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Feature Articles
Why We Develop Food Allergies
Coached by breast milk and good bacteria, the immune system strives to learn
the difference between food and pathogens before the first morsel crosses our lips
Per Brandtzaeg
o peanuts. No dairy. No eggs or
shellfish or soy. No wheat or corn,
no tree nuts or fin fish, no sesame seeds
or spices of any kind. Few people have
a diet this restrictive, but allergies to
foods affect at least 1 in 20 young children and about 1 in 50 adults in industrialized countries. The numbers are
rising: According to a recent study, the
prevalence of peanut allergy—which
accounts for the majority of emergency-room visits and deaths related to
food allergies each year—doubled between 1997 and 2002.
The story of food allergy is a story
about how the development of the immune system is tightly linked to the development of our digestive tract or, as
scientists and physicians usually refer to
it, our gut. A human being is born with
an immature immune system and an immature gut, and they grow up together.
The immune system takes samples of
gut contents and uses them to inform its
understanding of the world—an understanding that helps safeguard the digesPer Brandtzaeg trained in microbiology and immunology at the Medical Center of the University of
Alabama at Birmingham before earning his Ph.D.
in immunology from the University of Oslo. Until
recently he headed the Faculty Division of Rikshospitalet University Hospital, and he is the founder
of its Laboratory for Immunohistochemistry and
Immunopathology. Brandtzaeg’s research examines
the biology and pathology of the mucosal immune
system, including the study of mucosal diseases associated with chronic inflammation, allergy, immunodeficiency, and malignant and reactive disorders
of mucosal and peripheral lymphoid tissue. Brandtzaeg has been Norway’s most cited researcher over
the past two decades and was the first European
president of the international Society for Mucosal
Immunology. Address: Department of Pathology,
University of Oslo, Rikshospitalet, N-0027 Oslo,
Norway. Internet: [email protected]
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American Scientist, Volume 95
tive system (and the body that houses it)
against harmful microorganisms.
The many-layered defenses of the
immune system are designed to guard
against invaders while sparing our own
tissues. Food represents a special challenge to this system: an entire class of
alien substances that needs to be welcomed rather than rebuffed. An adult
may pass a ton of food through her
gut each year, nearly all of it distinct at
the molecular level from her own flesh
and blood. In addition, strains of normal, or commensal, bacteria in the gut
help with digestion and compete with
pathogenic strains; these good microbes
need to be distinguished from harmful
ones. The body’s ability to suppress its
killer instinct in the presence of a gutfull of innocuous foreign substances is
a phenomenon called oral tolerance. It
requires cultivating a state of equilibrium, or homeostasis, that balances aggression and tolerance in the immune
system. Intolerance, or failure to suppress the immune response, results in
an allergic reaction, sometimes with lifethreatening consequences.
Thanks, Mom
An infant floating in the womb enjoys
warmth, nutrition and an environment
free of microorganisms. During the
birth process—even before she takes
her first breath—a baby begins to encounter microbes and other foreign substances, collectively called antigens, that
can stimulate her new immune system.
Most of these immunological challenges take place on mucosal surfaces such
as the gut and airways.
The first line of defense in a newborn’s gut is the system of immune exclusion, which uses exported antibodies
to bind germs and potentially harmful
compounds on the mucosal surface.
Antibodies coat the pathogens to prevent them from invading the gut wall,
and they bind to unfamiliar cell fragments or macromolecules to regulate
their passage into the body. The class of
antibodies known as secretory immunoglobulin A (SIgA) is most responsible for
immune exclusion; it is a nice antibody
that is actively pumped out to the surface and seldom elicits inflammation
when it goes to work.
New babies, however, produce little
or no SIgA. They depend on other types
of antibodies during the first vulnerable
months of life, primarily residual IgG
from the mother and small amounts
of mucosal IgM. The only significant
source of SIgA antibodies during this
period is breast milk, which helps protect the newborn until her immune system is established. In developed countries, the child’s ability to produce SIgA
is quite variable, being completed between one and ten years of age. Babies
in developing countries often establish
secretory immunity much earlier, presumably because of greater exposure to
stimulating microbes.
