require-
m e n t for accessory cells and signal molecules to
achieve adult-like IL-2 mRNA expression and
proliferation in vitro.
Neontal T cells produce little IL-4. 5~ In-
terleukin-4 is necessary for T - c e l l - d e p e n d e n t
differentiation of B cells. Without supplemental
IL-4, neonatal T cells are unable to support im-
munoglobulin synthesis by B cells in vitro. 52 Acti-
vated m e m o r y T cells generate IL-4, whereas na-
ive T cells are p o o r producers of this cytokine.
The naivet6 of the neonatal host, rather than
genetic maturation, has been proposed to be re-
sponsible for diminished IL-4 production and
altered signaling to B l}a-nphocytes.
T-Cell Help
Adult, naive T cells have the capacity to provide
help to B cells. Neonatal T cells, 97% of which
bear a naive phenotype, have a diminished ca-
pacity to provide helper functions, and in con-
trast to adult naive T cells, the dominant immu-
noregulatory role is suppression. Neonatal T
cells lose their suppresor activity after activation
with exogenous cytokines in vitro47 '53 and ac-
quire the m e m o r y marker, CD45RO+. 54 These
activated T cells do not completely acquire an
adult phenotype as they continue to express
CD38, a marker of immature lymphoid cells. 54
Activated neonatal T cells express less CD25, an
activation marker, than similarly activated adult
T cells. 55 Neonatal T cells may acquire helper
executive function, but this requires a greater
array of activation signals than adult T cells. 47
These findings suggest that newborn T cells must
undergo age-related maturational changes to be
capable of helper functions.
Neonatal T cells poorly support B-cell Ig se-
cretion. Because newborn infants produce pri-
marily IgM and little IgG or IgA in response to
antigenic challenge, the neonatal condition has
been likened to the X-linked hyper-IgM syn-
drome. In this inherited condition, affected per-
9
sons lack the capacity to switch from IgM to IgG
or IgA secretion. Immunoglobulin heavy chain
isotype switching events require cognate T- and
B-cell interaction (Fig 2B) plus costimulation by
T-cell-derived cytokinesP 2'56'57 In X-linked
hyper-IgM syndrome, the inability to switch to
IgG or IgA secretion is due to a genetic defi-
ciency of CD40 ligand (CD40L) expression by
activated T cells. This led investigators to charac-
terize the expression of CD40L on neonatal T
cells.
T h e reported expression o f CD40L on acti-
vated neonatal T cells varies from nil to nor-
mal. 52'57'58 In contrast to adult T cells, neonatal
T cells fail to express CD40 ligand following acti-
vation with phorbol ester and ionomycin. 52'57
However, through optimal cell surface receptor
stimulation and the addition of supplemental cy-
tokines, CD40 ligand expression has been ob-
served, and these cells can provide help for Ig
isotype switchingP 2 A subpopulation of T cells
appears to be particularly efficient at helping
naive B cells undergo isotype switching and se-
cretion of IgG and IgA. T cells expressing the
h o m i n g receptor L-selectin efficiently supported
neonatal and adult naive B cells. 59These observa-
tions indicate that neonatal T cells are not inher-
ently defective in CD40 ligand expression per se,
but that they differ in signal requirements.
Cell-Mediated Cytolysis
Neonatal infection with herpes simplex virus and
enterovirus may be unusually severe or rapidly
progressive. An effective immune response to in-
tracellular pathogens first requires containment,
followed by eradication or latency. Cell-mediated
cytolysis plays a critical role in both phases of
viral clearance. During the first days of infection,
NK cells nonspecifically lyse virus-infected cells
without specific antigen recognition. This NK-
d e p e n d e n t containment phase is followed by
eradication with clonally expanded, antigen-spe-
cific cytolytic T cells. Certain viruses, including
the herpesviruses and retroviruses, establish la-
tent infection with lifelong persistence in the
host.
Cytolytic activity by NK and CD8 § cells is di-
minished in the newborn. The explanation for
deficient cytotoxicity appears to be mediated by
insufficient cytokine signals, particularly IL-12
and IFN-T. Cord blood m o n o n u c l e a r cells pro-
I0 Schdonka and Infante
duce less IL-12 than their adult counterparts,
and the diminished cytolytic activity of neonatal
cells can be reversed by supplementation with
exogenous IL-12 in vitro. These observations
point to the central signaling role of IL-12 in
the regulation of cell-mediated cytotoxicity and
suggest a mechanism to explain the diminished
cytolytic properties of neonatal NK and cytotoxic
T cells. 6~
B Lymphoeytes and I m m u n o g l o b u l i n
The entire population of B cells is dedicated to
one end: the production of a diverse spectrum
of Ig molecules that constitutes the humoral arm
of acquired immunity. Mature B cells generate
complete Ig molecules anchored to the cell sur-
face, which serves as an important marker for
this population. When activated, the B cell differ-
entiates into an antibody-secreting plasma cell.
