杏吧原创

LAST YEAR, one of Britain鈥檚 most promising athletes, the hurdler Ross
Baillie, was rushed to hospital in a coma. He had suffered a seizure brought on
by an allergic reaction to peanut oil in a sandwich. Baillie never regained
consciousness and a few days later he was dead. He was only 21. Up to 1 in 200
people suffers from peanut allergy and several die each year in Britain. Far
worse, 1 in 7 British children and 1 in 25 adults have asthma, and the figures
are rising. The disease kills around 1600 each year.

Allergies are caused by a damaging response of the immune system to
otherwise harmless features of the environment. Allergic symptoms, including the
sneezing of hay fever, wheezing of asthma, itching of dermatitis and violent
reactions to food, nearly all result from the same immune response. Pollen, cat
fur, house dust, peanuts and other allergens are only triggers鈥攊t
is the immune system that causes the problems.

Allergy was first described in 1906 by the Austrian doctor Clemens von
Pirquet as a 鈥渟pecific acquired altered reactivity which follows initial
exposure to a foreign protein鈥�. The body鈥檚 reaction to its first encounter with
an allergen is different to that on subsequent encounters. This description fits
all immune reactions. In fact, the only difference between immune and allergic
reactions is their outcome.

Our immune systems are remarkably successful at defending us. Every external
surface of our bodies is covered by a continuous cell layer called the
epithelium which keeps out most infectious agents (pathogens) and
other foreign particles. An army of immune cells is waiting on the other side to
challenge anything that does manage to cross this boundary. The first time a
particular pathogen infects the body, it takes some time for this army to fight
it off鈥攄uring which time we become ill. But the immune system has a
memory: when that pathogen is encountered again, our bodies are ready for
it. These later encounters are marked by a far more rapid and effective immune
response, which is the basis of immunity (see Inside Science, Nos. 7 and 8).

ARE YOU TOO SENSITIVE?

Allergic versus non-allergic

The first time a potential allergen is encountered, no symptoms are felt.
Whereas pathogens use the resources of their host to grow and multiply, causing
the symptoms of illness, allergens pose no such threat. Despite an absence of
symptoms, however, the allergic immune system silently reacts as if a pathogen
were present, memorising it for subsequent encounters
(Figure 1).

In non-allergic people, the immune system has already identified the
potential allergens as harmless, so no action is taken on subsequent encounters.
In allergic people, however, the immune system launches the rapid
response associated with an infection. This is doomed to failure, and in
attempting to kill off what it mistakes as a pathogen, the immune system causes
the symptoms of allergy.

Allergies affect about 30 per cent of the population in the developed world.
In Europe, hay fever afflicts between 10 and 20 per cent of the population and
eczema between 10 and 12 per cent. Of the children who develop eczema, up to one
in five will develop asthma in later life. In Britain, asthma affects between 10
and 15 per cent of children under 15, and about 5 per cent of
adults鈥攄ifferences that partly reflect changes in the immune system
throughout life.

But the number of people with allergies, both in terms of the dramatic
reaction suffered by the British athlete and more common allergies, has been
steadily increasing over the past 20 to 30 years. This is well illustrated by
the figures for asthma in Britain. In 1993, almost four times as many children
(aged 5-14) were diagnosed with asthma as had been in 1979. For infants (aged
0-4), the increase was closer to fivefold.

Many factors have been implicated. The development of allergic disease
depends on two things: genetics and the environment. Allergy tends to run in
families鈥攊f both parents have allergies, the risk to their children is 75
per cent, but if just one parent suffers, the risk is 50 per cent. The genetic
predisposition to allergic reactions is called atopy, and the activity of
atopy genes is governed by the environment鈥攚hich helps to explain why
identical twins do not always share the same allergies. Numerous candidates for
atopy genes are under investigation, with those for the most economically
important allergic disease of all, asthma (estimated by the National Asthma
Campaign to cost Britain 拢1 billion a year), receiving the most
attention.

