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Allergy And Anaphylaxis

Allergy And Anaphylaxis
By far the most common form of hypersensitivity is Gell and Coombs’ type I, which embraces such everyday allergic conditions as hay fever, eczema and urticaria but also the rare and terrifying anaphylactic reactions to bee stings, peanuts, penicillin, etc. In both cases the underlying mechanism is a sudden degranulation of mast cells (centre) with the release of inflammatory mediators, triggered by specific antibodies of the IgE class. It is therefore an example of acute inflammation (as already described in Fig. 7) but induced by the presence of a particular antigen rather than by injury or infection. With systemic release (anaphylaxis) there is bronchospasm, vomiting, skin rashes, oedema of the nose and throat, and vascular collapse, sometimes fatal, while with more localized release one or other of these symptoms predominates, depending on the site of exposure to the antigen. Type I hypersensitivity also underlies many cases of asthma, where continuous triggering of local inflammation leads to hypersensitivity of the lung wall and consequent prolonged bronchoconstriction and airway obstruction.

Allergy And Anaphylaxis

Antigens that can trigger these reactions are known as ‘allergens’. Allergens are often small molecular weight proteins (e.g. insect enzymes) or molecules that bind to host proteins (e.g. penicillins). People who suffer unduly from allergy usually have raised levels of IgE in their blood and are called ‘atopic’, a trait that is usually inherited, at least 12 genes being involved. As worm antigens are among the most powerful allergens, the existence of this unpleasant and apparently useless form of immune response has been assumed to date from a time when worm infections were a serious evolutionary threat. Inflammation itself, of course, is an invaluable part of the response to injury and infection, and where injury is minimal (e.g. worms in the gut), IgE offers a rapid and specific trigger for increasing access of blood cells, etc. to the area. It is important to note that the term ‘allergy’ is sometimes used more loosely to describe any adverse response to environmental stimuli, such as allergy to fungal spores experienced by some farmers, which has a totally different immuno- logical basis, or food ‘allergies’, some of which do not involve the immune system at all.
There is a close link between inflammation and the emotions via the autonomic nervous system, through the influence of the sympathetic (α and β) and parasympathetic (γ) receptors on intracellular levels of the cyclic nucleotides adenosine monophosphate (AMP) and guanosine monophosphate (GMP), which in turn regulate cell function – in the case of mast cells, mediator release (see Fig. 25). Note also that mast cell degranulation can be triggered directly by tissue injury (see Fig. 7) and complement activation (see Fig. 6), and by some bacteria.
IgE The major class of reaginic (skin sensitizing; homocytotropic) antibody. Normally less than 1/10 000 of total Ig, its level can be up to 30 times higher, and specific antibody levels 100 times higher, in allergic or worm-infested patients. Binding of its Fc portion to receptors (Fcε) on mast cells and basophils, followed by cross-linking of adjacent molecules by antigen, triggers degranulation. Injection of antigen into the skin of allergic individuals causes inflammation within minutes – the ‘immediate skin response’. A humanized monoclonal antibody against IgE (see Fig. 14) has recently been approved for the treatment of severe allergic asthma. IgG antibody, by efficiently removing antigens, can protect against mast cell degranulation.
TH Helper T cell. IgE production by B cells is dependent on the cytokine IL-4, released by TH2 cells. In atopic patients, allergens tend to induce an unbalanced production of the ‘TH2 type’ cytokines IL-4, IL-5, IL-13, etc., but very little of the TH1 cytokines such as IFNγ which downregulate IgE production. Drugs that inhibit these cytokines are being tested for treatment of these diseases.
Mast cells in the tissues and blood basophils are broadly similar, but there are differences in the content of mediators. There are also important differences between the mast cells in the lung and gut (‘mucosal’) and those around blood vessels elsewhere (‘connective tissue’). Mast cells are regulated by T lymphocytes via cytokine production.
Eosinophils have an important role in inflammation in the lung, which can lead to asthma, and perhaps also to gut inflammatory diseases, including those that may underlie some food allergies. Similar to mast cells they release a variety of inflammatory mediators, and they too are regulated by T-cell-derived cytokines, especially IL-5. They are prominent with PMN, in the ‘late phase’ reaction that follows up to 24 hours after the immediate response.
 Ca2+ Following the cross-linking of IgE receptors, membrane lipid changes lead to the entry of calcium, and an increase in adenylate cyclase, which in turn raises cyclic AMP (cAMP) levels.
cAMP, cGMP Cyclic adenosine/guanosine monophosphates, the relative levels of which regulate cell activity. A fall in the cAMP: cGMP ratio is favoured by Ca2+ entry and by activation of α and γ receptors, and results in degranulation. Activation of the β receptor (e.g. by adrenaline) has the opposite effect; atopic patients may have a partial defect of β-receptor function, permitting excessive mediator release.
Atopy is a condition characterized by high levels of circulating IgE antibodies, which predisposes the individual to the development of allergy. This is regulated by both genetic and environmental factors, which are currently the object of intense study. The genetic regulation of atopy is complex and multigenic, involving polymorphisms at 20 or more loci. These include polymorphisms in the Fcε receptor, but also non-immunological components such as the receptor for the neurotransmitter 5HT. Interestingly, the prevalence of atopy has increased over the past three decades. This has been variously attributed to increased levels of pollutants in the environment or, more convincingly, to decreased exposure to bacterial infection during early child- hood, and hence an imbalance in the developing TH1/ TH2 balance of the immune system (the so-called hygiene hypothesis).
Asthma is a chronic condition in which the airways become thickened and hypersensitive to environmental stimulation (e.g. during viral infection, or by allergens, dust or even changes in air temperature), which causes them to constrict, resulting in obstruction of the airways and shortness of breath; this can be severe and even fatal. Constriction is thought to be triggered initially by mast cell degranulation (the early phase). Mediators released by the mast cells activate muscle constriction and mucus secretion, but also recruit eosinophils to the lung wall, which in turn degranulate, causing a second delayed episode several hours later. Asthma has a strong genetic predisposition, and there has been an intensive search for gene polymorphisms associated with this disease. Over 25 candidate genes have been identified, and there are probably more. Treatment is still predominantly symptomatic by administering bronchodilators, often delivered by ‘inhalers’.

