All organ systems of the body undergo a dramatic
transition at birth, from a sheltered intra-uterine
existence to the radically distinct environment of the
outside world. This acute transition is then followed
by a gradual, age-dependent maturation. The fetal and
neonatal immune systems are associated with physi-
ological demands that are three-fold: protection against
infection, including viral and bacterial pathogens at
the maternal–fetal interface1,2, avoidance of potentially
harmful pro-inflammatory/T helper 1 (TH1)-cell-
polarizing responses that can induce alloimmune reac-
tions between mother and fetus3, and mediation of the
transition between the normally sterile intra-uterine
environment to the foreign antigen-rich environment
of the outside world, including primary colonization of
the skin4 and intestinal tract5 by microorganisms.
Given the limited exposure to antigens in utero and
the well-described defects in neonatal adaptive immun-
ity6, newborns must rely on their innate immune
systems for protection to a significant extent7,8. As
the innate immune system can instruct the adaptive
immune response9, distinct functional expression
of neonatal innate immunity, including a bias against
TH1-cell-polarizing cytokines, contributes to a distinct
pattern of neonatal adaptive immune responses. Mounting
evidence indicates that infection-induced production of
pro-inflammatory/TH1-cell-polarizing cytokines, includ-
ing tumour-necrosis factor (TNF) and interleukin-1β
(IL-1β), is associated with premature labour and
pre-term delivery10. In particular, TNF production
is thought to favour abortion through the induction
of apoptosis in placental and fetal cells. The ability of
pro-inflammatory cytokines to induce spontaneous
abortion is likely to be an important reason for the strong
bias of the maternal and fetal immune systems of mul-
tiple mammalian species towards TH2-cell-polarizing
Because of this impaired production of TH1-cell-
associated cytokines, it was initially thought that
the neonatal innate immune system was generally
impaired or depressed; however, stimulus-induced
production of certain cytokines (for example, IL-6,
IL-10 and IL-23) by neonatal monocytes and antigen-
presenting cells (APCs) actually exceeds that of
adults12–14. However, the bias against TH1-cell-polarizing
cytokines leaves the newborn susceptible to microbial
infection and contributes to the impairment of neo natal
immune responses to most vaccines, thereby frustrat-
ing efforts to protect this vulnerable population15.
After birth, there is an age-dependent maturation of
the immune response. Of note, prenatal and postnatal
exposure to environmental microbial products that can
activate innate immunity might accelerate this matura-
tion process, particularly if the exposure occurs repeat-
edly over time16, diminishing TH2-cell polarization
and/or enhancing TH1-cell polarization and thereby
potentially reducing allergy and atopy, in accord with
the hygiene hypothesis17,18.
The uterine and placental tissues (BOX 1; FIG. 1),
fetus and newborn have a unique anatomical distri-
bution and functional expression of innate immune
molecules, including Toll-like receptors (TLRs; recep-
tors that serve to detect the presence of microbes19–21),
cationic membrane-active antimicrobial proteins and
peptides (APPs) with microbicidal and microbial
toxin-neutralizing activities22,23, and chemokines.
Department of Medicine,
Division of Infectious Diseases,
Children’s Hospital Boston
and Harvard Medical School,
Boston, MA 02115, USA.
The theory that exposure
to microbial components,
including Toll-like receptor (TLR)
agonists during the neonatal,
infancy and early-childhood
phases of development serves
to polarize the immune
response towards T helper 1
(TH1)-cell, and away from
TH2-cell, responses, thereby
reducing the likelihood of
allergy and/or atopy. Consistent
with this hypothesis, there
are inverse epidemiological
relationships between the rates
of infection and autoimmunity
— for example, as the rates
of common infections have
dropped in wealthy
the rates of allergy and
autoimmune disease have
Innate immunity of the newborn: basic
mechanisms and clinical correlates
Abstract | The fetus and newborn face a complex set of immunological demands, including
protection against infection, avoidance of harmful inflammatory immune responses that
can lead to pre-term delivery, and balancing the transition from a sterile intra-uterine
environment to a world that is rich in foreign antigens. These demands shape a distinct
neonatal innate immune system that is biased against the production of pro-inflammatory
cytokines. This bias renders newborns at risk of infection and impairs responses to many
vaccines. This Review describes innate immunity in newborns and discusses how this
knowledge might be used to prevent and treat infection in this vulnerable population.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 7 | MAY 2007 | 379
© 2007 Nature Publishing Group
A common, transient and
benign rash of the newborn,
characterized by raised lesions
on an erythematous base.
Recent evidence reveals that
erythema toxicum probably
reflects an innate immune
response to initial skin
colonization by Gram-positive
bacteria (for example,
staphylococci) that penetrate
neonatal skin through hair
follicles. This bacterial
penetration is associated
with the activation of tissue
macrophages and production
of interleukin-1 (IL-1) and
IL-6, which are capable of
contributing to a systemic
Such innate immune molecules are increasingly impli-
cated in human health and disease and are currently
the subject of intense biopharmaceutical research23,24.
Therefore, the study of neonatal innate immunity is of
interest, not only as a biological phenomenon, but also
in identifying new methods to diagnose, prevent and
treat infection and allergy in the newborn and infant.
Here we focus on the distinct anatomical expression of
molecules associated with newborn innate immunity
and on unique aspects of neutrophil, monocyte and
APC function in the newborn. We will also highlight
correlations between innate immune function and
clinical diseases of newborns and infants.
In general, the tasks of the innate immune system are
to shield the body from microbial invasion, by redu-
cing the number and virulence of microorganisms,
and to coordinate and instruct the adaptive immune
response. The function of fetal and neonatal innate
immunity can be understood in relation to the ana-
tomical sites at which it has a sentinel role in protect-
ing the fetus. Therefore, the uterus must be kept sterile
and, to this end, it expresses robust antimicrobial
defence mechanisms (BOX 1; FIG. 1). Following birth,
the neo natal skin and gut are rapidly colonized with
microbial flora. Accordingly, birth is characterized by
a distinct expression pattern of innate immune mol-
ecules by the skin and mucosal epithelia, and by the
mobilization of an acute-phase response in peripheral
blood, all of which are thought to be aimed at prevent-
ing infection while avoiding excessive inflammatory
responses to microbial products.
Neonatal skin: fragile, yet primed for defence. Neonatal
skin is fragile at birth and even small breaks in the
integrity of the skin can serve as lead points for infec-
tion25. The vernix caseosa, a waxy coating on newborns
that is secreted by fetal sebaceous glands, contains
APPs, including lysozyme, α-defensins (also known as
HNP1–HNP3), ubiquitin and psoriasin, as well as anti-
microbial free fatty acids that can act in synergy with
APPs to kill microorganisms26. Accordingly, extracts
of vernix caseosa possess antimicrobial activity in vitro
against various bacteria and fungi, including Escherichia
coli and Candida albicans26–29. In addition, the skin from
embryonic and newborn mice, as well as human new-
born foreskin, shows a robust expression by epithelial
cells of cathelicidin and β-defensin antimicrobial pep-
tides that exceeds that of adult skin, with synergistic
antimicrobial activity against group B Streptococcus30.
Overall, it is evident that the newborn is initially covered
with a surface microbicidal shield to protect it during its
transition to extra-uterine life27.
Soon after birth, ~50% of all newborns develop a
prominent but transitory rash, characterized by small
erythematous papules often surrounded by a diffuse ery-
thematous halo, known as erythema toxicum neonatorum.
Emerging evidence indicates that erythema toxicum
neonatorum is caused by reaction of neonatal skin to
commensal flora, in particular Gram-positive staphylo-
cocci that colonize the skin and often penetrate into hair
follicles. Such bacterial skin penetration may activate
local macrophages to produce IL-6, (a multi-functional
cytokine, production of which increases in the first
days after birth31,32), which is likely to contribute to the
postnatal systemic acute-phase response, including an
increase in body temperature4,31 (FIG. 2a,b). Such early
microbial exposure and the resulting innate immune
response is likely to be important for maturation of the
neonatal immune system.
Newborn intestinal tract: colonization, tolerance and
modulation. The fetal intestinal tract is normally
bathed in sterile amniotic fluid that has been swallowed.
However, upon delivery there is a rapid transition to
primary colonization of the neonatal intestinal tract,
presenting a crucial challenge for the immune system of
the newborn (FIG. 2c).
With a growing appreciation of the role of TLR
signalling in the gut33, characterization of the devel-
opment of TLR-mediated innate immunity in the
fetal and newborn intestinal tract has been an area
of recent focus. Enterocytes in the small intestine of
the human fetus express basolateral TLR2 and TLR4
at 18–21 weeks of gestation34. Studies of mouse and
human tissue cultures show that fetal intestinal villous
and crypt epithelial cells express TLR4 and MD2, key
components of the lipopolysaccharide (LPS) receptor35.
Stimulation of fetal intestinal cells with LPS resulted in
higher levels of nuclear factor-κB (NF-κB) activation
and production of CXC-chemokine ligand 8 (CXCL8)
and CXCL2, compared with adult intestinal epithelial
cells36,37 (for more on neonatal chemokines see BOX 2).
However, such robust intestinal epithelial inflammatory
Box 1 | Innate immunity of the uterus, placenta and amniotic fluid
The uterine cavity contains innate immune detection and effector systems that
maintain sterility, detect infection and, under conditions of substantial microbial
invasion, induce the expression of mediators that speed lung maturation and labour
in order to deliver the fetus from a threatening environment (FIG. 1). The cervical plug,
a post-conception barrier between the non-sterile vagina and the normally sterile intra-
uterine cavity, contains antimicrobial proteins and peptides (APPs; including
lactoferrin, lysozyme and α-defensins), which are thought to protect against ascending
microbial infection139. Human uterine epithelial cells express Toll-like receptor 1 (TLR1)
to TLR9, which are capable of mediating the robust production of interleukin-6 (IL-6)
and IL-8 (cytokines that have important roles in cervical relaxation and labour140,141),
as well as the production of β-defensins and interferon-β141.
The trophoblast, a layer of fetal cells in the uterus that mediates the implantation of
the fetus into the placenta, expresses TLR2 and TLR4. TLR2 activation on these cells
induces apoptosis, indicating a pathway by which intra-uterine infections might
contribute to complications of pregnancy such as intra-uterine growth restriction142,143.