In addition to their job of binding up
troublesome antigens, SIgA antibodies
Figure 1. Only minutes after being born, a
baby has already begun to tune her immature
immune system against environmental microorganisms. Getting an early exposure to the
right kinds of microbes is important: Inoculation with normal bacteria from the mother’s
birth canal and stools encourages gut maturation that, in certain children, reduces the risk
of developing allergies. Although food allergies have more-visible effects among older
children and adults, the crucial steps that lead
to this condition take place very early in life.
The hour-old baby in this photograph is being
held by her father in a tub of warm water.
© 2007 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
© Suzanne Arms
N
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© 2007 Sigma Xi, The Scientific Research Society. Reproduction
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2007 January–February
29
10
objectively confirmed egg allergy
8
relative risk (odds ratio)
of allergy at 2.5 years
9.3
parent-reported food allergy
7.8
6
4
2.5
1.9
2
1.0
1.4
1.0
0.7
0
maternal
allergy
caesarian
section
+
+
+
+
Figure 2. The combination of delivery by caesarian section and a maternal history of allergy
elevates the risk that a child will be allergic to food. Babies who are born with both factors
are at least eight times as likely to develop a food allergy, as compared with babies who
have neither factor. By themselves, neither maternal history nor caesarian delivery leads to
significant changes in risk. The presumptive explanation for this phenomenon is that caesarian delivery does not expose the baby to vaginal and stool bacteria. This finding confirms
the importance of both genes and microbial exposure. The pink bars indicate the relative
levels of food allergies in general as determined by parental reports; green bars show the
relative levels of egg allergy in particular as confirmed by objective testing. Both measures
are normalized to baseline values from children who were born vaginally to mothers without a history of allergy. (Data from Eggesbø et al. 2003.)
a
help the gut to develop by enhancing
the barrier function of the epithelial lining. The gut mucosa of most infants
matures during the first months of life.
But in some children, the mucosal barrier remains inadequate for several years,
and incomplete secretory immunity
can contribute to the delay. Not surprisingly, genetically manipulated (knockout) mice that lack SIgA and SIgM have
leaky mucosal membranes.
The SIgA system seems to be important in setting an individual’s threshold for adverse reactions to food. The
risk of food allergy is higher when the
development of IgA-producing cells
is retarded or when SIgA-dependent
development of the gut barrier is insufficient. On the positive side, babies
who breastfeed exclusively for at least
the first four months appear to have
fewer allergies. This effect may be the
product of IgA-directed gut maturation,
but human milk also contains immune
cells, immune-regulating cytokines and
growth factors that exert positive biological effects.
Immunity Patch
Immune cells are woven into the fabric
of the gut rather than being restricted
B cell
gut
mucosa
T cell
gut
lumen
macrophage
Peyer’s
patch
b
blood
vessels
dendritic cell
c
villi
M cell
lymphatic duct
Figure 3. The immune system and the digestive tract are integrated systems, particularly in the intestines, where mucosal immunity is induced
and effected. Among the folds and fingerlike villi that line the small intestine are low, domed structures called Peyer’s patches (a). The patches
are specialized sites that allow the immune system to sample microbes and food particles from the gut lumen (b). The outer, epithelial-cell layer of
the Peyer’s patch contains thin, pocket-shaped M cells that engulf passing antigens and transport them to the primary cells of the immune system:
T cells, B cells, macrophages and dendritic cells (c). The exchange of chemical signals between the “stimulated” cells determines whether the immune system will tolerate or attack food antigens.
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American Scientist, Volume 95
© 2007 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
to one place, but there are also discrete structures for immune surveillance. Dotting the prairie of tiny villi
that lines the gastrointestinal tract are
swollen domes called Peyer’s patches.
These regions, part of a larger system of
gut-associated lymphoid tissue or GALT,
are covered by an epithelial-cell layer
containing specialized M cells (the M
stands for membrane or microfold),
which constantly scan the stream of
passing antigens and transport them to
the principal cell types in the immune
system—B cells (from the bone marrow), T cells (from the thymus) and antigen-presenting cells (APCs) such as
macrophages and dendritic cells. It is
here that mucosal immunity is induced
and regulated.
