Type I hypersensitivity – atopic allergy (Figure 62.1)

This involves IgE antibodies and mast cells: ‘atopy’ refers to a propensity for production of high levels of IgE. Allergen-specific IgE molecules, bound to Fcε receptors on mast cells, are cross-linked by specific allergens, triggering release of preformed inflammatory mediators by degranulation (e.g. histamine) and synthesis of newly formed mediators (e.g. leukotrienes and prostaglandins). These mediators induce inflammation and smooth muscle contraction.

T_H2 cells play a central role in the induction type I hypersensitivity, e.g. by secretion of IL-4 that stimulates IgE production by B cells, and IL-5 that stimulates eosinophils. The immediate elicitation phase of a type I hypersensitivity response is generated by mast cell activation, whereas T_H2 cells and eosinophils can be implicated in the late phase reaction that can result in chronic tissue damage.

Different types of atopic disorder are induced by different types of allergen and routes of exposure.

• Allergic rhinitis is commonly triggered by pollen allergens that activate mast cells in the upper respiratory tract – hence the name ‘hay fever’.
  
• Wheezing associated with allergic asthma involves bronchial constriction in the lower respiratory tract, often caused by an allergic response to house dust mite constituents.
  
• Food allergens may cause local symptoms in the gut (e.g. vomiting, diarrhoea), but once absorbed into the bloodstream may have wider effects, e.g. skin reactions (urticaria, eczema) or potentially life-threatening systemic effects (anaphylaxis) as exemplified in severe nut allergies.
  
• There are no clear examples of autoimmune diseases that involve type I hypersensitivity.

Type II hypersensitivity – cell or membrane reactive (Figure 62.2)

This involves IgG, IgA, or IgM antibodies that bind to cell surface membranes or connective tissue components. These induce damage by activating complement and/or triggering neutrophils to release digestive products and reactive oxygen species.

Allergic haemolytic anaemia can be induced by drugs that bind to erythrocytes and if antibodies are generated against these drugs, then erythrocyte lysis can result; similarly, autoimmune haemolytic anaemia involves autoantibodies specific for erythrocyte surface autoantigens, and autoimmune thrombocytopaenia involves autoantibody-induced platelet destruction. Naturally occurring antibodies to blood group antigens expressed by erythrocytes (e.g. anti-A and anti-B antibodies) can cause life-threatening reactions to incompatible blood transfusions. The main cause of haemolytic disease of the newborn is maternal IgG antibodies to the rhesus D antigen expressed by the erythrocytes of a D-positive fetus developing in a D-negative woman; these IgG antibodies cross the placenta from the mother to the fetus and cause destruction of fetal erythrocytes.

Autoantibodies to basement membranes cause tissue damage to the skin in pemphigoid (skin epidermal basement membrane) and Goodpasture’s disease (kidney glomerular basement membrane).

A special case of type II hypersensitivity (sometimes called type V) involves autoantibodies to membrane-associated receptor proteins. Myasthenia gravis can involve autoantibodies specific for the acetylcholine (ACh) receptors expressed on muscle cells at the neuromuscular junction (Chapter 22). These autoantibodies block binding of ACh released from nerve endings, and also induce internalisation and degradation of receptors. This results in extreme muscle weakness due to a lack of nerve stimulation of muscle contraction. In Graves’ disease, autoantibodies specifically bind to the TSH receptor expressed by thyroid follicular cells and stimulate thyroid hormone production. The action of these ‘thyroid-stimulating antibodies’ is not regulated (as is TSH itself), leading the overproduction of thyroid hormones and hyperthyroidism (Chapter 47).