B Cell Development
B-cell precursors can be defined by the expres-
sion of one or more components of Ig mole-
cules. Pre-B cells synthesize heavy chains but not
light chains. Their cell membranes lack surface
Ig. Immature B lymphocytes produce both heavy
and light chains, and express surface IgM but
not IgG or IgA. Mature B cells express both IgM
and IgD. Generation of IgG, IgA, and IgE is an
antigen-driven process of isotype switching in
mature B lymphocytes. Memory B cells express
a particular IgG isotype, IgA, or IgE on their cell
surface.
Plasma cells are the terminally differentiated
progeny of mature B cells, and their principal
function is the production of antibody. These
cells are capable of tremendous immunoglobu-
lin synthesis, achieving rates of thousands of mol-
ecules per second. Under normal circumstances,
the quantity of IgG produced is approximately
35 m g / k g / d . 61 At that rate, an average person
produces approximately 59 kg of IgG during a
lifetime.
Activation and Differentiation
B cells are activated by cell-cell interaction with
antigen and T cells. Surface IgM associates with
Ig-a and Ig-/3 molecules, analogous to CD3, to
form a B-cell receptor complex that mediates B-
cell activation by antigen. In addition, helper T
cells engage antigen/MHC complexes and CD40
expressed on the B cell surface, inducing the
upregulation of receptors for cytokines such as
II_~2, IL-4, IL-5, and IL-6, as well as IFN-T. This
collection of signals leads to B-cell differentia-
tion into memory B cells and plasma cells, the
latter being the active antibody-producing cells.
General Structure of Antibodies
Antibody molecules consist of two identical
heavy chains and two identical light chains.
Heavy and light chains are linked by covalent
disulfide bonds (Fig 1). The first ]00 amino acid
residues encode variable (V) domains; subse-
quent amino acids comprise the constant (C)
region. Protein folding of the variable regions
brings together the three complementarity-de-
termining regions to form the antigen recogni-
tion site. The genetic basis of antibody diversity
is similar to generation of TCRs. The amino acid
makeup of the complementarity-determining re-
gions defines the three-dimensional structure of
the antigen recognition site and explains the mo-
lecular basis of specificity. The amino acid com-
position of the heavy chain constant region de-
termines the antibody class and functional
properties. The class of Ig is determined by the
heavy chain genetic locus (#, 6, T, a, or e), which
encode IgM, IgD, IgG, IgA, and IgE, respectively.
Antibody Classes and Subclasses
Immunoglobulin M is formed early in the pri-
mary response to antigenic challenge. These an-
tibodies form pentamers with low affinity but
broad specificity because of multiple binding
sites. Highly repetitive polymeric antigenic struc-
tures of bacterial polysacharrides trigger T-cell-
independent IgM production. This contributes
significantly to the primary response against pyo-
genic infection, but does not generate immuno-
logic memory. Immunoglobulin D is expressed
on B-cell membranes along with IgM, but its role
in host defenses has not been elucidated.
Immunoglobulin G is a key component of the
specific immune response, and its production
generally requires cognate T- and B-cell interac-
tion. While production of IgG occurs late in the
primary response to antigenic encounter, it is
rapidly synthesized on secondary exposure to the
 Neonatal Immunology
same antigen. Different types of antigens elicit
particular IgG subclass proliferation. For exam-
ple, bacterial polysaccharides preferentially in-
duce IgG2 and, to a lesser degree, IgG4. Viral
pathogens tend to elicit IgG1 and IgG3. Expan-
sion of long-lived B-cell clones capable of pro-
ducing specific antibody to a particular antigen
is an integral part of immunologic memory.
Immunoglobulin A is the principal antibody
found in body secretions and mucosal surfaces.
Because there is B-lymphocyte traffic between
different mucosal sites, sensitized IgA-bearing B
cells in the intestinal mucosa may produce IgA
locally and travel to the lactiferous ducts to pro-
duce the same IgA in breast milk. When con-
sumed by the infant, maternally derived IgA con-
tributes to gut immunity.
~'v'nile IgE can be found in the sera of norTnaI
individuals, increased levels are found in allergic
and parasitic disease. Immunoglobulin E pro-
duction appears to be a T-cell-dependent pro-
cess. The role in neonatal immunity has been
incompletely characterized.
