Learning something about the functioning of
the immune system is essential to understanding the classic view of allergy.
For those of you who want to know a little about this fascinating defense
mechanism, take a deep breath and here goes!
First of all,
immunity is the ability to fight off unwanted
pathogens. There is natural
(innate) immunity and acquired
(adaptive) immunity. The former has been known about for a long time and relies
on non-specific processes taking place within the body designed to repel
intruders.
For example,
in normal circumstances the skin is impenetrable to nearly all microorganisms
and is therefore a very good line of defense. The nasal and respiratory
passages have minute hairs (cilia) for their defense: these cilia beat
constantly to and fro, sweeping out a stream of mucus to the back of the
throat, which in turn washes away bacteria. This mucus, along with other
secretions such as tears and saliva, contains lysozyme, a chemical substance
that inhibits the growth of bacteria and breaks down their protective coating.
pH (acidity) regulation can also be a crucial
factor. For example, the vagina contains malic acid,
which keeps the pH too low to be suitable for most organisms to flourish or
grow comfortably. Caprylic acid seems to serve the
same function in the bowel.
If all these
fail there are phagocytes
(literally “gobbling cells”) throughout the body to eat up mould spores, dead
bacteria, carbon particles and any other rubbish. Phagocytes generate on-board
hydrogen peroxide and superoxide anion. These free
radicals are lethal to invader cells. But of course they could also damage the
phagocyte and high levels of antioxidants must be present to prevent the
defender cell from being destroyed by the process (note that this phagocytosis takes place whether or not a
fully-fledged immune response is being mounted).
Finally, the
inflammatory process itself (reddening, swelling, tissue oedema)
has an important function in keeping foreign matter from leaving the site and
reaching the rest of the body. Although unpleasant for you, the sufferer, it is
nevertheless a very helpful survival process.
All the above
processes are common to everyone. They are not dependent upon the exact nature
of the invading organism. Hence the term natural or ‘innate’
immunity. Cellular memory is not involved.
Factors Operating in Innate Immunity
The rest of
this section concerns itself with responses of the all-important acquired or
adaptive type of immunity, since it is disharmony in this mechanism that leads
to troublesome allergies and other problems considered in this book. In
contrast to innate immunity, acquired immunity is all about cell ‘memory’ – the
cells’ ability to recognize an invader that they have net before. In fact there
are two aspects to acquired immunity: the cellular response and certain
chemical activities that supplement this.
Cellular Response
Several groups
of cells are involved in a cellular response to ‘invasion’:
1.
Phagocytes
of various types, that is, cells that eat bacterial and viral particles and
other debris. Principal among these are the macrophages – wandering scavengers
found in all parts of the body and particularly geared to respond to immune
system signals.
2.
T-lymphocytes,
which have a complex role. Two main types of T-cells are recognized: so-called helper T-cells and suppressor
T-cells. Helper cells work with macrophages to generate the immune
responses and elicit antibodies that partly paralyze the invader and so help
the macrophages lock on to the enemy cells or particles. Suppressor T-cells come into play towards the
end of an infection to bring a halt to this process. They effectively terminate
the battle with the invaders. Balance between the two types of T-cell helps to
keep the reactions orderly and stop them getting too fierce or going on too long.
3.
B-lymphocytes,
which secrete the anti-bodies
4.
Natural
killer (NK) cells. As their name implies, they are destroyers – but in a
regulated, specific way. They are taught to recognize sick body cells, such as
cancerous tissues or cells invaded by viruses, and to puncture and destroy
these cells, thus releasing their contents which can then be attacked by
antibodies and cleaned up by the macrophages.
Basic immune
response
Mounting An Immune
Response
When an
infective organism invades the tissues, a precise series of events are set up
to limit spread of the foreigner and ultimately to destroy it. First a
macrophage will encounter the intruder. It engulfs it and then ‘displays’ its
characteristic proteins on the surface of the cell as a kind of “flag” or gotcha
trophy. We call this chemical flag the
antigen,
since it generates the rest of the
reaction.
By means of
chemical language (a sort of local hormone called a lymphokine), the macrophage
attracts nearby T-helper lymphocytes. They ‘read’ the antigenic matter and go
off to program B-cells to produce antibodies to this pattern. The
antibody is our own, the good guys’
response, to lock onto antigen carriers and cripple them.
T-helpers also
secrete other lymphokines, which attracts further
T-cells, killer cells and boosts the function of the B-cells, resulting in more
antibodies against the invader.