By contrast, activation of TLR4, which is expressed at the maternal-facing plasma
membrane that is bathed in maternal blood144, results in cytokine production142 and
might mediate responses to maternal infection. The amniotic fluid contains acute-
phase proteins, such as soluble CD14 and lipopolysaccharide (LPS)-binding protein
(LBP)145 that modulate the endotoxic activity of LPS81, as well as APPs, such as
lactoferrin, bactericidal/permeability-increasing protein (BPI), histones146 and
defensins147,148. Pre-term labour increases amniotic-fluid concentrations of the 14 kDa
group II phospholipase A2 (PLA2)149, an enzyme with remarkable potency against
Gram-positive bacteria150. Consistent with its content of multiple APPs, amniotic fluid
possesses antimicrobial activity in vitro against multiple Gram-negative and
Gram-positive bacterial species151.
380 | MAY 2007 | VOLUME 7
© 2007 Nature Publishing Group
Antimicrobial proteins and peptides
Tubular invaginations of the
intestinal epithelium. Paneth
cells are found at the base of
the crypts and produce
antimicrobial proteins and
phospholipase A2 and
defensins, as well as stem cells,
which continuously divide and
are the source of all intestinal
epithelial cells. Villi are
projections into the lumen and
have an outer layer of cells that
mainly consists of mature,
absorptive enterocytes but
also contain mucus-secreting
responses to LPS could pose a serious danger shortly
after birth, when the newborn is rapidly colonized by
intestinal flora, including LPS-bearing Gram-negative
bacteria38. Accordingly, exposure of perinatal intestinal
cells to LPS has recently been shown to result in the
loss of intestinal-epithelial-cell responsiveness to LPS,
which was associated with downregulated expression of
IL-1-receptor-associated kinase 1 (IRAK1), an essential
intermediary for epithelial TLR4 signalling36 (FIG. 2c).
This postnatal endotoxin tolerance may facilitate the
adaptation of the newborn to subsequent microbial
colonization and to support host–microbe homeostasis
that is required for commensal interactions39. In parallel,
the development of Paneth cells (which are a rich source
of APPs) in the small intestine of newborns contributes
to the clearance of bacteria such as E. coli40.
The developmental expression of neonatal intestinal
innate immunity is of substantial interest given the
emerging evidence for an important role of endotoxin
and intestinal TLR4 expression in the development
of necrotizing enterocolitis37,41, an intestinal disease that
occurs most frequently in pre-term newborns42. Thus,
the failure of pre-term neonates to appropriately down-
regulate responses to LPS seems to significantly contrib-
ute to their susceptibility to necrotizing enterocolitis.
Although it is currently unclear what role(s) intestinal
TLR4 may have in utero, its distinct functional expres-
sion at birth clearly has important roles in neonatal
intestinal health and disease.
Neonatal intestinal immunity can be significantly
modified by breastfeeding, and it is hypothesized that
the overall effect of breast-milk-mediated intestinal
immunomodulation results in sub-clinical infections
that gradually stimulate immunological memory to
pathogens while reducing inflammation43. Breast milk
contains diverse immunological factors, including
innate immune molecules such as the APPs, lacto ferrin
and lysozyme8,44,45. Human breast milk also contains
factors that can modulate TLR signalling, including
soluble TLR2, which can competitively inhibit signalling
through membrane TLR2 (REF. 46), as well as an ~80 kDa
protein that, by an as-yet-unknown mechanism, inhibits
TLR2-mediated and activates TLR4-mediated trans-
criptional responses in human intestinal epithelial and
mononuclear cells47. It has been speculated that reduced
TLR2 reactivity at birth may facilitate the normal estab-
lishment of beneficial Gram-positive bifidobacteria
intestinal flora. Newborns fed breast milk that contains
relatively low levels of soluble CD14, a protein that
mediates LPS signalling in the absence of membrane-
bound CD14, have a higher risk of subsequent allergy,
which has been interpreted as being consistent with the
hygiene hypothesis48. Therefore, enhanced responses to
endotoxin might be associated with a diminished risk of
The neonatal respiratory tract: TLR and APP expression.
Mouse studies have shown that expression of TLR2 and
TLR4 is almost undetectable in the lungs of an immature
fetus (gestational days 14–15, which is the equivalent of
~30 weeks of gestation in humans), but increases sever-
al-fold during prenatal development and after birth49.
There is also evidence of post-natal impairment of TLR2
and TLR4 expression in a rat model, as intra pulmonary
inflammatory responses, including leukocyte recruit-
ment, following intratracheal administration of LPS
or Gram-negative bacteria are impaired early in life
and do not approach adult levels until approximately
4 weeks of age50. Of note, exposure of epithelia to TLR
agonists (for example endotoxin) activates expression of
APPs through the production of IL-1β and consequent
induction of human β-defensin-2 (HBD2)51. Therefore,
expression of HBD2 (the predominant β-defensin in
the human neonatal lung) by the respiratory epithe-
lium is developmentally regulated and inducible by
IL-1β in a myeloid differentiation primary-response
gene 88 (MyD88)-dependent fashion52. Accordingly,
the abundance of HBD2 in human neonatal tracheal
aspirates increases with increasing gestational age. Of
note, age-dependent susceptibility of newborn piglets
to Bordetella pertussis bronchopneumonia correlates
Figure 1 | Expression of antimicrobial proteins and peptides (APPs) in utero.
The cervical plug, which contains many APPs, including lactoferrin and α-defensin
peptides, serves to separate the vagina, which is normally colonized with multiple
microorganisms, from the normally sterile intra-uterine compartment. The maternal–
fetal membranes of the placenta secrete various APPs into the amniotic fluid, including
lactoferrin, bactericidal/permeability-increasing protein (BPI), histones, phospholipase
A2 (PLA2) and α-defensins. The fetus itself has altered expression of APPs: whereas
expression of cathelicidin and β-defensin peptides by skin epithelium is increased,
cellular concentrations of BPI in neutrophils are reduced.
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© 2007 Nature Publishing Group
To portal circulation (liver)
Erythema toxicum rash
(NEC). A gastrointestinal
affecting premature low-birth-
weight infants. NEC involves
infection and inflammation that
causes destruction of the
intestine. Although the
pathophysiology of NEC is not
yet completely defined,
increasing evidence indicates
that immaturity of intestinal
innate immune function of the
premature gut, characterized
by over-exuberant interleukin-8
responses of intestinal
epithelial cells to
lipopolysaccharide, is a major
with developmentally regulated upper respiratory tract
expression of the porcine β-defensin 1 (pBD1) and
exogenous replacement with pBD1 protects against
B. pertussis infection53.
The relevance of neonatal respiratory innate immu-
nity to the (patho)physiology of the newborn is begin-
ning to emerge. Chorioamnionitis is an infection of the
placental membranes and amniotic fluid by bacteria
that express TLR agonists such as E. coli and group B
Streptococcus. Chorioamnionitis induces the production
of IL-6, a cytokine that enhances fetal-lung branching
morphogenesis, possibly providing a mechanism
by which the innate immune system can hasten the
development of respiratory function in the context of
infection-induced pre-term birth54. Of note, TLR-mediated
responses can be modulated by respiratory infection.
For example, Ureaplasma urealyticum, a mycoplasmal
organism that can colonize the neonatal respiratory tract
Figure 2 | Postnatal microbial colonization and the acute-phase response. Shortly after birth the newborn is
colonized by microbial flora. a | Neonatal skin is colonized by Gram-positive bacteria (for example, coagulase-negative
staphylococci) that often gain access to the skin through hair follicles and induce a benign rash known as erythema
toxicum. At sites of eythema toxicum rash, neonatal macrophages produce interleukin-1 (IL-1) and IL-6. b | IL-1 and
IL-6, through activation of the transcription factor CCAAT/enhancer-binding protein-α (C/EBPα), can contribute to
the acute-phase response, triggering hepatocyte production of plasma proteins, such as C-reactive protein (CRP),
lipopolysaccharide (LPS)-binding protein (LBP), soluble CD14 and mannose-binding lectin (MBL), which have roles in
the clearance and detoxification of microbes and microbial toxins. c | At (or soon after) birth the intestinal tract of the
newborn is first exposed to LPS that is derived from Gram-negative flora. Fetal (and pre-term neonatal) intestinal epithelial
cells have markedly enhanced inflammatory responses to LPS. Mouse studies indicate that in full-term newborns,
potentially harmful inflammatory responses to LPS are usually dampened by internalization of LPS by intestinal epithelial
cells that induces downregulation of IL-1-receptor-associated kinase 1 (IRAK 1), thereby contributing to intestinal
endotoxin tolerance. Such adaptations are central to the development of commensal relationships. CXCL2, CXC-
chemokine ligand 2; IκB, inhibitor of nuclear factor-κB; MyD88, myeloid differentiation primary-response gene 88.
382 | MAY 2007 | VOLUME 7
© 2007 Nature Publishing Group
Infection of the placental
tissues and amniotic fluid as a
result of ascending infection by
bacteria that can be present in
the vagina, such as Escherichia
coli and group B Streptococcus.
Chorioamnionitis can cause
maternal bacteremia and can
lead to pre-term delivery and
(BPD). A disease of the
respiratory system that is most
frequent in pre-term infants,
and is characterized by
inflammation and scarring of
the lungs resulting in abnormal
development of lung tissue.
Recent evidence shows that
inflammatory responses can
reproduce the pulmonary
characteristic of BPD, raising
the possibility that innate
immune responses may
contribute to its
and is associated with pre-term birth and abnormal lung
development55, has TLR2 and TLR4 agonist activity56,
and induces the production of TNF, both directly and in
synergy with LPS, from pre-term neonatal monocytes57.
Thus, this common pathogen may have important
pathophysiological roles. Moreover, injection of LPS
into the amniotic fluid of fetal mice at day 15 — when
TLR4 expression first appears — induces, over a 2-day
span, TLR4-mediated inflammatory responses that alter
airway fibronectin expression, potentially inhibiting
distal-airway branching and alveolarization58. In addi-
tion, activation of TLR2 or TLR4 in the developing
mouse lung inhibits the production of fibroblast growth
factor 10, thereby disrupting normal myofibroblast posi-
tioning in lung development59. Overall, these observa-
tions potentially link innate immune responses with the
abnormal fetal lung development that is characteristic of
The respiratory tract is an important route of expo-
sure for environmental adjuvants (aeroadjuvants) and
antigens (aeroallergens), and therefore has an important
role in modulating the balance of immune maturation.
Age-dependent changes in the innate immune response
of the respiratory tract are, therefore, likely to also be
relevant for the development of allergy. A seminal
study revealed that in nasal mucosa explants from
atopic children, but not atopic adults, LPS enhances
allergen-induced T-cell reactivity and/or proliferation,
the production of TH1-cell-polarizing cytokines, IL-10
production and TLR4 expression by lymphocytes60.