What follows the identification of an
antigen is a complicated ballet of cells,
secreted signals and movement from
one compartment of the body to another. The keys to the system are the APCs,
the “decision makers” in the immune
system, which link innate and adaptive immunity. APCs process chunks
of antigen brought in by M cells and
then show the pieces, along with a selection of co-stimulatory signals, to socalled naive T cells, which have never
met their cognate antigens before. Those
specific T cells whose antigen receptors
match one of the pieces become primed
or activated; they then release cytokines
(hormone-like regulatory proteins) and
growth factors that instruct B cells to
proliferate, differentiate and begin producing IgA. Activated T and B cells migrate to nearby lymph nodes to receive
additional biological signals; most of
those cells then enter the bloodstream.
Many will return to the lamina propria of
the gut, the tissue layer beneath the surface epithelium, or to mammary glands
in lactating mothers through a kind
of chemical navigation system. There,
depending on what antigen-induced
“second signals” the B cells receive,
they may undergo one last, or terminal,
differentiation to become plasma cells,
which produce antibodies in quantity
(about 10,000 molecules per second).
The system works differently in newborns who have never encountered microbes. Very few IgA-producing B cells
circulate in the blood of newborns, although this number is approximately
75 times higher after the first month of
life, a period of continuous stimulation
of GALT by microbial antigens.
In the GALT structures, APCs need
to receive certain “danger signals”—
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of chewed-up microbes—particularly
the component of the bacterial cell wall
known as endotoxin or lipopolysaccharide (LPS)—because the cells contain an
intracellular receptor for this common
bacterial signature. Exposure to LPS in
the mother’s vaginal tract during birth
modulates the gut epithelium so that
it becomes tolerant to microbial patterns after birth. In remarkable contrast,
mice delivered by caesarean section do
not show signs of epithelial tolerance.
These observations may be relevant to
humans: Children who have a genetic
predisposition to produce excess IgE (as
indicated by mothers who suffer from
various allergic reactions—a condition
called atopy) are at least eight times as
likely to develop food allergy when delivered by caesarean section.
Judith Kuegler
Figure 4. For newborn babies, human milk
hastens the development of the gut and immune systems, which are immature at birth.
Breast milk reinforces the barrier function
of neonatal gut epithelium and provides the
principal source of secretory IgA antibodies
during the first months of life. These antibodies bind to food antigens to limit the reactivity
of the immune system and to microbial antigens to retard infection. Babies who consume
only breast milk for at least four months tend
to experience less asthma and eczema, particularly if they have a family history of allergy.
fragments of commensal bacteria from
the digestive tract—to provide the
right mix of co-stimulatory signals that
prime helper T (Th) cells to aid the B
cells. Without this timely inoculation
with bacteria, the IgA system fails to
develop normally. Bacteria from the genus Bacteroides and certain strains of
Escherichia coli seem to be particularly
good at stimulating the mucosal immune system. Lactic-acid–producing
bacteria (lactobacilli and bifidobacteria)
also contribute. These microbes help
establish and regulate the epithelial barrier as well.
At least in mice, many of the beneficial effects of the commensal microbiota come from the binding of bacterial components by pattern recognition
receptors on the surface of or inside the
epithelial cells. This binding starts a
back-and-forth, homeostasis-enhancing exchange of signals between epithelial cells and cells in the underlying
lamina propria, including macrophages
and dendritic cells. Experiments in
mice suggest that before birth, cells
lining the gut can detect certain parts
Cultivating Tolerance
Oral tolerance is not a single process but
a complex series of events that contribute to intestinal and systemic immunosuppression. Many variables influence
the development of oral tolerance (and
therefore of food allergy): genetics, age,
the dose and postnatal timing of fed
antigens, the structure and composition of those antigens, the integrity of
the epithelial barrier, and the extent to
which nearby immune cells are simultaneously activated.
Human milk helps the gut tolerate
certain food antigens early in life. Antibodies to gluten peptides from wheat
are present in breast milk, and breastfeeding has been shown to protect significantly against the development of
gluten-triggered celiac disease in children. This observation hints that mixed
feeding, rather than abrupt weaning,
may promote greater tolerance to food
proteins in general.
This tolerance depends in part on
the mothers’ own immune function. In
a study of breastfed infants, the ones
whose mothers had low levels of antibovine antibodies were more likely to
develop cow’s-milk allergy later in life.