Many of these are preformed in the mast cell granules, including histamine, which increases vascular permeability and constricts bronchi, chemotactic factors for neutrophils and eosinophils, and a factor that activates platelets to release their own mediators. Others are newly formed after the mast cell is triggered, such as prostaglandins (PG) and leukotrienes (LT; for details see Fig. 7), which have similar effects to histamine but act less rapidly.

Sodium cromoglycate (DSCG; Intal) and steroids (e.g. betamethasone) are thought to inhibit mediator release by stabilizing lysosomal membranes. Other drugs used in allergy include antihistamines (which do not, however, counteract the other mediators, and are not helpful in asthma); adrenaline, isoprenaline, etc., which stimulate β receptors; anticholinergics (e.g. atropine), which block γ receptors; and theophylline, which raises cAMP levels. It has been gratifying to physicians to see the molecular pharmacology of cell regulation confirming so many of their empirical observations on the control of allergic disease.

Non-IgE triggering
The complement products C3a and C5a can cause mast cells to degranulate, and so can some chemicals and insect toxins. Such non-IgE- mediated reactions are called ‘anaphylactoid’.

Allergic diseases
The term ‘allergy’ is often used to cover a whole range of different disorders. Originally, the term ‘atopy’ referred only to hay fever and asthma, which are usually due to plant or animal ‘allergens’ in the air, such as pollens, fungi and mites. However, similar allergens may also cause skin reactions (urticaria), either from local contact or following absorption. Urticaria after eating shellfish, strawberries, cows’ milk, etc. is a clear case where the site of entry and the site of reaction are quite different, due to the ability of IgE antibodies to attach to mast cells anywhere in the body.
Some allergies do not result from type I hypersensitivity. The allergic reaction of some farmers to hay (farmer’s lung) or some individuals to their pets (e.g. pigeon fancier’s disease) seem to be due to immune complex formation (type III hypersensitivity). Allergy to wheat gluten (coeliac disease) is probably mediated predominantly by T cells, and may therefore be classified as type IV hypersensitivity. Some food ‘allergies’, e.g. to milk, do not have an immunological basis at all and are more properly termed ‘food intolerance’.