Therefore, in young children, LPS might inhibit aller-
gic inflammation by skewing local immune responses
from a TH2-cell to a TH1-cell response. Children who
have environmental exposure to muramic acids and/or
peptidoglycans (TLR2 agonists) have reduced risk of
wheezing (which is a symptom of reactive airways that
is predictive of asthma severity)61. Sterile house-dust
extracts have MyD88-dependent adjuvant activity,
which is TH2-cell polarizing when given as a weekly
intranasal vaccination (along with ovalbumin antigen)
but is actually tolerogenic when given daily as a low-dose
intranasal exposure16. From an epidemiological perspec-
tive, chronic exposure over the first 3 months of life to
farming, endotoxin contained in house dust (a TLR4
agonist) and household pets (such as cats and dogs) are
all associated with an enhanced ability of neonatal and
infant peripheral-blood cells to produce the TH1-cell-
polarizing cytokine interferon-γ (IFNγ) in response to
phorbol myristate acetate and concanavalin A62. These
observations indicate that certain patterns (for exam-
ple, dose, frequency or route) of exposure to microbial
TLR agonists early in life accelerate the maturation of
the TH1-cell response and protect against allergic and
atopic diseases, which is the essence of the hygiene
hypothesis18,63. Of note, it is increasingly recognized
that CD4+CD25+ regulatory T (TReg) cells, which inhibit
TH1-cell immunity thereby maintaining peripheral
T-cell tolerance, are particularly abundant and potent at
birth64. Moreover, TLR activation can enhance TH1-type
responses by reversing TReg-cell function by indirect
effects (through dendritic cell (DC)-derived IL-6)65 or by
direct effects (through activation of TLR8 on TReg cells)66.
Future work aimed at characterizing the developmental
expression of TLR-mediated effects on neonatal and
infant TReg cells will be of substantial interest in further
exploring and refining the hygiene hypothesis.
Overall, the innate immune mechanisms of the neo-
natal respiratory tract provide protection against microbial
infection and prevent over-exuberant inflammation, while
mediating the effects of environmental TLR agonists that
serve as aeroadjuvants to reduce the atopic potential of
Neonatal blood plasma: adenosine and acute-phase
products. The levels of multiple soluble plasma proteins
that have a role in innate immunity are lower in new-
borns than in adults. Neonatal plasma concentrations
of complement components are diminished compared
with those in adults, ranging from ~10–70% of adult
levels8. A deficiency in complement might contribute
to the inability of newborns to limit the replication of
many bacterial strains in the blood67 and, as complement
components also have a role in adaptive immunity68, it
might contribute to the impairment of neonatal adaptive
The metabolic state of the newborn, initially char-
acterized by low oxygen tension (that can be further
exacerbated by prolonged labour, uterine contractions
and/or fetal distress), modulates neonatal plasma con-
centrations of early-response cytokines. Such hypoxia
is known to increase the production of IL-6 and IL-8
(REF. 70), cytokines with important roles in labour,
while limiting production of TNF71. Endogenous
mediators are also elevated during hypoxia and/or
stress. Adenosine, an endogenous purine metabolite
Box 2 | The role of chemokines in the development of neonatal immunity
Chemokines and antimicrobial peptides are overlapping categories of host defence
molecules, as many chemoattractant cytokines often also possess direct antimicrobial
activity. In addition, many molecules that were originally characterized as
antimicrobial peptides are now known to also possess chemoattractant and other
immunomodulatory activities152,153. As such, chemokines and antimicrobial peptides
are an important link between innate and adaptive immunity. Of note, chemokines are
expressed in an age-dependent manner, have a role as early as embryonic
implantation154 and show gestational age-dependent expression155. Recent work in
an ovine model showed that fetal expression of CC-chemokine ligand 25 (CCL25;
expressed in the thymus and gut) and CCL28 (expressed in the large intestine, trachea,
tonsils and mammary gland), and their receptors, which are expressed in the thymus
and mucosal tissues, increase with gestational age156. By mediating lymphocyte
colonization of fetal tissues, chemokines might, therefore, have important roles
in the maturation of the fetal immune system.
Chemokines are also necessary for post-natal localization of lymphoid progenitors
to the thymus157 and secondary lymphoid tissues, including the mucosa-associated
lymphoid tissues. In a mouse model, impaired neonatal pulmonary chemokine
production corresponds to delayed clearance of Pneumocystis carinii pneumonia158.
Pre-term human neonates have particularly low basal serum levels of the chemokine
CCL5 (also known as RANTES)159. Influenza-virus-induced CCL3 production by full-
term human neonatal mononuclear cells is impaired160, and human newborns with
relatively lower levels of CCL3 production have an increased risk of perinatal HIV
transmission161. Certain chemokines, such as CXC-chemokine receptor 3 (CXCR3;
also known as IP10), are upregulated during neonatal bacterial infection, showing
potential use as diagnostic markers162.
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for which concentrations rise during hypoxia, has
immunomodulatory properties72 and is found at
relatively high concentrations in neonatal cord-blood
plasma where it inhibits TLR2-mediated TNF produc-
tion through the activation of A3 adenosine receptors
on neonatal mononuclear cells71 (discussed in greater
Plasma concentrations of multiple acute-phase
products that are derived from the liver change dra-
matically during the first days of life, probably reflect-
ing initial exposure of the newborn to microbes and
microbe-derived TLR agonists. Histological analysis
of erythema toxicum neonatorum lesions from human
newborns during the first week of life showed that skin
macrophages ingest bacteria and produce IL-1 (REF. 73),
and studies of neonatal blood plasma during this same
time frame showed rising plasma levels of IL-6, exceed-
ing basal adult blood plasma IL-6 levels12 (FIG. 2a). Both
IL-1 and IL-6 can trigger acute-phase responses by acti-
vating hepatocytes to synthesize and secrete an array of
acute-phase proteins. These include mannose-binding
lectin (MBL)74, soluble CD14 (REF. 75), C-reactive
protein (CRP) and LPS-binding protein (LBP)12, all of
which are initially low at birth but rise during the first
week of life (FIG. 2b).
Mouse studies have begun to define the transcrip-
tional control of the neonatal acute-phase response,
in that LPS- and IL-1-induced transcription of genes
encoding acute-phase proteins occurs through the
transcription factor CCAAT/enhancer-binding
protein-α (C/EBPα) and binding of signal transducer
and activator of transcription 3 (STAT3) to cognate
promoter sequences76 (FIG. 2b). Conversely, plasma con-
centrations of negative acute-phase plasma glycoproteins
such as prealbumin31 and fetuin, which suppresses TNF
production but preserves IL-6 production77, are initially
high at birth, then drop78–80. Given the role of multiple
acute-phase reactants, including LBP and soluble CD14
(which, at high or acute-phase concentrations actually
inhibit LPS activity)81, in the clearance and/or detoxifica-
tion of LPS and other TLR agonists, one might speculate
that the rapid activation of the acute-phase response
soon after birth may be directed at clearance of any
microbial products that have translocated across mucous
membranes during birth and/or initial colonization in
order to avoid excessive inflammation as the newborn
first meets the outside world.
Neutrophils: quantitative and qualitative defects.
Newborn mammals have a reduced number of quies-
cent granulocyte and monocyte progenitor cells and a
diminished precursor storage pool that can result in a
quantitative defect in neutrophil numbers during stress
conditions (for example, in sepsis). From a qualitative
standpoint, neonatal neutrophils show impairment
of multiple functional aspects, including chemotaxis,
rolling adhesion, transmigration and lamellipodia
formation82–84. Such functional defects correlate with
a relatively high proportion of immature neutrophils
in umbilical cord blood that show reduced expression
and function of complement receptor 3 (CR3; also
known as CD11b/CD18)85 and diminished expression
of L-selectin86. In general, as with other aspects of
immune function, these neutrophil defects are even
more pronounced with prematurity, but begin to cor-
rect within the first weeks of life82. Impaired recruit-
ment of neonatal neutrophils to inflammatory sites
might be related not only to diminished integrin and
selectin expression, but also to the propensity of neo-
natal monocytes and APCs to produce relatively large
amounts of IL-6 (REFS 12,87), a cytokine that inhibits
neutrophil migration to inflammatory sites88.
Neonatal neutrophils also exhibit impairments in
microbicidal mechanisms. These neutrophils contain
reduced amounts of some APPs, including lactoferrin
(~50% of adult levels)89 and BPI (~30% of adult levels)90,
but normal amounts of defensin peptides90. Reduced
expression of BPI correlated with diminished activity
of neonatal neutrophil extracts against Gram-negative
bacteria90. Neutrophils of pre-term newborns show
impaired upregulation of oxidase activity in response to
staphylococci, which are common neonatal pathogens91.
LPS-induced priming of neutrophils for enhanced oxi-
dase activity (in response to a second stimulus) is also
impaired in neutrophils from newborns, possibly owing
to diminished upregulation of membrane CD14 that
normally contributes to enhancement of LPS signal-
ling92. Compartmentalization of the protein tyrosine
kinase p53/56lyn in a membrane-granule fraction of neo-
natal neutrophils, as opposed to its cytosolic localization
in neutrophils from adults, may limit its mobility and
thereby diminish LPS priming of neutrophils from new-
borns93. Overall, neonatal defects in the amplification,
mobilization and function of the neutrophil response
have clinical relevance in that neutropaenia is a well-
described and ominous finding in newborns presenting
with bacterial sepsis1.
Monocytes and APCs. There are both quantitative and
qualitative differences between monocytes and APCs
from newborns and adults. Qualitative differences in
monocytes are evident in utero, as third-trimester pheno-
typing of fetal or neonatal circulating monocytes by flow
cytometry reveals that human fetal monocytes express
reduced levels of MHC class II molecules, which poten-
tially contributes to impaired APC activity94. Mouse
studies show that the neonatal DC system is immature,
and includes a distinct population of splenic DCs (having
a higher ratio of CD4–CD8α+ DCs to CD4+CD8α– DCs
compared with the adult DC system) and impaired
in vitro production of IL-12 p70 in response to a CpG
oligodeoxynucleotide motif (ODN 1668), a pattern that
normalized at ~5 weeks of age95. However, this defect in
APC activity may be stimulus-specific, in that a differ-
ent CpG motif (ODN 1826) stimulated CD11c+ splenic
DCs purified from 7-day-old newborn mice to produce
at least as much IL-12 p70 as their adult counterparts96.
Mouse CD5+ B cells may contribute to the impairment of
neonatal APC function by TLR9-mediated IL-10 produc-
tion, which inhibits IL-12 synthesis by neonatal DCs97.
