The Immune System
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
- Skin and other physical barriers
- Ciliated epithelium
- Lysozyme in secretion
- PH regulation
- Phagocytosis
- Inflammation containment
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.
Factors Operating in Acquired Immunity
Humoral
- Antibodies
- Complement cascade
- Opsonins
Cellular
- Macrophages
- Granulocytes
- B-lymphocytes
- T-cells
- Natural killer cells
- Memory cells
- Intercellular messenger chemicals (lymphokines)
Cellular Response
Several groups of cells are involved in a cellular response to ‘invasion’:
- 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.
- 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.
- B-lymphocytes, which secrete the anti-bodies
- 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.
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
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!
Is Food Allergy A Serum Sickness?
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.
Histamine and Mast Cells
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).
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.