Eventually,
the enemy is overwhelmed by force majeur.
Two further
steps are important. One is the introduction of memory T-cells. This really is
the essence of lasting immunity; the cells learn to ‘remember’ the particular
antigen involved. When a subsequent infection takes place, they can almost
instantly mount the antibody response, without going through the above steps,
because they remember the antigen and already have the antibodies ‘on tap’.
Finally, there
must be some way of switching off the reaction. This is where the T-suppressor
lymphocytes come in. They scale down the whole process and limit further
response. Nature doesn’t want this destructive process to go on any longer than
necessary.
It is a clever and spectacularly successful system,
the detailed complexity of which surpasses our full understanding so far. The
main drawback is that the body has to meet the foreign protein (antigen) before
it can mobilize its counter-attack (the antibody). In other words, we must be
invaded before we can fight back. This may not matter much with an illness like
German measles or chicken-pox, but it is a serious inadequacy when it comes to
potentially fatal diseases such as smallpox and diphtheria. Basically, those
who survive such dangerous infections do so because their immune systems work
very fast and start to produce antibodies in the nick of time, just before
death supervenes. Those with a slower immune response are not so lucky and will
die.
Or at least they used to. Now we can use vaccination
to prevent such deaths. We introduce an artificial infection, commonly done by
injecting a dead or weakened virus which does not harm the patient, but teaches
his or her body to recognize the virus protein and make antibodies. Thus when
the real invaders come along the body is ready and can start its
counter-offensive by mobilizing antibodies within hours, instead of days, and
so beat off the attack.
The frightening new disease AIDS (Acquired Immune
Deficiency Syndrome) destroys T-lymphocytes and B-lymphocytes so that the body
cannot make enough antibodies. The victim, therefore, dies of simple everyday
infections which can no longer be resisted in the way in which a healthy
individual routinely shrugs them off. Ironically, of course, it means also that
the body is hampered in its ability to round on the AIDS virus and so this is a
particularly grim infection. The search for a vaccine seems very bleak.
Other Cells which may be involved
The
eosinophil is a cell mobilized especially against
parasites and allergens. The monocyte is a
short-lived circulating phagocyte that differentiates into the
macrophage, a cell that may live from months
to several years. The macrophages (literally “great gobbler” cells) are the sweep clean army of
the immune system, engulfing bacteria, viruses, circulating cell debris and
aggregations of immune complexes.
These cells
tend to reside in various organ systems, where they selectively differentiate
according to the needs of their host organ. For example, macrophages in the
liver are celled
Küpffer’s cells, and those in the lung are
termed alveolar macrophages. The
macrophage, like other phagocytes, depends on the generation of free radicals
such as peroxide to destroy its target matter.
Mast cells are involved in the histamine response
(redness, swelling and itching) that characterizes allergic reactions, such as
dermatitis.
Click here to learn more about mast cells and
histamine release.
Complement
The complement
system is another immune response highway which helps to amplify the efficacy
of immune reactions. “Complement” is actually a group of active enzymes which work
in a cascade or tumbledown effect; the release of one triggers the next and so
on, in sequential fashion. They are generally identified in the laboratory as
C1 to C9.
The antigen-antibody complex combines
with C1, which in turn acts on C2 and C4. This acts on C3 and son on, in what
is called a cascade effect, each step leading to the next. The resultant enzymes act on the invader in a
variety of ways and also participate in a local tissue reaction, familiar to us
as inflammation. Although this is unpleasant and can be painful, it does serve
a purpose in containing the attack.
Hypersensitivity
(a heightened state of extreme sensitivity) is another word you will hear
applied to allergy. There are four distinct types of hypersensitivity: Types I
to IV. These divisions are useful for discussion but may not necessarily occur
as single entities in an individual.
There is good evidence that Types I and
III hypersensitivity can cause food-allergic symptoms, and some evidence that
Type III mechanisms can be associated with gut disorders such as colitis.
However, it is vital for doctors to appreciate that reactions to food and
environmental substances may occur, proven empirically, without any of these
mechanisms appearing to be invoked.
TYPE I
HYPERSENSITIVITY
Type I
reactions are basically antigen-antibody reactions.
This is what is usually meant by a classic allergic reaction. Mast
cells release chemical mediators such as histamine, bradykinin,
anaphylotxin, slow-reacting substance-S and others.