Overall, reduced TH1-cell-polarizing fetal APC activity is
384 | MAY 2007 | VOLUME 7
© 2007 Nature Publishing Group
thought to be necessary to reduce the risk of alloimmune
reactions between mother and fetus, and phenotypic and
stimulus-specific functional immaturities are present at
birth in both mice and humans14,95,98–100.
The potential relevance of TLR expression in
neonatal health and disease includes the recent dem-
onstration that TLRs participate in the recognition
of microbial pathogens that are relevant to neonates,
including pathogens recognized by TLR2 (group B
Streptococcus84, Listeria monocytogenes, Mycoplasma
hominis101, C. albicans hyphae102 and cytomegalovirus102),
TLR4 (Enterobactericeae, C. albicans blastoconidia102,
and respiratory syncitial virus103) and, in mice, TLR11
(Toxoplasma gondii)104. In this context, the functional
maturation of TLR expression has been of substantial
interest. Cord-blood monocytes of pre-term humans
(25–37 weeks) have diminished basal TLR4 expression
but normal basal TLR2 expression compared with adult
peripheral-blood monocytes105. Several studies have
established that cord-blood monocytes that are derived
from full-term human newborns express comparable
amounts of TLRs to adult monocytes75,106.
Although basal TLR expression of full-term neo-
natal blood monocytes is similar to that of adults, the
functional consequences of neonatal TLR activation are
very different. It has been appreciated for some time that,
despite the presence of higher concentrations of mono-
cytes at birth, the addition of LPS to whole cord blood
from human newborns results in diminished production
of TNF compared with adult peripheral blood107. Indeed,
newborn-derived monocytes cultured in whole blood or
purified and cultured in autologous (newborn) blood
plasma show a 1–3-log impairment in TNF production
in response to agonists of TLR1–TLR7 (REFS 12,71,75).
Human neonatal APCs also have impaired production of
type I IFNs (that is, IFNα and IFNβ), including impaired
IFNα production by neonatal plasmacytoid DCs in
response to polyinosinic–polycytidylic acid (polyI:C; a
TLR3 agonist) and CpG (a TLR9 agoinst)108 and impaired
IFNβ production by neonatal monocyte-derived DCs in
response to LPS (a TLR4 agonist)109. Similarly, CpG ODN
fails to fully overcome the bias of neonatal mononuclear
cells towards the production of the TH2-cell-polarizing
cytokine IL-13 (REF. 110).
Such a pattern is not confined to microbial TLR
agonists: upon phagocytosis of necrotic cells, DCs from
neonates show impaired production of TNF, upregula-
tion of co-stimulatory molecules (CD80 and CD86) and
stimulation of T-cell proliferation when compared with
DCs from adults111. Neonatal mice injected subcutan-
eously with LPS show impaired IFNγ production and
delayed kinetics, but a greater peak, of TNF levels, as well
as impaired staphylococcal enterotoxin B (now known to
be a TLR2 agonist112)-induced TNF production113. This
and other studies indicate that neonatal monocytes and
APCs may have a greater impairment in TLR2-mediated,
rather than in TLR4-mediated, TNF production47,71.
Overall, upon birth, neonatal APCs manifest selective
impairments in the production of TH1-type immune
responses following innate immune recognition of
multiple exogenous and endogenous stimuli.
By contrast, TLR-mediated production of IL-6,
IL-10 and IL-23 by neonatal monocytes, macrophages
and myeloid DCs is actually enhanced relative to adult
cells12–14 (TABLE 1). Robust production of IL-23 by human
neonatal DCs is noteworthy in that it increases expres-
sion of IL-17 (REF. 13), a cytokine that can induce epi-
thelial antimicrobial peptides114, and expression of these
Table 1 | Polarization of TLR-mediated cytokine responses of neonatal cord-blood-derived monocytes and antigen-presenting cells
Effect of cAMP
General function CommentReferences
Pro-inflammatory; activates neutrophils;
Antiviral; contributes to vaccine
Activation of macrophages; induction of
IL-12; TH1-cell response
p40–p35 heterodimer activates cell-
mediated immunity; TH1-cell response
Endothelial adhesion; fever; acute-phase
Acute-phase response; inhibits tissue
neutrophilia; inhibits TReg cells and
promotes TH17 cells
TNF associated with spontaneous
abortion and pre-term labour
Important for MHC class I expression
Newborns have impaired killing of
Neonatal defect in p35 promoter
Newborn febrile response is blunted
May contribute to acute-phase
response at birth
Expression increased during
hypoxia; role in parturition
Blocking IL-10 can restore IL-1
IL-17 enhances epithelial expression
of antimicrobial peptides
Anti-inflammatory; inhibits TNF, IL-1
and IFNγ production
p40–p19 heterodimer promotes
↑, increased; ↓, decreased; ↔, unchanged; cAMP, cyclic AMP; IFN, interferon; IL, interleukin; TH, T helper; TLR, Toll-like receptor; TNF, tumour-necrosis factor;
TReg, T regulatory.
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© 2007 Nature Publishing Group
A disorder of posture and
movement due to damage
to motor areas of the brain,
often associated with a history
of perinatal complications.
The pathophysiology of
cerebral palsy is still under
investigation, but recent
evidence indicates that a
combination of hypoxic–
ischemic insult and Toll-like-
peptides is elevated at birth30. Importantly, the neonatal
bias away from TH1-cell-polarizing cytokine responses,
as reflected by a high ratio of IL-6 to TNF production by
mononuclear cells, is not only evident in the response
to individual TLR agonists12, but also to whole com-
mensal bacteria5 and to herpes simplex virus115 in vitro.
In line with these observations, a recent mouse model
of neo natal sepsis produced by generalized peritonitis
(through cecal slurry administration) showed mark-
edly diminished neonatal plasma TNF levels (<10% of
adult levels), but enhanced neonatal IL-6 production116.
Moreover, the bias of neonatal cytokine responses in
favour of IL-6 might also be relevant in vivo in human
newborns, as shown by a rising basal serum ratio of IL-6
to TNF, and of IL-6-inducible acute-phase reactants CRP
and LBP, during the first week of life12. Overall, the IL-6-
induced acute-phase response induced by birth, together
with a preserved IL-23–IL-17 axis, can be seen as mobi-
lizing both an external (mucosal and/or epithelial) and
internal (blood plasma) shield of anti-infective proteins
and peptides to protect the newborn against the risks of
infection upon initial microbial colonization.
The explanation of the distinct bias in neonatal
cytokine production relates to the potentially negative con-
sequences of excessive production of pro-inflammatory
cytokines such as TNF, including associations with
intra-uterine growth restriction117 and spontaneous
abortion10. In addition, emerging evidence indicates that
TLR-mediated pro-inflammatory cytokine induction by
microglia might contribute to central nervous system
damage in pre-term newborns that can culminate in
cerebral palsy118,119, providing further rationale for this
pattern of neonatal cytokine responses. Although such
polarization is therefore beneficial, it also comes at a
significant cost, leaving neonates particularly sensitive
to infection with a broad array of microorganisms,
including intracellular pathogens requiring efficient
pro-inflammatory TH1-cell responses for clearance,
such as L. monocytogenes and herpes simplex virus,
Although many studies have shown a distinct pattern
of neonatal cytokine production by monocytes and/or
APCs, few have addressed the mechanisms for such
differences as compared with adults. Recent evidence
Figure 3 | Mechanisms for distinct function of human neonatal monocytes and antigen-presenting cells.
a | High concentrations of adenosine, an endogenous immunomodulatory purine metabolite, in neonatal blood plasma
act through adenosine A3 receptors on neonatal mononuclear cells to induce high (~20-fold greater than adult levels)
intracellular concentrations of cyclic AMP (cAMP). cAMP is a secondary messenger that, through both protein kinase A
(PKA)-dependent and PKA–independent pathways, can inhibit Toll-like receptor 2 (TLR2)-mediated tumour-necrosis factor
(TNF) production while preserving production of interleukin-6 (IL-6). b | Neonatal monocytes have diminished expression of
myeloid differentiation primary-response gene 88 (MyD88), a key adaptor molecule for TLR-mediated signalling. c | Failure
of nucleosome remodelling of the Il12p35 gene promoter contributes to diminished TLR-mediated IL-12 p35 production
by neonatal dendritic cells (DCs), an example of distinct regulation of neonatal cytokine production at the chromatin level.
d | Lipopolysaccharide (LPS)-induced association of interferon (IFN)-regulatory factor 3 (IRF3) with cAMP-responsive-
element-binding protein (CREB)-binding protein (CBP) and IRF3 binding of DNA are reduced in human neonatal
monocyte-derived DCs, resulting in impaired expression of IFNβ. AP1, activator protein 1; NF-κB, nuclear factor-κB;
TBK1, TANK-binding kinase 1; TRAF, TNFR-associated factor; TRIF, TIR-domain-containing adaptor protein inducing IFNβ.
386 | MAY 2007 | VOLUME 7
© 2007 Nature Publishing Group
indicates that the distinct physiological state of neonatal
mononuclear cells at birth, including their exposure to
distinct humoral factors inherent to gestation and/or
birth, may substantially contribute to the polarization of
their TLR-mediated cytokine responses. Of note, human
neonatal cord-blood mononuclear cells contain ~20-fold
greater intracellular concentrations of the second mes-
senger cyclic AMP (cAMP)71, a molecule that can act
through both a protein kinase A (PKA)-dependent and
PKA-independent pathway to inhibit the stimulus (for
example LPS)-induced production of TNF72 (FIG. 3a).
cAMP may reduce TNF production through the inhibi-
tion of phosphorylation of p38 mitogen-activated protein
kinase (MAPK)121, a cytosolic signalling intermediate for
which activation is crucial for LPS-induced TNF pro-
duction122; the phosphorylation of p38 is impaired in
cord-blood monocytes from term and pre-term human
newborns123,124. Intriguingly, cAMP is also known to
inhibit the production of several other cytokines for
which production is impaired in newborns (such as
IFNα, IFNγ and IL-12), while preserving or enhancing
the expression of cytokines that neonatal monocytes
and APCs produce in abundance (for example IL-6,
IL-10 and IL-23)125. Therefore, the elevated intracellular
cAMP concentrations of neonatal cells might provide
a general physiological mechanism that contributes to
the polarization of TLR-mediated cytokine responses by
neonatal monocytes13,71 (TABLE 1). This ‘cAMP hypoth-
esis’ remains to be proven, and the postnatal duration
of the high cytosolic cAMP content of neonatal mono-
nuclear cells remains to be defined. Nevertheless, even
if limited in effect to the immediate perinatal period,
such cAMP-mediated polarization during initial expo-
sure to microbes (including maternal-derived urinary
and enteric microorganisms) and antigens might have
profound effects on early immune responses.