Human milk also contains cytokines
and growth factors that might account
for its tolerance-promoting properties by modulating the activation of
GALT and enhancing the function of
the epithelial barrier. Most epidemiological studies support the view that
breastfeeding protects against asthma
and atopic dermatitis, or eczema, although this notion remains controversial. Nonetheless, the reinforcing effect
of breast milk on mucosal barrier func-
© 2007 Sigma Xi, The Scientific Research Society. Reproduction
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2007 January–February
31
a
b
IgA
IgA
pump
B cell
T cell
lymph
node
blood
vessel
plasma
cell
lymphatic
vessel
Figure 5. Mucosal immunity is induced at the Peyer’s patch (a) and effected at mucosal sites
throughout the gut (b). M cells transport antigens from the gut lumen to underlying macrophages
and dendritic cells. These antigen-presenting cells repackage the antigen pieces, along with a
selection of co-stimulatory signals that are adapted to certain antigens, and activate T and B cells.
After this local priming, the B and T cells travel to nearby lymph nodes for further chemical
instruction. Most of the cells then enter the bloodstream and return later to the gut mucosa, as
shown in panel b. Depending on what antigens they encounter in their new location, B cells may
change into plasma cells to produce large quantities of antibodies pumped into the gut lumen.
a
c
immunoregulatory conditioning
homeostasis
tion in infants is robust and has special
significance in families with a history
of allergy.
As we currently understand it, oral
tolerance is effected mainly through Tcell maturation events, such as anergy
(a kind of cellular hibernation), clonal
deletion (which removes T cells with
undesirable targets) and, particularly,
amplification of the immune system’s
voice of reason, the regulatory T (Treg)
cell. As a result, healthy people have
hardly any hyperactivated effector T
cells (Teff) in their gut mucosa, scant
mucosal production of proinflammatory IgG, and only low levels of IgG
antibodies to food antigens in serum.
Food allergies vary in their severity
and how swiftly symptoms appear. The
immediate, life-threatening reactions experienced by some people (most often
to peanuts) happen when the allergen
binds to IgE-type antibodies, which
then trigger the release of histamine,
the compound responsible for acute inflammation with itching, sneezing and
other allergy symptoms. Other types of
food allergies result from IgG or IgM
antibodies, or from so-called delayedd
allergic response
immune
exclusion
and barrier
enhancement
B
IgA
lactic acid
bacteria
Treg
Teff
prevention
of excessive
inflammation
b lack of appropriate microbial stimulation
immunemediated
diseases
Treg
Teff
Teff
IgE
Figure 6. According to the extended hygiene hypothesis, lactic-acid–producing and other “good” commensal bacteria trigger the conditioning
of immune responses (a) through increased production of regulatory T cells (Treg) and IgA-secreting B cells. Treg cells, in turn, suppress the
activity of effector T cells (Teff), which release proinflammatory chemical signals in response to certain antigens. When appropriate microbial
stimulation does not take place (b), Treg cells are not produced. The result is an aggressive immune response that can include production of
IgE antibodies, which mediate acute allergic reactions to foods such as peanuts, eggs or milk. Thus, the gut in homeostasis (c) contains good
bacteria that promote the activity of Treg cells, provide secretory IgA and develop a tight epithelial barrier. By contrast, the loss of homeostasis
found in allergy sufferers (d) is characterized by high levels of undesirable bacteria such as clostridia in the gut, unrestrained proinflammatory signals from Teff cells, the production of IgE antibodies to food antigens and poor epithelial barrier function.
32
American Scientist, Volume 95
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Th2:Th1 ratio
atopic
child
window for fine-tuning
© Dr. P. Marazzi/ Science Photo Library
relative T-cell memory
response patterns
atopic
disease
birth
sensitization
(IgE antibodies)
tolerance
3
6
12
18
healthy
child
24
age (months)
Figure 7. The ratio of two types of T cells—helper 1 (Th1) and helper 2 (Th2)—indicates the presence or absence of allergy in young children. A
newborn’s immune system is skewed toward the Th2 response, but the system gradually becomes dominated by Th1 signals in a healthy child
(brown line). In a child who suffers from allergies (purple line), the continued dominance of Th2 signals may lead to conditions such as eczema
(left). Homeostatic balancing of the Th2:Th1 ratio appears subject to microbial modulation, particularly during a narrow postnatal window (shaded
region). Even for “sensitized” infants with high levels of IgE antibodies, an increase in beneficial gut bacteria may coax the release of cell signals
that balance the Th2:Th1 ratio to promote homeostasis (green line). (Modified from Rautava et al. 2004.)
