IMMUNOLOGY - Roit I. - Mir 2000

Chapter 23. Hypersensitivity - Type I

BRONCHIAL REACTIONS

Bronchi also respond to allergens with a biphasic reaction (Fig. 23.19). Sodium cromoglicate is a highly effective Treatment for allergic asthma; it prevents both the immediate reaction and the late-phase reaction following an allergen bronchoprovocation test. This indicates that The Development of the late-phase pulmonary reaction requires an initial interaction between the allergen, IgE, and mast Cells; by blocking degranulation, sodium cromoglicate prevents all subsequent events. If patients are pretreated with corticosteroids or prostaglandin synthase inhibitors, only the late-phase reaction disappears, whereas the immediate response remains completely intact. This highlights The Role of arachidonic acid metabolites, such as Prostaglandins and Leukotrienes, in the Development of the late-phase reaction (see Fig. 23.14).

Most asthma patients with recurrent attacks benefit from inhaled corticosteroids, which reduce inflammatory cellular infiltration of the bronchi, particularly that associated with the late-phase reaction (Fig. 23.20).

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Fig. 23.19. The graph shows the forced expiratory volume (FEV) – an index of lung function – in three groups of subjects before and several hours after a provocation test (application of an allergen to the bronchial mucosa). In the control group (Group 1), a biphasic (immediate and late) bronchial constriction is observed. The immediate reaction lasts for 1 h and is followed by the late-phase reaction (LPR), lasting several hours. Histamine, released by mast cells upon their degranulation, is considered the primary mediator of the immediate reaction in humans. Subjects in the other two groups received various pretreatments. Pretreatment with sodium cromoglicate (SCG) (Group 2) blocked mast Cell degranulation and prevented both the immediate and late-phase reactions. Pretreatment with indomethacin or corticosteroids, which block arachidonic acid METABOLISM, inhibited only the late-phase reaction (Group 3). This indicates the involvement of leukotrienes and prostaglandins in the development of this response. Long-term corticosteroid treatment may also attenuate the immediate reaction, but the LPR is completely blocked. Asthma patients often use inhaled corticosteroid preparations as a first-line treatment because they reduce inflammatory infiltration of the bronchi. This underscores the paramount clinical importance of the LPR and its consequences in chronic asthma.

Fig. 23.20. Mast cell mediators include chemotactic and spasmogenic factors. Spasmogens trigger the immediate bronchial constriction response and increase the permeability of small vessels, causing edema and cellular influx into the interstitial space. Chemotactic factors and cytokines, such as GM-CSF, IL-5, and TNFα, promote the active accumulation of neutrophils (1), basophils (2), eosinophils (3), macrophages (4), and platelets (5). These tissue-infiltrating cells produce inflammatory molecules, driving the late-phase reaction and sustaining the chronic inflammation characteristic of asthma. Subacute or chronic asthma is driven by multiple interacting factors, including hypersecretion of mucus (M), smooth Muscle hypertrophy (SM), and cellular infiltration (CI) accompanied by bronchial hyperresponsiveness. Corticosteroids reduce cellular infiltration and nitric oxide production.

Bronchoalveolar mast cells play a crucial role in the asthmatic reaction

The number of mast cells in the bronchial lumen is increased in asthma patients. The Location of these cells places them in a prime position to interact with inhaled allergens and initiate an IgE-mediated response in the Lungs. Cells isolated from bronchoalveolar lavage (BAL) exhibit a low degranulation threshold (as evidenced by high mediator levels in BAL fluid). These cells appear to be the primary target for the anti-asthma action of sodium cromoglicate, as well as likely other agents such as cyclosporin: they are inhibited more readily than cells derived from the lung parenchyma (Fig. 23.19). Furthermore, recent findings show that T cells present in the BAL of asthma patients are predominantly Th2 cells, supporting the role of IgE in the allergic Immune Response of the lungs in asthmatics. Pronounced cellular infiltration is also observed in the bronchial mucosa, which may contribute to the chronicity of asthma.