Additional mechanisms, which are not mutually
exclusive, for the polarization of neonatal TLR-mediated
responses have been identified. Although human neo-
natal cord-blood monocytes contain normal levels of
mRNA of the TLR adaptor molecule MyD88 (REF. 75),
expression of the MyD88 protein is reduced, possibly
contributing to impaired TLR-mediated TNF produc-
tion106,124 (FIG. 3b). Of interest, regulation of neonatal
APC cytokine responses also occurs downstream of
cytosolic signalling pathways, in that regulation of IL-12
expression by human neonatal monocyte-derived DCs
is limited by a defect in nucleosome remodelling126
(FIG. 3c). Although many aspects of transcription-factor
binding to relevant cis-acting elements of the IL-12 p35
promoter are similar in DCs from adults and newborns,
chromatin-accessibility assays reveal that LPS-induced
nucleosome remodelling, required for effective func-
tioning of the upstream SP1 transcription factor sites,
is substantially impaired in neonatal DCs. Therefore,
neonatal IL-12 p35 gene transcription is repressed at the
chromatin level. Of note, administration of IFNγ, possi-
bly acting through IFNγ-activated transcription factors,
restored both nucleosome remodelling and IL-12 p35
gene transcription in vitro, indicating that the modula-
tion of nucleosome remodelling is central to efficient
activation of neonatal APCs126. Impaired LPS-induced
production of IFNβ by neonatal monocyte-derived DCs
is associated with impaired interaction of IFN-regulatory
factor 3 (IRF3) with cAMP-responsive-element-binding
protein (CREB)-binding protein (CBP)109 (FIG. 3d).
There are some exceptions to the general neo natal
impairment in TH1-cell-polarizing responses to micro-
bial agonists. Although neonatal monocytes and APCs
show impaired production of TH1-cell-polarizing
cytokines to agonists of TLR1–TLR7 (REF. 75), agonists
of TLR8 (or TLR7 and TLR8), such as small antiviral
imidazoquinoline compounds that are purine analogues
and single-stranded viral RNAs, induce robust (compar-
able to adults) production of TNF and IL-12/IL-23 p40
by these cells, as well as upregulation of the expression
of CD40 by neonatal myeloid DCs75,100. These strong
adjuvant effects correlate with the ability of agonists
of TLR8 (or TLR7 and TLR8) to robustly induce p38
MAPK phosphory lation and prolong the degradation
of IκB (inhibitor of NF-κB)100. Similarly, certain CpG
ODNs can enhance neonatal TH1-cell responses127, and
are protective against neonatal lethality in a mouse
model when co-administered as an immunostimulatory
agent at the time of neurotropic Tacaribe arenavirus
Whole group B streptococci, through robust activa-
tion of the alternative complement pathway and engage-
ment of integrin-based complement receptors, induce
marked TNF production by neonatal cord-blood mono-
cytes that is equivalent to that of adult monocytes129.
Mycobacterium bovis bacillus Calmette–Guérin (BCG)
is an example of one of the few vaccines that are active
at birth and can induce a strong TH1-cell-polarizing
cytokine response, including the expression of IFNγ, by
CD4+ T cells in response to a mycobacterial purified-
protein derivative (PPD)130. These examples indicate that
stimuli with certain characteristics, including the abil-
ity to effectively activate certain TLR pathways and/or
the complement system, are able to overcome neonatal
impairments and induce robust production of TH1-cell-
polarizing cytokines. The mechanisms, teleology and
potential translational implications for preservation of
neonatal TH1-cell responses to such stimuli remain to
be fully explored.
From a basic standpoint, much remains to be learned
about the distinct functional expression and age-
dependent maturation of innate immune molecules at
birth. Unravelling the relationships between distinct
aspects of neonatal humoral and cellular immunity,
including the impact of physiological mediators on
neonatal cellular responses, will enhance our mecha-
nistic understanding of the innate immune system of
the newborn. The microbiological and immunological
events during the first days of life, including establish-
ment of a commensal gut flora, probably impact on
health, infection and allergy. What are the implica-
tions of the acute-phase response that is initiated at
birth? What impact does this have on the newborn’s
first responses to antigens and microbes? How do
NATURE REVIEWS | IMMUNOLOGY
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© 2007 Nature Publishing Group
such responses affect adaptive immunity? The impact
of genetic variation in innate immune molecules on
susceptibility of newborns to infection will also be of
Owing to the important role of innate immunity
in neonatal health and disease, the intense biopharma-
ceutical development of molecules that are derived
from or that modulate the innate immune system,
including antimicrobial proteins and peptides and TLR
agonists, is likely to have clinical relevance to neonatal
medicine. Given the limited manner (that is, the lim-
ited range of symptoms) by which neonates manifest
a broad array of diseases, one area of unmet medical
need is the development of efficient diagnostic markers
that can distinguish infection from other causes of neo-
natal inflammation and/or clinical deterioration132. The
acute-phase reactant CRP is already used in this con-
text, and additional innate immune markers, including
surface expression of neutrophil TLRs133, are also under
evaluation for this purpose.
Clinical trials of granulocyte/monocyte colony-
stimulating factor (GM-CSF) to enhance the quantity
and quality of neonatal neutrophils and monocytes
have not yet shown a significant clinical benefit, but
further clinical evaluation focusing on a subpopulation
of pre-term newborns at high risk for severe neutro-
paenia is on-going134. The evaluation of recombinant
APPs as adjunctive therapy for neonatal infection is
also proceeding23. TLR agonists might represent tools to
enhance the defence against microorganisms128,135,136 or
to shift innate immune responses of neonatal APCs away
from the production of TH2-cell-polarizing cytokines,
thereby potentially reducing allergy24. Finally, as birth
is a relatively reliable point of contact with health-care
systems worldwide, and therefore vaccines given at
birth reach a relatively high proportion of the popula-
tion137, the potential of certain TLR agonists capable
of efficiently activating TH1-cell-polarizing responses
from neonatal APCs are of substantial interest as novel
neonatal vaccine adjuvants69,100,138.
Klein, J. & Remington, J. in Infectious Diseases of
the Fetus and Newborn Infant (eds Remington, J. &
Klein, J.) 1–23 (W. B. Saunders Company, Philadelphia,
McDonagh, S. et al. Viral and bacterial pathogens
at the maternal–fetal interface. J. Infect. Dis.
190, 826–834 (2004).
Makhseed, M. et al. Th1 and Th2 cytokine profiles in
recurrent aborters with successful pregnancy and with
subsequent abortions. Hum. Reprod. 16, 2219–2226
Marchini, G. et al. Erythema toxicum neonatorum is
an innate immune response to commensal microbes
penetrated into the skin of the newborn infant.
Pediatr. Res. 58, 613–616 (2005).
This paper reveals that erythema toxicum lesions
contain common Gram-positive bacteria (coagulase-
negative staphylococci) that penetrate the skin
through hair follicles to recruit APCs, correlating
with increases in body temperature that are
consistent with an acute-phase response at birth.
Karlsson, H., Hessle, C. & Rudin, A. Innate immune
responses of human neonatal cells to bacteria from
the normal gastrointestinal flora. Infect. Immun.
70, 6688–6696 (2002).
Adkins, B., Leclerc, C. & Marshall-Clarke, S.
Neonatal adaptive immunity comes of age.
Nature Rev. Immunol. 4, 553–564 (2004).
Krishnan, S., Craven, M., Welliver, R. C., Ahmad, N. &
Halonen, M. Differences in participation of innate and
adaptive immunity to respiratory syncytial virus in
adults and neonates. J. Infect. Disease 188, 433–439
Firth, M. A., Shewen, P. E. & Hodgins, D. C.
Passive and active components of neonatal innate
immune defenses. Anim. Health Res. Rev. 6, 143–158
Janeway, C. A., Jr. & Medzhitov, R. Innate immune
recognition. Annu. Rev. Immunol. 20, 197–216
10. Vitoratos, N. et al. Elevated circulating IL-1β and
TNF-α, and unaltered IL-6 in first-trimester pregnancies
complicated by threatened abortion with an adverse
outcome. Mediators Inflamm. 2006, 1–6 (2006).
11. Marodi, L. Innate cellular immune responses in
newborns. Clin. Immunol. 118, 137–144 (2006).
12. Angelone, D. et al. Innate immunity of the human
newborn is polarized toward a high ratio of
IL-6/TNF-α production in vitro and in vivo. Pediatr.
Res. 60, 205–209 (2006).
This paper shows that in vitro TLR-mediated
responses by monocytes from human newborns,
as well as basal (in vivo) neonatal plasma, are
characterized by low levels of TNF but high levels
13. Vanden Eijnden, S., Goriely, S., De Wit, D., Goldman,
M. & Willems, F. Preferential production of the
IL-12(p40)/IL-23(p19) heterodimer by dendritic cells
from human newborns. Eur. J. Immunol. 36, 21–26
14. Chelvarajan, R. L. et al. Defective macrophage
function in neonates and its impact on
unresponsiveness of neonates to polysaccharide
antigens. J. Leukoc. Biol. 75, 982–994 (2004).
15. Siegrist, C. A. Vaccination in the neonatal period and
early infancy. Int. Rev. Immunol. 19, 195–219 (2000).
16. Ng, N., Lam, D., Paulus, P., Batzer, G. & Horner, A. A.
House dust extracts have both TH2 adjuvant and
tolerogenic activities. J. Allergy Clin. Immunol.
117, 1074–1081 (2006).
17. Bach, J. F. The effect of infections on susceptibility to
autoimmune and allergic diseases. N. Engl. J. Med.
347, 911–920 (2002).
18. Liu, A. H. & Leung, D. Y. Renaissance of the hygiene
hypothesis. J. Allergy Clin. Immunol. 117, 1063–1066
19. Imler, J. L. & Hoffmann, J. A. Toll receptors in innate
immunity. Trends Cell Biol. 11, 304–311 (2001).
20. Doyle, S. L. & O’Neill L. A. Toll-like receptors: From the
discovery of NFκB to new insights into transcriptional
regulations in innate immunity. Biochem. Pharmacol.
72, 1102–1113 (2006).
21. Akira, S. Mammalian Toll-like receptors. Curr. Opin.
Immunol. 15, 5–11 (2003).
22. Ganz, T. Antimicrobial polypeptides. J. Leukoc. Biol.
75, 34–38 (2004).
23. Levy, O. Antimicrobial proteins and peptides:
anti-infective molecules of mammalian leukocytes.
J. Leukoc. Biol. 76, 909–925 (2004).
24. Fasciano, S. & Li, L. Intervention of Toll-like receptor-
mediated human innate immunity and inflammation
by synthetic compounds and naturally occurring
products. Curr. Med. Chem. 13, 1389–1395 (2006).