Decisions, Decisions
Upon encountering a novel antigen,
the immune system must decide
whether the antigen is pathogenic
(meriting a so-called productive immune reaction, which tries to eliminate
the antigen) or harmless (leading to a
suppressed response). If commensal
bacteria have in the past modulated
APCs (macrophages and dendritic
cells) via their pattern-recognition receptors, then these cells are more likely
to express co-stimulatory molecules
and secrete the types of cytokines that
encourage Treg cell development and,
therefore, tolerance.
In a healthy gut, the APCs are continuously exposed to components
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of the normal gut microbiota. Like a
sleepy sheriff in a peaceful town, a dendritic cell raises only a negligible alarm
of proinflammatory cytokines on getting a whiff of microbial LPS. In this
quiescent state, the dendritic cells carry
antigens from the gut to nearby lymph
nodes, where, in a normal maturation
process, the cells become further conditioned for tolerance and drive the
expansion of Treg cells. Some of the
Treg cells travel through lymphatic and
blood vessels back to the gut mucosa to
maintain homeostasis.
Altogether, the body avoids unnecessary hyperactivation of its immunological sentinels (along with potentially
harmful inflammation) in two ways:
initially, with the restrained alarm, and
also later when the activated Treg cells
migrate to the mucosa to exert homeostatic control. At the same time, the
macrophage deputies in town, which
retain their ability to engulf and kill
microbial invaders, continue to do the
work of getting rid of commensal bacteria that sneak past the gut lining.
In the gut-associated lymph nodes,
conditioning for oral tolerance depends on the menu of microbial components that the dendritic cells receive.
Tolerance to food proteins is more likely to develop in the presence of telltale
components from certain commensal
bacteria as well as from harmless bacteria native to soil and from surface
water or parasites such as flatworms
180
160
relative change (%) in Treg cells
type hypersensitivity (not depending on
antibodies). The latter reaction is typified
by gluten-triggered celiac disease and
may involve local dysregulation of both
innate and adaptive immune functions.
Delayed-type reactions may not show
the hallmarks of classical inflammation
that characterizes faster reactions.
Food allergies can be serious enough
by themselves, but they can also announce the start of an “allergic march”
that leads to antigen-triggered respiratory diseases. People who inherit a
predisposition to atopy are at particular
risk. Asthma and other atopic respiratory diseases have certainly become more
common in developed countries during
the past two decades.
140
120
100
prechallenge
level
80
60
allergic
children
tolerant
children
40
Figure 8. Most children with cow’s-milk allergy outgrow their intolerance within a few
years. This change from allergy to tolerance
is reflected in the blood levels of Treg cells induced by drinking milk. In a study conducted
by the author and his colleagues, children with
milk allergy maintained a dairy-free diet for
several months, a period of time during which
some participants outgrew their intolerance.
For those who were no longer allergic, a milk
challenge at the end of the study caused a rise
in circulating Treg cells. The same challenge in
children who remained allergic led to an apparent decrease in Treg cells, probably because
existing ones were sequestered in the gut. The
difference between groups was significant.
(Based on data from Karlsson et al. 2004.)
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2007 January–February
33
Treg cells (% of total lymphocytes)
90
T cell–dependent manner. In a doubleblind study of infants with a family
history of atopy, babies who received
a daily dose of a probiotic (Lactobacillus
GG strain) for the first six months of
life had 50 percent less atopic dermatitis at age two than did babies who
received a placebo. Allergy prevalence
still differed between study groups
four years later. It’s unclear whether
this remarkable result is the product of
reinforced barrier function from SIgA,
enhanced oral tolerance or both.