NATURE AND NURTURE

Humid, hygienic homes

The environment and genes interact in complex ways to produce the symptoms of
allergic disease. There are large differences worldwide in the prevalence of
particular allergies, with the highest reports in Britain, Australia, New
Zealand and Ireland, and the lowest in several eastern European countries, China
and India. These patterns suggest that environmental factors related to Western
living conditions are important. There is even tantalising evidence that
exposure to pathogens in dirt during childhood may train the immune
system and reduce the incidence of allergy in later life, which suggests that
the Western obsession with hygiene may distort the immune response.

Although it is tempting to blame the increasing incidence of asthma on
factors such as atmospheric pollution from cars and factories, the links between
the domestic environment and allergy are just as worrying. We spend an average
75 per cent of our time at home, and it can be no coincidence that the most
important source of allergens in the world is the house dust mite. The warm,
humid environment of double-glazed homes provides ideal conditions for these
creatures. The environment also determines which allergies predominate in
particular areas. Studies in cities in the US have shown that, in wealthier
areas, the primary asthma-causing allergens are house dust mite and cat
fur, while in poorer areas, house dust mite and cockroach are the main
offenders. This has led to speculation that the increasing incidence of
allergies may relate to increasing exposure to allergens. The average American
eats about 5 kilograms of peanut products each year, with about 80 per cent of
infants having been exposed before their first birthday. Increasing reports of
peanut allergy may simply reflect increased peanut intake. Consequently, many
clinicians now advocate peanut avoidance in young children with suspected
atopy.

Nearly all allergic reactions are the result of an immune response called
type I immediate hypersensitivity. Like the response to infection by
pathogens, type I immediate hypersensitivity has two stages:
sensitisation, when an allergen is first encountered, and provocation,
which may follow weeks or even years later, when the allergen next
appears.

Once past the epithelium, allergens are ingested by antigen-presenting
cells. These cells process the allergen and present a fragment of it (an
antigen) on their cell membranes. They do this by binding the allergen to
the class II major histocompatibility complex molecule, MHC II for short
(Figure 2). Another class of MHC molecule, MHC I,
presents antigens that originate from within the cell, for instance fragments of
a virus that has infected it.

The antigen-MHC II complex is recognised by a member of the next group of
cells in the immune response, the lymphocytes. There are two types of
lymphocyte: B-cells and T-cells. B-cells make antibodies
(immunoglobulins), which are responsible for immune responses targeted at
specific antigens. But they can鈥檛 mount this response until they have
communicated with T helper cells (TH cells). There are two types of TH
cell: TH2 cells help to tackle infection by bacteria or parasitic worms
and are central to the regulation of the allergic response, and TH1 cells
are more often involved with cell-mediated immunity鈥攊mmune reactions
particularly suited to dealing with cells infected with viruses.

The outcome of the interaction between antigen-presenting cells and T-cells
dictates the subsequent course of events. At this point, in a non-allergic
individual, no further action would be taken by the immune system. However, in
the allergic individual, TH2 cells then instruct B-cells to produce
immunoglobulins. There are five classes of immunoglobulin: IgA,
IgD, IgE, IgG and IgM. Each is suited to different
roles. IgE, for example, is produced in response to parasitic infection, but
came to the attention of biologists in 1966 because of its role in allergy. TH2
cells involved in the allergic reaction stimulate B-cells to produce IgE.

CLONAL SELECTION

Memory is made of this

IgE has two types of binding site: a pair of antigen-binding sites (called
Fab fragments) and a cell-binding site (Fc fragment)
(Figure 3). One IgE
molecule binds specifically to one antigen. The immunoglobulins in our bodies
have an almost infinite variety of binding preferences, but each B-cell produces
just one kind. When an antigen is first encountered, the B-cell that produces
the relevant immunoglobulin must be chosen from the thousands available. This
B-cell is then stimulated to proliferate and mature into antibody-producing
cells. Moreover, memory B-cells are produced so that the immune system will
remember and react more quickly the next time the antigen is encountered. This
is known as clonal selection.