25. Larson, A. A. & Dinulos, J. G. Cutaneous bacterial
infections in the newborn. Curr. Opin. Pediatr.
17, 481–485 (2005).
26. Tollin, M. et al. Vernix caseosa as a multi-component
defence system based on polypeptides, lipids and their
interactions. Cell. Mol. Life Sci. 62, 2390–2399
27. Zasloff, M. Vernix, the newborn, and innate defense.
Pediatr. Res. 53, 203–204 (2003).
28. Yoshio, H. et al. Antimicrobial polypeptides of human
vernix caseosa and amniotic fluid: implications for
newborn innate defense. Pediatr. Res. 53, 211–216
29. Tollin, M., Jagerbrink, T., Haraldsson, A., Agerberth, B.
& Jornvall, H. Proteome analysis of vernix caseosa.
Pediatr. Res. 60, 430–434 (2006).
30. Dorschner, R. A., Lin, K. H., Murakami, M. &
Gallo, R. L. Neonatal skin in mice and humans
expresses increased levels of antimicrobial peptides:
innate immunity during development of the adaptive
response. Pediatr. Res. 53, 566–572 (2003).
Shows that at birth, neonatal skin epithelia express
increased levels of the antimicrobial peptides
β-defensin and cathelicidin.
31. Marchini, G., Berggren, V., Djilali-Merzoug, R. &
Hansson, L. O. The birth process initiates an acute
phase reaction in the fetus–newborn infant.
Acta Paediatr. 89, 1082–1086 (2000).
32. Angelone, D. F. et al. Innate immunity of the
human newborn is polarized toward a high ratio of
IL-6/TNF-α production in vitro and in vivo. Pediatr.
Res. 60, 205–209 (2006).
33. Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling
in the gut in health and disease. J. Immunol.
174, 4453–4460 (2005).
34. Fusunyan, R. D., Nanthakumar, N. N., Baldeon, M. E.
& Walker, W. A. Evidence for an innate immune
response in the immature human intestine:
toll-like receptors on fetal enterocytes. Pediatr. Res.
49, 589–593 (2001).
35. Gioannini, T. L. et al. Isolation of an endotoxin–MD-2
complex that produces Toll-like receptor 4-dependent
cell activation at picomolar concentrations. Proc. Natl
Acad. Sci. USA 101, 4186–4191 (2004).
36. Lotz, M. et al. Postnatal acquisition of endotoxin
tolerance in intestinal epithelial cells. J. Exp. Med.
203, 973–984 (2006).
A landmark study revealing a mechanism by
which initial intestinal endotoxin exposure at
birth downregulates subsequent responses,
paving the way for commensal interactions.
37. Nanthakumar, N. N., Fusunyan, R. D., Sanderson, I. &
Walker, W. A. Inflammation in the developing human
intestine: a possible pathophysiologic contribution to
necrotizing enterocolitis. Proc. Natl Acad. Sci. USA
97, 6043–6048 (2000).
38. Fanaro, S., Chierici, R., Guerrini, P. & Vigi, V.
Intestinal microflora in early infancy: composition
and development. Acta Paediatr. 91 (Suppl.), 48–55
39. Rakoff-Nahoum, S. & Medzhitov, R. Role of the
innate immune system and host-commensal
mutualism. Curr. Top. Microbiol. Immunol.
308, 1–18 (2006).
40. Sherman, M. P., Bennett, S. H., Hwang, F. F.,
Sherman, J. & Bevins, C. L. Paneth cells and
antibacterial host defense in neonatal small
intestine. Infect. Immun. 73, 6143–6146
41. Jilling, T. et al. The roles of bacteria and TLR4 in
rat and murine models of necrotizing enterocolitis.
J. Immunol. 177, 3273–3282 (2006).
42. Lin, P. W. & Stoll, B. J. Necrotising enterocolitis.
Lancet 368, 1271–1283 (2006).
43. Newburg, D. S. & Walker, W. A. Protection of
the neonate by the innate immune system of
developing gut and of human milk. Pediatr. Res.
61, 2–8 (2007).
388 | MAY 2007 | VOLUME 7
© 2007 Nature Publishing Group
44. Labbok, M. H., Clark, D. & Goldman, A. S.
Breastfeeding: maintaining an irreplaceable
immunological resource. Nature Rev. Immunol.
4, 565–572 (2004).
45. Armogida, S. A., Yannaras, N. M., Melton, A. L. &
Srivastava, M. D. Identification and quantification
of innate immune system mediators in human breast
milk. Allergy Asthma Proc. 25, 297–304 (2004).
46. LeBouder, E. et al. Soluble forms of Toll-like receptor
(TLR)2 capable of modulating TLR2 signaling are
present in human plasma and breast milk. J. Immunol.
171, 6680–6689 (2003).
47. LeBouder, E. et al. Modulation of neonatal microbial
recognition: TLR-mediated innate immune responses
are specifically and differentially modulated by human
milk. J. Immunol. 176, 3742–3752 (2006).
48. Jones, C. A. et al. Reduced soluble CD14 levels in
amniotic fluid and breast milk are associated with the
subsequent development of atopy, eczema, or both.
J. Allergy Clin. Immunol. 109, 858–866 (2002).
49. Harju, K., Glumoff, V. & Hallman, M. Ontogeny of
Toll-like receptors Tlr2 and Tlr4 in mice. Pediatr. Res.
49, 81–83 (2001).
50. Martin, T. R., Ruzinski, J. T., Wilson, C. B. &
Skerrett, S. J. Effects of endotoxin in the lungs of
neonatal rats: age-dependent impairment of the
inflammatory response. J. Infect. Dis. 171, 134–144
51. Liu, L., Roberts, A. A. & Ganz, T. By IL-1 signaling,
monocyte-derived cells dramatically enhance the
epidermal antimicrobial response to lipopolysaccharide.
J. Immunol. 170, 575–580 (2003).
52. Starner, T. D., Agerberth, B., Gudmundsson, G. H. &
McCray, P. B., Jr. Expression and activity of β-defensins
and LL-37 in the developing human lung. J. Immunol.
174, 1608–1615 (2005).
53. Elahi, S. et al. The host defense peptide β-defensin 1
confers protection against Bordetella pertussis in
newborn piglets. Infect. Immun. 74, 2338–2352
Impressive correlation of β-defensin expression in
neonatal respiratory epithelium and resistance to
B. pertussis infection.
54. Nogueira-Silva, C., Santos, M., Baptista, M. J.,
Moura, R. S. & Correia-Pinto, J. IL-6 is constitutively
expressed during lung morphogenesis and
enhances fetal lung explant branching. Pediatr. Res.
60, 530–536 (2006).
55. Schelonka, R. L., Katz, B., Waites, K. B. &
Benjamin, D. K., Jr. Critical appraisal of the role of
Ureaplasma in the development of bronchopulmonary
dysplasia with metaanalytic techniques. Pediatr.
Infect. Dis. J. 24, 1033–1039 (2005).
56. Peltier, M. R., Freeman, A. J., Mu, H. H. & Cole, B. C.
Characterization of the macrophage-stimulating
activity from Ureaplasma urealyticum. Am. J. Reprod.
Immunol. 57, 186–192 (2007).
57. Manimtim, W. M. et al. Ureaplasma urealyticum
modulates endotoxin-induced cytokine release by
human monocytes derived from preterm and term
newborns and adults. Infect. Immun. 69, 3906–3915
58. Prince, L. S., Dieperink, H. I., Okoh, V. O.,
Fierro-Perez, G. A. & Lallone, R. L. Toll-like receptor
signaling inhibits structural development of the distal
fetal mouse lung. Dev. Dyn. 233, 553–561 (2005).
59. Benjamin, J. T. et al. FGF-10 is decreased in
bronchopulmonary dysplasia and suppressed
by Toll-like receptor activation. Am. J. Physiol.
Lung Cell. Mol. Physiol. 292, L550–L558 (2007).
60. Tulic, M. K. et al. Role of toll-like receptor 4 in
protection by bacterial lipopolysaccharide in
the nasal mucosa of atopic children but not adults.
Lancet 363, 1689–1697 (2004).
61. van Strien, R. T. et al. Microbial exposure of rural
school children, as assessed by levels of N-acetyl-
muramic acid in mattress dust, and its association
with respiratory health. J. Allergy Clin. Immunol.
113, 860–867 (2004).
62. Roponen, M., Hyvarinen, A., Hirvonen, M. R.,
Keski-Nisula, L. & Pekkanen, J. Change in IFN-γ-
producing capacity in early life and exposure to
environmental microbes. J. Allergy Clin. Immunol.
116, 1048–1052 (2005).
63. Vercelli, D. Mechanisms of the hygiene hypothesis —
molecular and otherwise. Curr. Opin. Immunol.
18, 733–737 (2006).
64. Godfrey, W. R. et al. Cord blood CD4+CD25+-derived
T regulatory cell lines express FoxP3 protein and
manifest potent suppressor function. Blood
105, 750–758 (2005).
65. Pasare, C. & Medzhitov, R. Toll pathway-dependent
blockade of CD4+CD25+ T cell-mediated suppression
by dendritic cells. Science 299, 1033–1036 (2003).
66. Peng, G. et al. Toll-like receptor 8-mediated reversal
of CD4+ regulatory T cell function. Science
309, 1380–1384 (2005).
67. Levy, O. et al. Enhancement of neonatal innate
defense: effects of adding an N-terminal recombinant
fragment of bactericidal/permeability-increasing
protein (rBPI21) on growth and TNF-inducing activity of
Gram-negative bacteria tested in neonatal cord blood
ex vivo. Infect. Immun. 68, 5120–5125 (2000).
68. Carroll, M. C. The complement system in B cell
regulation. Mol Immunol 41, 141–146 (2004).
69. Pihlgren, M. et al. Influence of complement C3
amount on IgG responses in early life: immunization
with C3b-conjugated antigen increases murine
neonatal antibody responses. Vaccine 23, 329–335
70. Jokic, M. et al. Fetal distress increases interleukin-6
and interleukin-8 and decreases tumour necrosis
factor-α cord blood levels in noninfected full-term
neonates. Br. J. Ob. Gyn. 107, 420–425 (2000).
71. Levy, O. et al. The adenosine system selectively
inhibits TLR-mediated TNF-α production in the human
newborn. J. Immunol. 177, 1956–1966 (2006).
Shows, in human neonatal cord blood, that
high plasma adenosine levels and increased
mononuclear-cell sensitivity to adenosine
action results in greatly increased cellular
cAMP concentrations that impair TLR2-mediated
TNF production but preserve production of IL-6.