Placental Transport of Immunoglobulin
The bulk of the newborn's lg pool is derived
from the mother. Placental transfer of Ig is re-
stricted to the IgG isotypes. Trophoblast cells
recognize epitopes on the Fc portion of Ig and
by receptor-mediated endocytosis, IgG is incor-
porated into vesicles and released into the fetal
circulation. Active transport of maternal IgG
across the placenta begins at 17 weeks' gestation
and increases proportionally with gestational
age. By 33 weeks' gestation, lgG levels in the
fetus approximate those of the mother. By full
term, fetal IgG levels exceed maternal values. 62
Passively acquired IgG is rapidly catabolized and
has a half-life of approximately 20 days. Some
maternal specificities, such as antibodies to the
human immunodeficiency virus, persist for
months and may be detected with sensitive tech-
niques. Immunoglobulin G loss is accelerated in
ill preterm infants with small antibody pools who
require repeated phlebotomy.
[mmunoglobtdin Production by the Neonate
Infants fail to respond to certain types of anti-
gens, primarily certain bacterial polysaccharides,
and have a limited capacity to develop immuno-
11
logic memory. While IgM may be produced in
response to antigenic challenge, synthesis of IgG
and IgA is limited. This is clinically evident by
the need for repeated immunizations and the
use of protein-conjugated polysaccbaride vac-
cines in infancy and early childhood to achieve
protective levels of antibody. Whether the lim-
ited production of antibodies is due to an innate
B-cell developmental program or lack of ade-
quate signals from accessory immune cells re-
mains an open question. Transplacental passage
of maternally derived immunoglobulin to the fe-
tus is a specific adaptation that ameliorates these
deficiencies in neonatal antibody production.
Immunoglobulin class switching is triggered
by engagement of the B-cell molecule CD40 by
its ligand on activated T cells. 6~ Newborn B lym-
phocytes preferentially secrete IgM and IgD, and
do not switch efficiently to IgG and IgE produc-
tion. Comparisons of neonatal and adult naive
B cells have demonstrated differences in the pro-
files of IgG subclass and IgA production. In neo-
natal B cells, production of IgG1 and IgG3 pre-
dominates while IgG2 and IgG4 is absent. Adult
naive B cells generate more IgG2 and IgG4, al-
though less than the amount produced by adult
memory B c e l l s . 64 Notably, the T3 heavy chain
gene is the most 5' of the y hea W chain genes,
followed by 9' 1, 9'2, and y4, suggesting that the
disproportionate increase in IgG3 secretion by
neonatal lymphocytes may be consistent with a
tendency to switch from IgM to the most proxi-
mal 2/ heavy chain gene. 65 Responses to poly-
saccharide antigens are typically IgG2 in the
imunocompetent host. The neonate, however,
produces little IgG2 in response to polysaccha-
ride antigens and vaccines. Whether this poor
IgG2 response is due to ineffective "downstream
switching" by B cells or lack of appropriate sig-
nals from T cells is not known.
Sununary and Conclusions
The systems mediating innate immunity have
certain quantitative deficiencies that affect the
newborn's response to infections. Neonatal neu-
trophils ingest and kill bacteria as efficiently as
their adult counterparts, but adhesion and sub-
sequent migration of these cells to sites of infec-
tion is impaired. The inherent sluggish move-
ment of neonatal neutrophils is exacerbated by
12
insufficient complement activity. Deficiencies of
the early complement components limit produc-
tion of the chemoattractant, C5a. The neutro-
phil response is further delayed by limited gener-
ation of C3b, which is necessary for opsonization
and phagocytosis. Neutrophil storage pools are
rapidly exhausted in the face of serious infec-
tion, and the capacity to replenish those stores
is limited. When the pace of bacterial replication
exceeds clearance by innate defenses, systemic
infection supervenes.
Acquired immunity in the newborn is affected
by qualitative and quantitative deficiencies. Cell-
mediated killing by NK and cytotoxic T cells is
diminished, leaving the newborn vulnerable to
certain viral and intracellular pathogens. The
newborn infant produces primarily IgM, and lit-
tle IgG and IgA, in response to antigenic chal-
lenge. Antigen inexperience explains the pre-
ponderance of neonatal T and B cells expressing
a naive phenotype. While these cells can rapidly
differentiate into cells with adult-like functional
capacities when activated by optimal signals in
vitro, their signal requirements are more strin-
gent than those of antigenically experienced
lymphocytes from adults. Since the lymphocyte
maturation process is directed largely by cyto-
kines, and the capacity of neonatal cells to pro-
duce key cytokines such as IL-4 and IFN-T is
limited, the acquisition of adult-type functional
capabilities is delayed in vivo.
Despite encountering a pathogen-rich envi-
ronment at the time of birth, most newborn in-
fants, although immunodeficient when judged
against adult standards, do not become ilia The
relative immunodeficiency of the neonate is
most likely an adaptive mechanism to optimize
survival by balancing the conflicting immuno-
logic requirements oi7 life in utero with those of
the external environment.
Acknowledgment
T h e a u t h o r s are grateful for Dr F r a n k M. R a a p h o r t ' s
critical review o f this m a n u s c r i p t .
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