Other factors in the Pathogenesis of chronic asthma

Eosinophils. Extensive evidence points to a central role for inflammatory cellular infiltration in the development of the late-phase reaction. During this phase (but not the early phase) of asthmatic reactions, an increased number of eosinophils, among other cells, is detected in BAL. IL-5, secreted by Th2 and mast cells, acts as a chemoattractant for eosinophils and enhances their production of mediators and cytokines (Fig. 23.21). By releasing major basic Proteins from their granules, eosinophils damage the airway epithelium (Fig. 23.22). This facilitates deeper allergen penetration and provides inflammatory mediators easier access to afferent nerve endings, triggering bronchospasm via axon Reflexes. Released Neuropeptides, such as vasoactive intestinal peptide, substance P, and Calcitonin Gene-related peptide, amplify the inflammatory response and thereby increase bronchial hyperresponsiveness.

Fig. 23.21. Eosinophil degranulation can be stimulated by an allergen interacting with IgE bound to FcεRI and FcεRII, or by soluble mediators such as PAF and LXB₄. Eosinophils release various proinflammatory cytokines and membrane-newborn mediators. In addition, they release highly cytotoxic major basic proteins from their granules, which damage epithelial cells in chronic asthma.

Fig. 23.22. Localization of major basic protein (MBP) in the lungs of a patient with severe asthma. 1. Marked eosinophilic infiltration of the submucosa of the respiratory epithelium and accumulation of desquamated epithelial cells in the bronchial lumen (indicated by the arrow) adjacent to "fibrous" carbon deposits. Hematoxylin and eosin staining. 2. The same section stained for major basic protein, which is identified by immunofluorescence localized in tissue-infiltrating eosinophils. MBP deposits are also visible on desquamated epithelial cells located on the luminal surface. 3. Control section stained using normal rabbit serum. Eosinophils and bronchial tissue do not fluoresce, but slight non-specific staining of carbon deposits is observed. (Photographs kindly provided by Dr. G. Gleich, from J. Allergy Clin. Immunol. 1982; 70: 160-9. Reproduced with permission.)

Bronchial hyperresponsiveness. The sensitivity of bronchi to histamine and non-specific stimuli, such as cold and humid air, is increased in asthma. Indeed, healthy individuals experience an asthma attack upon inhaling 10 ng of histamine, whereas asthma patients react to as little as 0.5 ng or less. As demonstrated by Platts-Mills, a three-month stay for asthma patients in a clean hospital environment, free from domestic triggers (such as the inhalation of house dust mite feces), drastically reduces or completely normalizes their sensitivity to histamine, and the course of asthma improves as well. These findings support the concept that bronchial hypersensitivity in asthma is linked to chronic allergen exposure.

Nitric oxide. In response to cytokine stimulation, many cells begin to produce nitric oxide (NO) via the action of inducible nitric oxide synthase (iNOS). It has recently been established that this enzyme is present in high concentrations in the bronchial epithelium of asthma patients, unlike healthy individuals (Fig. 23.23). Nitric oxide generated by iNOS activity can be detected in the exhaled breath of untreated asthma patients; its levels decrease following corticosteroid inhalation (Fig. 23.23), which is known to inhibit the expression of both cytokines and iNOS. These findings suggest a potential role for NO in the pathogenesis of asthma and highlight Structure/19.html">The Importance of measuring its exhaled levels for the Diagnosis, monitoring, and Treatment of the disease.

Fig. 23.23. 1. Biopsy specimen from an asthma patient. The bronchial epithelium, showing signs of damage in localized areas, stains intensely with Antibodies against iNOS. 2. In untreated patients with mild asthma, exhaled NO levels are often higher compared to normal values. In patients receiving corticosteroid treatment, exhaled NO levels are close to normal. (Figure kindly provided by Dr. D. Springall.)