72. Hasko, G. & Cronstein, B. N. Adenosine:
an endogenous regulator of innate immunity.
Trends Immunol. 25, 33–39 (2004).
73. Marchini, G. et al. Erythema toxicum neonatorum:
an immunohistochemical analysis. Pediatr. Dermatol.
18, 177–187 (2001).
74. Aittoniemi, J. et al. Age-dependent variation in
the serum concentration of mannan-binding protein.
Acta Paediatr. 85, 906–909 (1996).
75. Levy, O. et al. Selective impairment of Toll-like
receptor-mediated innate immunity in human
newborns: neonatal blood plasma reduces
monocyte TNF-α induction by bacterial lipopeptides,
lipopolysaccharide, and imiquimod but preserves
response to R-848. J. Immunol. 173, 4627–4634
76. Burgess-Beusse, B. L. & Darlington, G. J. C/EBPα
is critical for the neonatal acute-phase response to
inflammation. Mol. Cell Biol. 18, 7269–7277 (1998).
77. Gangneux, C. et al. The inflammation-induced down-
regulation of plasma Fetuin-A (α2HS-Glycoprotein)
in liver results from the loss of interaction between
long C/EBP isoforms at two neighbouring binding
sites. Nucleic Acids Res. 31, 5957–5970 (2003).
78. Dziegielewska, K. M., Andersen, N. A. &
Saunders, N. R. Modification of macrophage
response to lipopolysaccharide by fetuin. Immunol.
Lett. 60, 31–35 (1998).
79. Dziegielewska, K. M. & Andersen, N. A. The fetal
glycoprotein, fetuin, counteracts ill-effects of the
bacterial endotoxin, lipopolysaccharide, in pregnancy.
Biol. Neonate 74, 372–375 (1998).
80. Ombrellino, M. et al. Fetuin, a negative acute
phase protein, attenuates TNF synthesis and the
innate inflammatory response to carrageenan.
Shock 15, 181–185 (2001).
81. Kitchens, R. L. & Thompson, P. A. Modulatory effects
of sCD14 and LBP on LPS–host cell interactions.
J. Endotoxin Res. 11, 225–229 (2005).
82. Carr, R. Neutrophil production and function in
newborn infants. Br. J. Haematol. 110, 18–28
83. Urlichs, F. & Speer, C. P. Neutrophil function in
preterm and term infants. Neonatology Rev.
5, e417–e430 (2004).
84. Henneke, P. & Berner, R. Interaction of neonatal
phagocytes with group B streptococcus: recognition
and response. Infect. Immun. 74, 3085–3095
85. Reddy, R. K., Xia, Y., Hanikýrová, M. & Ross, G. D. A
mixed population of immature and mature leucocytes
in umbilical cord blood results in a reduced expression
and function of CR3 (CD11b/CD18). Clin. Exper.
Immunol. 114, 462–467 (1998).
86. Rebuck, N., Gibson, A. & Finn, A. Neutrophil adhesion
molecules in term and premature infants: normal or
enhanced leucocyte integrins but defective L-selectin
expression and shedding. Clin. Exper. Immunol.
101, 183–189 (1995).
87. Schultz, C. et al. Enhanced interleukin-6 and
interleukin-8 synthesis in term and preterm infants.
Pediatr. Res. 51, 317–322 (2002).
88. Jones, S. A. Directing transition from innate
to acquired immunity: defining a role for IL-6.
J. Immunol. 175, 3463–3468 (2005).
89. Ambruso, D. R., Bentwood, B., Henson, P. M. &
Johnston, R. B., Jr. Oxidative metabolism of cord
blood neutrophils: relationship to content and
degranulation of cytoplasmic granules. Pediatr.
Res. 18, 1148–1153 (1984).
90. Levy, O. et al. Impaired innate immunity in the
newborn: newborn neutrophils are deficient in
bactericidal/permeability-increasing protein (BPI).
Pediatrics 104, 1327–1333 (1999).
91. Bjorkqvist, M., Jurstrand, M., Bodin, L., Fredlund, H.
& Schollin, J. Defective neutrophil oxidative burst in
preterm newborns on exposure to coagulase-negative
staphylococci. Pediatr. Res. 55, 966–971 (2004).
92. Qing, G., Rajaraman, K. & Bortolussi, R. Diminished
priming of neonatal polymorphonuclear leukocytes by
lipopolysaccharide is associated with reduced CD14
expression. Infect. Immun. 63, 248–252 (1995).
93. Yan, S. R., Byers, D. M. & Bortolussi, R. Role of
protein tyrosine kinase p53/56lyn in diminished
lipopolysaccharide priming of formylmethionylleucyl —
phenylalanine-induced superoxide production
in human newborn neutrophils. Infect. Immun.
72, 6455–6462 (2004).
94. Jones, C. A., Holloway, J. A. & Warner, J. O.
Phenotype of fetal monocytes and B lymphocytes
during the third trimester of pregnancy. J. Reprod.
Immunol. 56, 45–60 (2002).
95. Dakic, A. et al. Development of the dendritic
cell system during mouse ontogeny. J. Immunol.
172, 1018–1027 (2004).
96. Sun, C. M., Fiette, L., Tanguy, M., Leclerc, C. &
Lo-Man, R. Ontogeny and innate properties of
neonatal dendritic cells. Blood 102, 585–591 (2003).
97. Sun, C. M., Deriaud, E., Leclerc, C. & Lo-Man, R.
Upon TLR9 signaling, CD5+ B cells control the
IL-12-dependent Th1-priming capacity of neonatal
DCs. Immunity 22, 467–477 (2005).
98. Hunt, D. W., Huppertz, H. I., Jiang, H. J. & Petty, R. E.
Studies of human cord blood dendritic cells: evidence
for functional immaturity. Blood 84, 4333–4343
99. Darmochwal-Kolarz, D. et al. CD1c+ immature
myeloid dendritic cells are predominant in cord
blood of healthy neonates. Immunol. Lett. 91, 71–74
100. Levy, O., Suter, E. E., Miller, R. L. & Wessels, M. R.
Unique efficacy of Toll-like receptor 8 agonists in
activating human neonatal antigen-presenting cells.
Blood 108, 1284–1290 (2006).
101. Peltier, M. R., Freeman, A. J., Mu, H. H. &
Cole, B. C. Characterization and partial purification
of a macrophage-stimulating factor from Mycoplasma
hominis. Am. J. Reprod. Immunol. 54, 342–351
102. van der Graaf, C. A., Netea, M. G., Verschueren, I.,
van der Meer, J. W. & Kullberg, B. J. Differential
cytokine production and Toll-like receptor signaling
pathways by Candida albicans blastoconidia and
hyphae. Infect. Immun. 73, 7458–7464 (2005).
103. Kurt-Jones, E. A. et al. Pattern recognition receptors
TLR4 and CD14 mediate response to respiratory
syncytial virus. Nature Immunol. 1, 398–401
104. Yarovinsky, F. et al. TLR11 activation of dendritic
cells by a protozoan profilin-like protein. Science
308, 1626–1629 (2005).
105. Forster-Waldl, E. et al. Monocyte toll-like receptor 4
expression and LPS-induced cytokine production
increase during gestational aging. Pediatr. Res.
58, 121–124 (2005).
106. Yan, S. R. et al. Role of MyD88 in diminished
tumor necrosis factor alpha production by newborn
mononuclear cells in response to lipopolysaccharide.
Infect. Immun. 72, 1223–1229 (2004).
107. Cohen, L. et al. CD14-independent responses to LPS
require a serum factor that is absent from neonates.
J. Immunol. 155, 5337–5342 (1995).
108. De Wit, D. et al. Blood plasmacytoid dendritic cell
responses to CpG oligodeoxynucleotides are impaired
in human newborns. Blood 103, 1030–1032 (2004).
109. Aksoy, E. et al. Interferon regulatory factor
3-dependent responses to lipopolysaccharide are
selectively blunted in cord blood cells. Blood 30
November 2006 (doi:10.1182/blood-2006-06-
NATURE REVIEWS | IMMUNOLOGY
VOLUME 7 | MAY 2007 | 389
© 2007 Nature Publishing Group
110. Prescott, S. L. et al. Cytosine-phosphate-guanine Download full-text
motifs fail to promote T-helper type 1-polarized
responses in human neonatal mononuclear cells.
Clin. Exp. Allergy 35, 358–366 (2005).
111. Wong, O. H., Huang, F. P. & Chiang, A. K. Differential
responses of cord and adult blood-derived dendritic
cells to dying cells. Immunology 116, 13–20 (2005).
112. Mandron, M. et al. Human dendritic cells conditioned
with Staphylococcus aureus enterotoxin B promote
TH2 cell polarization. J. Allergy Clin. Immunol.
117, 1141–1147 (2006).
113. Cusumano, V. et al. Neonatal hypersusceptibility
to endotoxin correlates with increased tumor
necrosis factor production in mice. J. Infect. Disease
176, 168–176 (1997).
114. Kao, C. Y. et al. IL-17 markedly up-regulates
β-defensin-2 expression in human airway epithelium
via JAK and NF-κB signaling pathways. J. Immunol.
173, 3482–3491 (2004).
115. Kurt-Jones, E. A. et al. The role of toll-like receptors
in herpes simplex infection in neonates. J. Infect.
Dis. 191, 746–748 (2005).
116. Wynn, J. et al. Increased mortality and altered
immunity in neonatal sepsis produced by generalized
peritonitis. Shock (in the press).
117. Xu, D. X. et al. Tumor necrosis factor α partially
contributes to lipopolysaccharide-induced intra-
uterine fetal growth restriction and skeletal
development retardation in mice. Toxicol. Lett.
163, 20–29 (2006).
118. Lehnardt, S. et al. Activation of innate immunity in
the CNS triggers neurodegeneration through a Toll-
like receptor 4-dependent pathway. Proc. Natl Acad.
Sci. USA 100, 8514–8519 (2003).
119. Sherwin, C. & Fern, R. Acute lipopolysaccharide-
mediated injury in neonatal white matter glia:
role of TNF-α, IL-1β, and calcium. J. Immunol.
175, 155–161 (2005).
120. Lewis, D. B. & Wilson, C. B. in Infectious Diseases of
the Fetus and Newborn Infant (eds Remington, J. &
Klein, J.) 25–138 (W. B. Saunders, Philadelphia,
121. Zhang, J., Bui, T. N., Xiang, J. & Lin, A. Cyclic AMP
inhibits p38 activation via CREB-induced dynein
light chain. Mol. Cell. Biol. 26, 1223–1234
122. Ajizian, S. J., English, B. K. & Meals, E. A. Specific
inhibitors of p38 and extracellular signal-regulated
kinase mitogen-activated protein kinase pathways
block inducible nitric oxide synthase and tumor
necrosis factor accumulation in murine macrophages
stimulated with lipopolysaccharide and interferon-γ.