*
80
*
70
60
50
40
30
20
10
0
day 0
day 6
control
group
day 0
day 6
allergy
risk group
Figure 9. Immune cells from umbilical-cord
blood can indicate the state of a baby’s immune system at birth. By using cell-surface
markers to sort different cell types, the author
and his colleagues were able to count Treg cells
in cord-blood samples. They found that even
at birth, babies who had a family history of
allergy had significantly fewer inducible Treg
cells than did babies who had no such family
history. After six days in culture media that
contained milk protein and fragments of bacterial cell walls, samples from children with
no family allergies had produced significantly
more Treg cells in vitro. Statistically significant differences are indicated with asterisks.
(Based on data from Haddeland et al. 2005.)
or flukes. (It’s nice to know these pests
are good for something.) This evidence
supports the extended hygiene hypothesis, which argues that a too-hygienic
lifestyle in industrialized countries can
prevent the mucosal immune system
from maturing, leading to inadequate
secretory immunity and fewer Treg
cells. In a way, you could say that our
immune system has lost its stimulating
“old friends.” Supporters of the hypothesis speculate that this inadequacy
could help explain the increasing incidence of allergy and other immunemediated inflammatory disorders in
Westernized society.
Several clinical studies have tested
the hygiene hypothesis by evaluating the effect of probiotic preparations, which deliver to the gut new
colonists—certain strains of commensal bacteria or intestinal parasites
from other species. (Eggs from the pig
whipworm Trichuris suis, which don’t
pose an infection risk to humans, are
the stimulants of choice in the latter
experiments.) Reports from studies
in humans and animals indicate that
lactobacilli and bifidobacteria enhance
the production of SIgA, apparently in a
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American Scientist, Volume 95
Alarm Calibration
Microorganisms existed billions of
years before the first immune systems.
Rather than waging war on them,
our immune systems evolved a mutually beneficial partnership (mutualism) with certain bacterial strains
that would compete for resources,
in the environment of the gut or on
other body surfaces, with more harmful microbes. An average adult carries
1014—100 million million—bacteria in
his gut, or about 10 times more bacterial cells than there are human cells in
the body. Our mechanisms of defense
are shaped by this mutualism.
According to the original hygiene
hypothesis, reduced or aberrant microbial exposure early in infancy
doesn’t provide enough stimulation
to the so-called helper T cell type 1
(Th1). As a result, Th1 cells don’t sufficiently antagonize the other type of
helper T cell, Th2. Without this suppression, Th2 cells release cytokines
that induce B cells to produce too
much IgE, leading to atopy. Thus, the
right commensal microbiota promotes
mucosal homeostasis by helping to
shift the newborn’s immune system
from a state dominated by Th2 signals
(the allergy track) to one in which the
cytokine profile is more balanced.
The extended hygiene hypothesis
postulates that Treg cells, which have
identifying proteins called CD25 receptors on their surfaces, are an important
part of the homeostatic mechanism. Treg
cells limit Th1 and Th2 cells when they
act as proinflammatory effector T cells,
thereby avoiding inflammation and
tissue damage. Treg cells also suppress
immune responses indirectly, either by
reducing APC function or by secreting
suppressive cytokines.
The window for fine-tuning a baby’s
mucosal immune system is relatively
narrow, starting when the infant is
colonized with vaginal and intestinal
bacteria from the mother’s birth canal.
In healthy individuals, this initial exposure shifts the Th2-skewed cytokine
profile of the newborn toward a Th1
profile, a sign of immunological maturation. But in atopic children, cytokines
from Th2 cells continue to predominate,
increasing the output of IgE, which predisposes the newborn to later allergy.
Fortunately, the system retains some
plasticity. Infants may be able to correct their ratio of Th2 to Th1 responses,
and most children with overt food allergy outgrow it. (Some reactions, such
as peanut sensitivity, are more likely
to persist.) As alluded to above, there
is hope for the future in that Treg cells
can be stimulated intentionally through
bacterial or parasitic products.
Clearly some stimuli are better than
others at balancing the immune system. Several studies have reported
that atopic infants have more of the
intestinal bacterium Clostridium and
less bifidobacteria in their stools than
non-atopic controls. Similarly, another
study found that children in Sweden
tended to have more clostridia as well
as allergies, whereas an age-matched
group in Estonia had fewer allergies
and high levels of lactobacilli and eubacteria. This research raises the possibility that various feeding and treatment regimens (particularly antibiotics)
could exert long-term effects on the
developing immune system through
the composition of the gut microbiota.