This gives rise to severe local inflammation, which may cause bronchospasm (asthma), sneezing (rhinitis), urticaria (or other skin rashes) or diarrhoea
and vomiting if the gut is the target
organ.
The occurrence
of Type I reactions to foods is undisputed. Typical offenders are milk, eggs,
fish and nuts, though any food can do it. Reactions normally occur shortly
after food ingestion and are usually associated with positive skin prick tests
and generally a positive radio allergosorbent test
(RAST) to the relevant food (see
conventional allergy tests).
Type I reactions are more common in
children and have a tendency to disappear as the patient gets older.
Reactions to insect bites and stings are
Type I in nature and can be fatal, if severe, though this is rare.
TYPE II
HYPERSENSITIVITY (CYTOTOXIC)
This type of
reaction occurs when an antibody is directed against a cell-surface or tissue
antigen. Complement activation leads to the generation of inflammatory
mediators, with resulting tissue damage. Cytotoxic tests probably rely on
this process.
Diseases
caused by Type II hypersensitivity include certain haemolytic
(cell-destroying) anaemias, purpura
(bruising) and systemic lupus erythematosus; it is
also usually to blame in incompatible blood transfusions. The infamous Minamata disease (mercury poisoning) was of this type.
Diagnosis is
done by detecting serum antibodies. Raised levels of circulating serum
anti-bodies are seen in many cases of bowel disorder thought to be due to food
sensitivities but, unfortunately, they are also seen in healthy individuals and
their role in food allergy seems confusing and unclear.
TYPE III
HYPERSENSITIVITY
Type III reactions result from the deposition of antigen/antibody
complexes in the tissues.
These complexes are commonly produced after eating, and indeed would be
expected. Normally they are removed by the reticulo-endothelial
system. But if the formation of immune complexes is excessive, the quality of
the complex is abnormal or the reticulo-endothelial
function is impaired, then this normal process is unworkable and disease
results.
Tissue damage
occurs as a result of the inflammation surrounding these abnormal deposits.
Rheumatoid arthritis is an example deposits. Rheumatoid arthritis is an example
of a Type III process, systemic lupus another. These are all types of
auto-immune (self-damaging) diseases.
TYPE IV
HYPERSENSITIVITY
This is often
called the delayed hyper-sensitivity reaction, so-named because of the fact
that in skin testing the reaction may not show up for 12 to 48 hours.
Antibodies are not involved. Contact dermatitis is one clinical condition
caused by this process.
Conventional allergists say this
reaction has little to do with food allergy. Clinical ecologists disagree: it
quite commonly causes food allergy. Many patients react late after challenge
testing. The reason the patients’ reactions are considered irrelevant is
that most doctors do not see them (the patients have gone home) and, since some
doctors are not in the habit of listening to information from their patients,
they miss it!
It has been
suggested that patients with delayed onset food allergy (as opposed to the
immediate IgE type I) have a from
of chronic serum sickness caused by (possibly undetected) circulating immune
complexes of the sort described above. This in an attractive theory and would
explain the widespread organ involvement responsible for the characteristic
multiple symptoms. What governs the selection of the target organ by these
immune complexes is still a mystery.
The presence
of immune complexes would also lend an explanation to
the well-known effect of ‘withdrawal symptoms’ when patients go on a exclusion diet. As long as the patient is eating the food,
excess allergen means immune complexes remain soluble and relatively harmless.
The result, at worst, would be mild, chronic symptoms. But when the food is
excluded from the diet, antigen concentrations will fall, causing the immune
complexes to deposit in the tissues, with well-recognized and predictable
pathological effects.
This could be
behind the paradoxical effect most of us have observed, that if a patient eats more
of an allergy food, the reaction sometimes switches off. It is possible to
construct a sort of dose-response curve (hypothetical) showing this effect (see
Figure).
The graph
line, showing symptoms (effect) in response to the dose (quantity), shows that
small amounts cause little effect, larger amounts
produce an exacerbation of symptoms. Then, if the patient is desensitized, the
whole response curve shifts to the right (the dotted line). In general,
tolerance has improved. But a food customarily ingested at level A-A and well
tolerated at that level is now unmasked and starts to cause trouble. All the
patient observes is that treatment has ‘made things worse’; he or she does not
see this hidden mechanism. The answer, of course, is to eat more – or less – of
the culprit food.