Also found in the tissue just the other side of the epithelium are mast
cells. These are responsible for the earliest symptoms of allergic reactions. On
the surface of each mast cell are numerous sites where IgE can bind (IgE
receptors). IgE that has been produced in response to sensitisation by an
allergen docks on the surface of these cells and lies in wait. Following
provocation, allergens bind specifically to these receptor-bound IgE molecules.
When an allergen cross-links two adjacent IgE molecules
(Figure 4), the mast
cell releases chemicals called inflammatory mediators, which cause allergic
symptoms. Some, including histamine, are released from specialised compartments
(granules) within the cell and others, including prostaglandin D₂
(PGD₂), and leukotriene C₄ (LTC₄), are newly
synthesised for the purpose.

Histamine dilates capillaries and increases their permeability,
causing plasma leakage into surrounding tissues and swelling (oedema). It
also promotes mucus secretion and smooth muscle contraction, and stimulates the
sensory nerves responsible for itchiness. PGD₂ dilates capillaries and is
a more potent stimulator of smooth muscle contraction than histamine. LTC
₄ also dilates capillaries, but is a more potent stimulator of smooth muscle
contraction than either PGD₂ or histamine.

Allergic symptoms depend entirely on where in the body the immune system is
provoked. Capillary dilation, oedema, mucus secretion and smooth muscle
contraction in the gut wall cause the symptoms of an upset stomach. This mirrors
the response to infection by multicellular parasites鈥攁 reaction that
probably evolved to prevent parasites anchoring themselves in the gut.

In the airways, the same mediators produce the symptoms of asthma,
with smooth muscle contraction being responsible for the characteristic wheeze
as the tubes that carry air to and from the lungs are constricted. The heat,
redness and itch associated with urticaria or eczema (dermatitis) are
caused by capillary dilation, oedema and sensory nerve stimulation. In the nose,
meanwhile, mucus secretion, oedema and itch are the dominant symptoms (hay
fever). The airways and gut are not supplied with the same sensory nerves,
so they do not itch.

These symptoms are localised to the site of allergen entry. But if allergens
enter the circulation, for example after an insect sting or
following absorption from the gut, they may cause systemic reactions
culminating in an extreme allergic response, or anaphylaxis. This
involves respiratory difficulty (particularly related to oedema in the airways)
and a sudden drop in blood pressure. Anaphylaxis is caused by an enormous number
of mast cells, and functionally equivalent cells in the circulation called
basophils releasing their mediators around the body. The rapid onset of
anaphylaxis can lead to death in a matter of minutes. In almost all cases,
however, immediate administration of intravenous adrenalin causes equally rapid
recovery.

Immune responses are regulated by chemical messengers called cytokines
that are released by most, if not all, of the cells involved in these responses
(see Inside Science No. 12). Interestingly, TH1 cells produce cytokines that
reduce TH2 cell responses, and TH2 cells produce cytokines that reduce TH1 cell
responses.

TH2 cytokines activate the next type of cell in the allergic reaction, the
eosinophils. These produce a number of powerful toxins that have evolved
to kill parasitic worms. In the absence of worms, host tissue is damaged
instead. If an allergen is continuously present, for instance in house dust,
eosinophils remain active leading to chronic inflammation. This in turn leads to
hyperreactivity, which is characterised either by an increased response
to allergen鈥攆or instance identical doses of the same pollen making hay
fever symptoms progressively worse鈥攐r by an increased response to
nonspecific stimuli, for example when inhaling cold air provokes asthmatic
symptoms.

Allergies can鈥檛 be attributed to a single gene. In the case of asthma, genes
for immunoglobulin production, IgE receptors, cytokines, histamine, leukotrienes
and T-cell response have all been implicated. Candidate genes such as these have
been investigated in 13 of the 23 pairs of human chromosomes. Asthma may turn
out to be a range of disorders with up to 30 genes involved. One day it may be
possible to screen people for genes that predispose them to particular
allergies, and it may even be possible to target the products of these genes
with drugs.

Why are the genes for allergy so common? Have they conveyed some evolutionary
advantage in the past? IgE is an important component of the immune response
against multicellular parasites, many of which, including the intestinal worm
Ascaris lumbricoides, are endemic in most of the world鈥檚 population.
Recently, a study was carried out on two groups of Venezuelan children from
similar economic backgrounds and with similar frequencies of A.
lumbricoides infection, but with different prevalences of allergic disease.
The results revealed that children from the population with the higher
prevalence of allergies had less severe parasitic infection. So perhaps atopy
has conferred a selective advantage that could compensate for its involvement in
allergic disease.