Certainly the possibility of promoting
immune homeostasis through probiotic adjustment of the gut microbiota
deserves further research.
Milk Model
Four out of five children who are allergic to cow’s milk outgrow the problem
before school age, which makes this disorder a good model for exploring the
complexities of oral tolerance. Experiments in mice suggest that oral tolerance is brought about mainly by the actions of CD25+ Treg cells, although other
mechanisms may also be involved.
In a recent study, our research team
at the University of Oslo looked at a
group of children who were all initially allergic to cow’s milk. After a
two-month dairy-free period, we gave
the children cow’s milk for up to one
week. The challenged kids who then
had outgrown the allergy (13 of 21)
showed numerically more, and functionally better, Treg cells in peripheral
blood than did children who remained
© 2007 Sigma Xi, The Scientific Research Society. Reproduction
with permission only. Contact [email protected].
allergic. And when we studied effector
T cells from the children in vitro, those
from the first group did not react as
strongly to cow’s-milk protein as did
cells taken from children whose allergy persisted. However, in the same
blood samples, removing the CD25+
cells (including Treg cells) caused a
five-fold increase in the immune response to milk protein, which suggested to us that this subset of T cells had
contributed to the developed tolerance
to cow’s-milk antigens.
Our study provided the first human
data that link the induction of oral tolerance to the development of CD25+ Treg
cells. This insight could prove useful as
a diagnostic tool, and Treg cells might
someday be candidates for preventing
or treating allergy.
Blood Will Tell
One common tool for studying neonatal immune responses is blood taken
from the umbilical cord at birth. The
blood cells are from the baby rather
than the mother, and such cord blood
mononuclear cells, or CBMCs, can be
studied in culture as a proxy for the
fetal immune system.
We wanted to examine how exposure
to LPS from bacteria during early antigen encounters might influence the responsiveness of neonatal T and B cells,
including the activation of Treg cells
by a food antigen. We also wondered
whether it would be possible to use this
measure to distinguish neonates with a
high risk of allergy (because of family
history) from controls with no hereditary risk. In fact, the stimulation with
cow’s-milk protein did cause greater
(less controlled) proliferation of CBMCs
from infants predisposed to atopy, suggesting that this test might predict later
allergies. Various subsets of T cells, as
determined by their immunological
cell-surface markers, were also distinct
between groups. After stimulation with
a combination of milk antigen and
LPS, the cells from babies with a family history of atopy expressed less of
the markers overall, a trait that implied
delayed development of a balanced
immune system. The induction of Treg
cells was also significantly impaired.
These data support the idea that induction of immunity should normally
be modulated very early in life under
the influence of genes and microbes.
However, the CBMC model can only
reveal small pieces of the mechanistic
puzzle. Immunological events in the
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gut are much more complex, and mucosal homeostasis probably involves a
multitude of processes.
Last Course
Zooming out from all this complexity, the phenomenon of oral tolerance
rests on a few primary processes: SIgA
antibodies, the barrier function of the
gut epithelium, the timing and dose of
inoculation with commensal bacteria,
and family history. These variables are
interdependent, and no single factor
predominates in maintaining mucosal
homeostasis. There is no single cause of
food allergy.
From an evolutionary perspective,
intolerance to certain dietary antigens is
not too surprising. It has not been long
since human beings began growing and
preparing their food rather than hunting and gathering it. And evolution is
slow when the undesirable phenotype
is so seldom deadly.
We must also keep in mind that the
current epidemic of allergy in industrialized countries is a small price to pay
for the remarkable reduction of infant
mortality provided by the elimination
of pathogens through improved hygiene. Having too few microbes in our
immediate environment seems to be
problematic, but having many pathogens is far, far worse. Nevertheless, the
pace of research raises hope that future
therapies will compensate for the missing good microbes needed to develop
homeostasis of mucosal immunity.
Bibliography
Benn, C. S., J. Wohlfahrt, P. Aaby, T. Westergaard, E. Benfeldt, K. F. Michaelsen, B.
Björksten and M. Melbye. 2004. Breastfeeding and risk of atopic dermatitis, by parental history of allergy, during the first 18
months of life. American Journal of Epidemiology 160:217–223.