J. Infect. Disease 179, 939–944 (1999).
123. Levy, O. et al. Selective impairment of TLR-mediated
innate immunity in human newborns: neonatal
blood plasma reduces monocyte TNF-α induction
by bacterial lipopeptides, lipopolysaccharide, and
imiquimod, but preserves the response to R-848.
J. Immunol. 173, 4627–4634 (2004).
124. Sadeghi, K. et al. Immaturity of infection control
in preterm and term newborns is associated with
impaired toll-like receptor signaling. J. Infect. Dis.
195, 296–302 (2007).
125. Schnurr, M. et al. Extracellular nucleotide signaling
by P2 receptors inhibits IL-12 and enhances IL-23
expression in human dendritic cells: a novel role for
the cAMP pathway. Blood 105, 1582–1589 (2005).
126. Goriely, S. et al. A defect in nucleosome remodeling
prevents IL-12(p35) gene transcription in neonatal
dendritic cells. J. Exp. Med. 199, 1011–1016 (2004).
Shows that expression of IL-12 p35 by human
neonatal DCs is regulated at the chromatin level
by a defect in nucleosome remodelling.
127. Krieg, A. M. Therapeutic potential of Toll-like receptor
9 activation. Nature Rev. Drug Discov. 5, 471–484
128. Pedras-Vasconcelos, J. A. et al. CpG
oligodeoxynucleotides protect newborn mice from
a lethal challenge with the neurotropic Tacaribe
arenavirus. J. Immunol. 176, 4940–4949 (2006).
129. Levy, O. et al. Critical role of the complement system
in Group B streptococcus-induced tumor necrosis
factor alpha release. Infect. Immun. 71, 6344–6353
130. Vekemans, J. et al. Neonatal bacillus Calmette–Guérin
vaccination induces adult-like IFN-γ production by
CD4+ T lymphocytes. Eur. J. Immunol.
31, 1531–1535 (2001).
131. Strunk, T. & Burgner, D. Genetic susceptibility
to neonatal infection. Curr. Opin. Infect. Dis.
19, 259–263 (2006).
132. Mishra, U. K., Jacobs, S. E., Doyle, L. W. &
Garland, S. M. Newer approaches to the diagnosis
of early onset neonatal sepsis. Arch. Dis. Child. Fetal
Neonatal Ed. 91, F208–F212 (2006).
133. Viemann, D. et al. Expression of toll-like receptors in
neonatal sepsis. Pediatr. Res. 58, 654–659 (2005).
134. Carr, R., Modi, N. & Dore, C. G-CSF and GM-CSF
for treating or preventing neonatal infections.
Cochrane Database Syst. Rev., 3, CD003066 (2003).
135. Ito, S. et al. CpG oligodeoxynucleotides enhance
neonatal resistance to Listeria infection. J. Immunol.
174, 777–782 (2005).
Shows that administration of CpG ODNs can
protect newborn mice from subsequent challenge
with L. monocytogenes.
136. Barrier, M. et al. Oral and intraperitoneal
administration of phosphorothioate
oligodeoxynucleotides leads to control of
Cryptosporidium parvum infection in neonatal
mice. J. Infect. Dis. 193, 1400–1407 (2006).
137. Lambert, P. H. Vaccines for the world: major
challenges for the future. Southeast Asian J. Trop.
Med. Public Health 28, 122–126 (1997).
138. Kovarik, J. et al. CpG oligodeoxynucleotides
can circumvent the Th2 polarization of neonatal
responses to vaccines but may fail to fully redirect
Th2 responses established by neonatal priming.
J. Immunol. 162, 1611–1617 (1999).
139. Hein, M., Valore, E. V., Helmig, R. B., Uldbjerg, N. &
Ganz, T. Antimicrobial factors in the cervical mucus
plug. Am. J. Obstet. Gynecol. 187, 137–144 (2002).
140. Schaefer, T. M., Desouza, K., Fahey, J. V.,
Beagley, K. W. & Wira, C. R. Toll-like receptor (TLR)
expression and TLR-mediated cytokine/chemokine
production by human uterine epithelial cells.
Immunology 112, 428–436 (2004).
141. Schaefer, T. M., Fahey, J. V., Wright, J. A. &
Wira, C. R. Innate immunity in the human female
reproductive tract: antiviral response of uterine
epithelial cells to the TLR3 agonist poly(I:C).
J. Immunol. 174, 992–1002 (2005).
142. Abrahams, V. M. et al. Divergent trophoblast
responses to bacterial products mediated by TLRs.
J. Immunol. 173, 4286–4296 (2004).
143. Huppertz, B., Kadyrov, M. & Kingdom, J. C.
Apoptosis and its role in the trophoblast.
Am. J. Obstet. Gynecol. 195, 29–39 (2006).
144. Beijar, E. C., Mallard, C. & Powell, T. L. Expression
and subcellular localization of TLR-4 in term and first
trimester human placenta. Placenta 27, 322–326
145. Espinoza, J. et al. Lipopolysaccharide-binding protein
in microbial invasion of the amniotic cavity and human
parturition. J. Matern. Fetal Med. 12, 313–321
146. Kim, H. S. et al. Endotoxin-neutralizing antimicrobial
proteins of the human placenta. J. Immunol.
168, 2356–2364 (2002).
147. Pacora, P. et al. Lactoferrin in intrauterine infection,
human parturition, and rupture of fetal membranes.
Am. J. Obstet. Gyn. 183, 904–910 (2000).
148. Cherry, S. H., Filler, M. & Harvey, H. Lysozyme content
of amniotic fluid. Am. J. Obstet. Gyn. 116, 639–642
149. Koyama, M. et al. Elevations of group II phospholipase
A2 concentrations in serum and amniotic fluid in
association with preterm labor. Am. J. Obstet. Gyn.
183, 1537–1543 (2000).
150. Weinrauch, Y., Abad, C., Liang, N. S., Lowry, S. F. &
Weiss, J. Mobilization of potent plasma bactericidal
activity during systemic bacterial challenge.
Role of group IIA phospholipase A2. J. Clin. Invest.
102, 633–638 (1998).
151. Mathai, M., Jairaj, P., Thangavelu, C. P., Mathai, E. &
Balasubramaniam, N. Antimicrobial activity of
amniotic fluid in South Indian women. Br. J. Obstet.
Gynaecol. 91, 560–564 (1984).
152. Durr, M. & Peschel, A. Chemokines meet defensins:
the merging concepts of chemoattractants and
antimicrobial peptides in host defense. Infect. Immun.
70, 6515–6517 (2002).
153. Bowdish, D. M., Davidson, D. J. & Hancock, R. E.
Immunomodulatory properties of defensins
and cathelicidins. Curr. Top. Microbiol. Immunol.
306, 27–66 (2006).
154. Dominguez, F., Pellicer, A. & Simon, C. The chemokine
connection: hormonal and embryonic regulation at
the human maternal-embryonic interface — a review.
Placenta 24, S48–S55 (2003).
155. Liu, C. et al. The role of CCL21 in recruitment of
T-precursor cells to fetal thymi. Blood 105, 31–39
156. Meurens, F. et al. Expression of mucosal chemokines
TECK/CCL25 and MEC/CCL28 during fetal
development of the ovine mucosal immune system.
Immunol. 120, 544–555 (2007).
157. Plotkin, J., Prockop, S. E., Lepique, A. &
Petrie, H. T. Critical role for CXCR4 signaling in
progenitor localization and T cell differentiation in the
postnatal thymus. J. Immunol. 171, 4521–4527
158. Garvy, B. A. & Qureshi, M. H. Delayed inflammatory
response to Pneumocystis carinii infection in neonatal
mice is due to an inadequate lung environment.
J. Immunol. 165, 6480–6486 (2000).
159. Krolak-Olejnik, B., Beck, B. & Olejnik, I. Umbilical
serum concentrations of chemokines (RANTES
and MGSA/GRO-α) in preterm and term neonates.
Pediatr. Int. 48, 586–590 (2006).
160. Zhou, J. et al. Differential expression of chemokines
and their receptors in adult and neonatal
macrophages infected with human or avian influenza
viruses. J. Infect. Dis. 194, 61–70 (2006).
161. Meddows-Taylor, S. et al. Reduced ability of newborns
to produce CCL3 is associated with increased
susceptibility to perinatal human immunodeficiency
virus 1 transmission. J. Gen. Virol. 87, 2055–2065
162. Ng, P. C. et al. IP-10 is an early diagnostic marker
for identification of late-onset bacterial infection in
preterm infants. Pediatr. Res. 61, 93–98 (2007).
163. Collado-Hidalgo, A., Sung, C. & Cole, S. Adrenergic
inhibition of innate anti-viral response: PKA blockade
of Type I interferon gene transcription mediates
catecholamine support for HIV-1 replication.
Brain Behav. Immun. 20, 552–563 (2006).
164. Peters, A. M., Bertram, P., Gahr, M. & Speer, C. P.
Reduced secretion of interleukin-1 and tumor
necrosis factor-α by neonatal monocytes.
Biol. Neonate 63, 157–162 (1993).
165. Bettelli, E. et al. Reciprocal developmental
pathways for the generation of pathogenic effector
TH17 and regulatory T cells. Nature 441, 235–238
166. Bowen, R. S., Gu, Y., Zhang, Y., Lewis, D. F. & Wang, Y.
Hypoxia promotes interleukin-6 and -8 but reduces
interleukin-10 production by placental trophoblast
cells from preeclamptic pregnancies. J. Soc. Gynecol.
Investig. 12, 428–432 (2005).
167. De Wit, D. et al. Impaired responses to toll-like
receptor 4 and toll-like receptor 3 ligands in human
cord blood. J. Autoimmun. 21, 277–281 (2003).
I thank P. Elsbach, R. Geha, R. Munford, P. Pizzo, J. Weiss and
M. Wessels for their mentorship. P. Bibbins created concept
illustrations for FIGS 2,3. O.L.’s laboratory is supported by
the National Institutes of Health, a Dana Human Immunology
Award and by XOMA (U.S.) L.L.C.
Competing interests statement
Among the funding sources to the author’s laboratory is
research support from XOMA (U.S.) L.L.C. that manufactures
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
IL-1β | IL-6 | IL-12 | MYD88 | TLR2 | TLR4 | TNF
Ofer Levy’s homepage: http://www.childrenshospital.org/
Access to this links box is available online.
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