CATCH A COLD

The vital early years

Another area of growing interest is fetal and infant programming of immunity.
The importance of the environment in the development of allergies has long been
acknowledged, but the environment before birth has only recently been addressed
(see 鈥淚n the womb: the earliest responses鈥�).
Following birth, the immune system continues to develop and
the symptoms of allergy vary with age

Since the fall of the Berlin Wall in 1989, the inhabitants of East Germany
have seen a dramatic swing towards Western living conditions. This has been
accompanied by a rise in the incidence of allergic diseases, but in a very
age-dependent fashion. Studies have been carried out on children who lived in
the former socialist system until they were three years old. Between 1991-92 and
1995-96 there was a significant increase in the prevalence of hay fever in these
children, but there was no corresponding increase in the number of children with
asthma. This suggests that there are important differences in the development of
childhood asthma compared with hay fever.

Factors acting before a child鈥檚 third birthday, perhaps including family
size, day-care facilities and socioeconomic status, evidently play a more
important role in the development of asthma. Viral infection may be the common
link. Younger children in larger families tend to catch the most colds and other
viruses early in their lives (courtesy of their elder siblings), and are
statistically less likely to develop asthma. In turn, viral infection is
associated with cell-mediated immune responses, which tend to increase the
production of TH1 cells at the expense of TH2 cells. It seems likely that by
pushing the immune system towards TH1-mediated responses early in life (and
even before birth), the risk of developing asthma later in life may be
significantly lower.

Given the apparent worldwide increase in allergies to foods, particularly
anaphylactic reactions, the issue of labelling has come to the fore. By law,
supermarkets in Europe are obliged to show the ingredients that make up a
product. However, 鈥渃ompound ingredients鈥� (for example pastry in a quiche) do not
have to be fully listed if they account for less than 25 per cent of the
product. This can be a problem if they contain allergens such as nuts.
Fortunately, most supermarkets take labelling very seriously, but there is a
danger that in an effort to protect the customer (and the supermarket from legal
action) they will overdo it. Putting: 鈥淭his product may contain nuts鈥� labels on
every loaf of bread and packet of biscuits may lead to complacency. To this end,
doctors and patients are demanding a more considered approach to labelling.

There is huge pressure to tackle the rising incidence of allergies. In 1997,
the direct and indirect costs of allergies in Europe were estimated to be
拢22 billion per year, and a pan-European response to the problem was
initiated. The International Study of Asthma and Allergies in Childhood is
investigating patterns of disease across Europe and the extent to which they
relate to allergens, other environmental agents and factors such as previous
infections and immunisations. The WHO has announced plans to halve the number of
asthma-related deaths worldwide within five years (each year there are about
25 000 avoidable deaths from asthma).

At a time when the prevalence of allergic disorders is increasing everywhere,
the hope is that further understanding of the complex interactions involved in
their development will reveal new opportunities for prevention and
treatment鈥攁nd help to avoid tragedies like the one that took the life of
athlete Ross Baillie.

The children of allergic mothers are more likely to develop allergies than
those of allergic fathers, suggesting that mothers play a unique role in the
genesis of allergy鈥攑erhaps even before birth. Research at the University
of Southampton has shown that when expectant mothers are exposed to birch tree
pollen 22 weeks into pregnancy, their infants display elevated immune responses
to the pollen at birth. In fact, these elevated responses are only seen in
children whose mothers are exposed to allergens during months 5 to 7 of
pregnancy. This implies that there is a period in the early development of the
immune response when allergen exposure does not trigger the development of
immune memory and a period later in pregnancy when exposure may result in a lack
of response to the allergen or a form of tolerance.

Pregnancy is associated with a depression in maternal cell-mediated (
TH1) immune responses and therefore it is likely that expectant mothers have
increased TH2-mediated immune responses鈥攂ecause TH1 cytokines
normally reduce TH2 cell responses. It has been suggested
that this shift towards TH2 responses is exaggerated in allergic mothers, and
that this might encourage the development of similar responses in the unborn
child.