Figure-17 HLA associatio n of IgE responses to allergens from ragweed and ryegrass.

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1 Figure-16 (1) The serum concentration of IgE (which is around 100 IU/ml) is only ~0.001% that of IgG (around 10 mg/ml) and comprises less than 0.001% of the total immunoglobulin. Levels in atopic patients tend to be raised, and this is especially so in atopic eczema (1 IU=2.4 ng). (2) The higher the level of IgE the smaller the percentage of the population affected, but the greater the likelihood of atopy. Where the level is greater than 450 IU/ml the majority of subjects are atopic. Figure-17 HLA associatio n of IgE responses to allergens from ragweed and ryegrass.

2 Figure-18 Allergic diseases run in families, however the inheritance is not simple. Population-based studies have established that the inheritance of allergic diseases is influenced by multiple genes. Some of these, such as HLA-linked control of the response to pollen antigens or genes controlling total IgE, are related to the immune response. However, many others are related to the mechanisms of inflammation, e.g. IL-4 and IL-5 gene polymorphisms, or to the response to treatment, e.g. leukotrienes receptor genes or polymorphisms of the β 2 -adrenergic receptor.

3 Figure-19 Skin tests are carried out by introducing 0.02 ml of extract intradermally. With allergens such as pollen, cat or dust mite, the positive reaction is an immediate (i.e. within 20 min) wheal, when in some cases is followed by an indurated response occurring late (i.e. at 4-12 hours). Non-allergic individuals make no discernable reaction to testing with these allergens. A delayed skin response is the commonest form of positive response to tuberculin, tetanus and mumps, or to fungi such as Trichophyton and Candida. The skin typically shows no reaction up to 12 hours and then gradually develops an erythematous indurated, delayed hypersensitivity response, which is maxium at hours. Patch tests are peformed by applying a gauze pad with allergen to a patch of skin which has been mildly abraided. This procedure may give an immediate wheal response, but this is followed at hours by an indurated, erythematous response, which has many of the features of eczema. The patch test is not a diagnostic test but has provided extensive information about the role of allergens in atopic dermatitis. Figure-20 Eczema induced by patch test with mite allergen. An erythematous and eczematous skin response 48 hours after the application of 5 μg of the mite allergen Der p 1 to the skin of a patient with atopic dermatitis who had 56 IU/ml of IgE antibody to the dust mite Dermatophagoides pteronyssinus. Biopsy of the patch site revealed an infiltrate of eosinophils, basophils and lymphocytes.

4 Figure-21 Eosinophil major basic proteins in the skin of atopic dermatitis. Skin biopsy from a patient with severe atopic dermatitis. The hematoxylin and eosin (1) shows an inflammatory infiltrate but very few intact eosinophils are present. The same section stained with antibodies to eosinophil major basic protein (MBP) (2) shows extensive deposition of MBP in the dermis, demonstrating that eosinophils had degranulated in the skin. Inflammatory response in asthmatic bronchi

5 Figure-22 Mast cells release factors that can induce immediate bronchospasm, e.g. histamine and LTD 4, but also release chemotactic factors such as LTB4, IL 5 and TNFα. The spasmogens can induce oedema, increased mucus and smooth muscle constriction resulting in immediate decrease in airway conductance and a fall in the forced expiratory volume at 1 second (FEV 1 ). By contrast, chemotactic factors recruit cells out of the circulation including eosinophils, neutrophils, lymphocytes and macrophages. These cells can chronically modify the lung with goblet cell hyperplasia, collagen deposition below the basement membrane and possibly smooth muscle hyperplasia. In addition, these cells and their products produce non-specific bronchial hyper-reactivity (BHR). Thus chronic bronchospasm includes elements of hypersecretion, inflammatory infiltrate thickening the walls of the small bronchi and bronchial smooth muscle spasm. Evidence for this inflammatory response can be obtained from increased exhaled nitric oxide (eno); increased eosinophils or ECP in induced sputum; and experimentally from biopsies of the lung, neutrophils=1; basophils=2; eosinophils=3; monocytes=4. Figure-23 Locally active steroids are widely used in seasonal rhinitis perennial rhinitis, asthma and atopic dermatitis. In addition, courses of systemic steroids are used for the treatment of exacerbations of asthma.

6 Figure-24 Localization of MBP in the lung of a severe asthmatic (1) Respiratory epithelium showing striking submucosal eosinophil infiltration and a cluster of desquamated epithelial cells in the bronchial lumen (arrowed) next to a 'stringy' deposit of soot. H&E stain. (2) The same section stained for major basic protein (MBP) showing immunofluorescent localization in infiltrating eosinophils. MBP deposits are also seen on desquamated epithelial cells on the luminal surface. (3) A control section stained with normal rabbit serum does not stain eosinophils or bronchial tissue but does show some non-specific staining of the sooty deposit.

7 Figure-25 Nasal eosinophils. Nasal smear from an 8-year-old boy presenting with acute asthma. The majority of the cells are eosinophils, polymorphonuclear cells with a cytoplasm that stains red using H&E stain. He was known to be allergic to dust mites and had recently had a rhinovirus infection as judged by PCR on nasal secretions.

8 Figure-26 During desensitization or immunotherapy the allergic patient receives regular subcutaneous injections of the relevant allergen. The immunological changes that occur include an initial increase in IgE antibodies followed by a gradual decline, which in pollen-allergic patients is largely due to a blunting of the seasonal increase progressively and may reach concentration of ten times those present prior to treatment. Symptoms decline starting as early as 3 months but generally not maximally until 2 years. Changes in T cells are less well defined but include decreased in vitro response to allergens and increased production of IL-10.

9 Figure-27 (1) Schistomosomule being killed by eosinophils. A schistomosomule being killed by eosinophils which had been cultured from mouse bone marrow in the presence

10 of IL-5. The larval helminth had been first treated with IgG antibodies and the eosinophils adhere by means of their Fcγ receptors. (2) Electron micrograph of eosinophil. Transmission EM of an eosinophil, degranulation of eosinophils usually leads to death of the cells. The mediators released include major basic protein (MBP) eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil derived neurotoxin (EDN). In addition, eosinophils can produce leukotrienes and the cytokines IL-5, granulocyte macrophage colony-stimulating factor (GM-CSF) and TGFα. img = immature granules; mg=mature granules with crystalline core. The scale bar is 1 μm. Dr. MUSTAFA HASSAN LINJAWI