Mast cells are
large granulated cells found in the lymph nodes, the skin and in mucous
membranes such as those in the gut and lung linings. When a Type I
hypersensitivity response takes place, the mast cell granules release a number
of chemical mediator substances into the blood and the surrounding tissues,
which results in the classic allergic reaction – and sometimes true
anaphylaxis. Best known of these mediator substances is histamine. Others
include heparin, serotonin, kinins, arachidonic acid and certain prostaglandins.
Histamine has
two modes of action on the body. This presupposes two kinds of ‘receptors’,
which we call H1 and H2. H1 reactions are related to the classic allergic
reaction and include increased capillary permeability and dilation of blood
vessels, which may lead to circulatory shock (anaphylaxis), and smooth muscle
spasm, which affects the bronchial passages, leading to asthma. These H1 receptors
are blocked by antihistamines.
(H2 receptors lead mainly to the increased secretion of stomach acid; this
is blocked by drugs such as cimetidine).
Mast cell degranulation
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Anaphylaxis is the state of sudden shock or
collapse after an acute allergic reaction (Type I Hypersensitivity). Death sometimes
results. It was first witnessed by the French scientist Charles Richet in 1903. He was trying to immunize a dog against
the poison of a jellyfish by giving it repeated injections (prophylaxis). It
had the exact opposite effect and on the second injection the animal died in
seconds. Hence his term ‘anaphylaxis’.
Anaphylaxis
usually takes place in response to a widespread attack of an allergen
throughout the body. Large quantities of histamine and other mediator
substances (by which the reaction is initiated) are released and the severity
of the reaction is such that fluid loss into the tissues, together with
accompanying lack of muscle tone in the blood vessels, causes circulatory
collapse. Among other effects the lungs rapidly fill with fluid and breathing
becomes difficult.
Death
can be extremely rapid and there are many tragic cases of victims dropping
down dead as they rush to get their emergency aid drugs. It is one of the
most acute of all medical emergencies and there is very little time in which
to act. The only treatment, once anaphylaxis is established, is an injection
of adrenalin which restores the blood circulation. Any other medication is
too slow.
Anaphylaxis
can occur in response to a wide variety of allergens. Most common are foods
such as nuts, egg and fish, or insect stings, where the patient has become
sensitized to these substances. These are always the Type I immediate
hyper-sensitivity reactions.
Fortunately,
this kind of severe reaction is rare, though a number of high-profile deaths
occur each year. Patients at risk must always carry an emergency treatment
kit. The EpiPen emergency dispenser of epinephrine
(adrenalin) is now established, is consists of a syringe with a drug drawn up
in readiness, for self-injection if necessary. Learn how to use it.
However injectable antihistamine blocks the problem
before anaphylaxis supervenes and
is not as unpleasant in its effects as epinephrine. Antihistamine tablets will not protect you in time. If in doubt
go for the EpiPen.
It is sensible for individuals in this risk
category to carry a Medic-Alert emblem. This charitable foundation was
started in 1956 by a doctor whose daughter almost died after being injected
with a serum she was allergic to. It is now registered in many countries (see
Useful Addresses for the Medic-Alert Foundation address). The patient wears a
stainless steel bracelet or necklace showing the warning logo. The patient
also carries a card giving details of what the problem is, so that if found
unconscious or unable to explain the difficulty he or she will not be harmed
by well-meaning attendants.
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Histamine
in Food
Many foods
contain histamine, usually in only small amounts. Red wine has many times more histamine
than white, which may be why it is more prone to cause headache and somnolence.
Histamine levels in food can rise while the food is in storage. This results
from the conversion of histidine to histamine in the
food by bacteria.
Foods that may contain histamine include
‘mould’ foods such as cheese and sauerkraut as well as a number of manufactured
foods, including sausages. Large amounts of histamine usually occur only in
old, fermented products or those that have undergone spoilage.
Scombroid fish
poisoning (or scombrotoxin illness) is a condition
that arises from eating badly stored scombroid fish
(such as mackerel) containing high levels of histamine. The symptoms, which
cannot be distinguished clinically from an allergic reaction, may be provoked
by canned, uncanned
and smoked fish; they include urticaria
(raised, itchy patches of skin), nausea, vomiting, facial flushing, intense
headache, epigastric pain, a burning sensation in the
throat, dysphagia (difficulty swallowing), thirst and
a swelling of the lips.
For asthmatics and those who suffer from
giant urticaria, it might be best to avoid cheeses
and certainly no aged or suspect food should be eaten, especially if it is
fermented.
Other food
toxin reactions, such as shellfish poisoning, can also be mistaken for an
allergy.