Bischoff, S., and S. E. Crowe. 2005. Gastrointestinal food allergy: New insights into
pathophysiology and clinical perspectives.
Gastroenterology 128:1089–1113.
Brandtzaeg, P. 2002. Current understanding of
gastrointestinal immunoregulation and its
relation to food allergy. Annals of the New
York Academy of Sciences 964:13–45.
Brandtzaeg, P. 2002. Role of local immunity
and breast-feeding in mucosal homeostasis
and defence against infections. In Nutrition and Immune Function, eds P. C. Calder,
C. J. Field and H. S. Gill, 273–320. No. 1 of
Frontiers in Nutritional Science. Oxford, UK:
CABI Publishing.
Brandtzaeg, P. 2006.The changing immunological paradigm in coeliac disease. Immunology
Letters 105:127–139.
Eggesbø, M., G. Botten, H. Stigum, P. Nafstad
and P. Magnus. 2003. Is delivery by cesar-
ean section a risk factor for food allergy?
Journal of Allergy and Clinical Immunology
112:420–426.
Guarner, F., R. Bourdet-Sicard, P. Brandtzaeg,
H. S. Gill, P. McGuirk, W. van Eden, J. Versalovic, J. V. Weinstock and G. A. W. Rook.
2006. Mechanisms of disease: The hygiene
hypothesis revisited. Nature Clinical Practice
Gastroenterology & Hepatology 3:275–284.
Haddeland, U., P. Brandtzaeg and B. Nakstad.
In press. Maternal allergy influences the
proliferation of neonatal T cells expressing
CCR4, CXCR5 or CD103. Clinical & Experimental Allergy.
Haddeland, U., A. B. Karstensen, L. Farkas, K.
L. Bø, J. Pirhonen, M. Karlsson, W. Kvåvik,
P. Brandtzaeg and B. Nakstad. 2005. Putative
regulatory T cells are impaired in cord blood
from neonates with hereditary allergy risk.
Pediatric Allergy and Immunology 16:104–112.
Holt, P. G., and C. A. Jones. 2000. The development of the immune system during pregnancy and early life. Allergy 55:688–697.
Ivarsson, A., O. Hernell, H. Stenlund and L.
A. Persson. 2002. Breast-feeding protects
against celiac disease. American Journal of
Clinical Nutrition 75:914–921.
Karlsson, M., M. R. Karlsson, J. Rugtveit and
P. Brandtzaeg. 2004. Allergen-responsive
CD4+CD25+ regulatory T cells in children
who have outgrown cow’s milk allergy. Journal of Experimental Medicine 199:1679–1688.
Rakoff-Nahoum, S., J. Paglino, F. Eslami-Varzaneh, S. Edberg and R. Medzhitov. 2004.
Recognition of commensal microflora by
toll-like receptors is required for intestinal
homeostasis. Cell 118:229–241.
Rautava, S., O. Ruuskanen, A. Ouwehand, S.
Salminen and E. Isolauri. 2004. The hygiene
hypothesis of atopic disease—an extended
version. Journal of Pediatric Gastroenterology
and Nutrition 38:378–388.
Sicherer, S. H., A. Muñoz-Furlong and H. A.
Sampson. 2003. Prevalence of peanut and
tree nut allergy in the United States determined by means of a random digit dial
telephone survey: A 5-year follow-up study.
Journal of Allergy and Clinical Immunology
112:1203–1207.
Sicherer, S. H., and H. A. Sampson. 2006. 9.
Food allergy. Journal of Allergy and Clinical Immunology 117(2 Supplemental MiniPrimer): S470–475.
van Odijk, J., I. Kull, M. P. Borres, P. Brandtzaeg,
U. Edberg, L. Å. Hanson, A. Høst, M. Kuitunen, S. F. Olsen, S. Skerfving, J. Sundell
and S. Wille. 2003. Breastfeeding and allergic
disease: A multidisciplinary review of the
literature (1966–2001) on the mode of early
feeding in infancy and its impact on later
atopic manifestations. Allergy 58:833–843.
For relevant Web links, consult this issue
of American Scientist Online:
http://www.americanscientist.org/
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