Immunology and asthma Flashcards

Question

Describe sensitjsation and activation of mast cells

Answer 1

Sensitization and Activation of Mast Cells Because mast cells are central to the development of imme- diate hypersensitivity, we first review some of their salient characteristics. Mast cells are bone marrow–derived cells that are widely distributed in the tissues. They are abun- dant near blood vessels and nerves and in subepithelial tissues, which explains why local immediate hypersensi- tivity reactions often occur at these sites. Mast cells have cytoplasmic membrane-bound granules that contain a variety of biologically active mediators, described later. The granules also contain acidic proteoglycans that bind basic dyes such as toluidine blue. (Mast in German refers to fattening of animals, and the name of these cells came from the erroneous belief that their granules fed the tissue where the cells were located.) As is detailed next, mast cells (and their circulating counterpart, basophils) are activated by the cross-linking of high-affinity IgE Fc receptors; in addition, mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a (called anaphylatoxins because they elicit reactions that mimic anaphylaxis), both of which act by binding to receptors on the mast cell membrane. Other mast cell secre- tagogues include some chemokines (e.g., IL-8), drugs such as codeine and morphine, adenosine, melittin (present in bee venom), and physical stimuli (e.g., heat, cold, sunlight). Basophils are similar to mast cells in many respects, includ- ing the presence of cell surface IgE Fc receptors as well as oplasmic granules. In contrast to mast cells, however, basophils are not normally present in tissues but rather circulate in the blood in extremely small numbers. Similar to other granulocytes, basophils can be recruited to inflam- matory sites. Mast cells and basophils express a high-affinity recep- tor, called FcεRI, which is specific for the Fc portion of IgE and therefore avidly binds IgE antibodies. IgE-coated mast cells are said to be sensitized, because they are sensitive to subsequent encounter with the specific antigen. When a mast cell, armed with IgE antibodies previously pro- duced in response to an antigen, is exposed to the same antigen, the cell is activated, leading eventually to the release of an arsenal of powerful mediators responsible for the clinical features of immediate hypersensitivity reactions. In the first step in the sequence of mast cell acti- vation, the antigen binds to the IgE antibodies previously attached to the mast cells. Multivalent antigens bind to and cross-link adjacent IgE antibodies. The underlying Fcε receptors are brought together, and this activates signal transduction pathways from the cytoplasmic portion of the receptors. These signals lead to the production of media- tors that are responsible for the initial, sometimes explo- sive, symptoms of immediate hypersensitivity, and they also set into motion the events that lead to the late-phase reaction.

Answer 2

Mast cell activation leads to degranulation, with the dis- charge of preformed (primary) mediators that are stored in the granules, and de novo synthesis and release of second- ary mediators, including lipid products and cytokines (Fig. 6-15). Preformed Mediators. Mediators contained within mast cell granules are the first to be released and can be divided into three categories: • Vasoactive amines. The most important mast cell-derived amine is histamine (Chapter 3). Histamine causes intense smooth muscle contraction, increased vascular perme- ability, and increased mucus secretion by nasal, bron- chial, and gastric glands. • Enzymes. These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and acti- vated components of complement (e.g., C3a) by acting on their precursor proteins. • Proteoglycans. These include heparin, a well-known anti- coagulant, and chondroitin sulfate. The proteoglycans serve to package and store the amines in the granules. Lipid Mediators. The major lipid mediators are arachidonic acid–derived products (Chapter 3). Reactions in the mast cell membranes lead to activation of phospholipase A2, an enzyme that converts membrane phospholipids to arachidonic acid. This is the parent compound from which leukotrienes and prostaglandins are produced by the 5-lipoxygenase and cyclooxygenase pathways, respectively. • Leukotrienes. Leukotrienes C4 and D4 are the most potent vasoactive and spasmogenic agents known. On a molar basis, they are several thousand times more active than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. Leukotriene B4 is highly chemotactic for neutrophils, eosinophils, and monocytes Prostaglandin D2. This is the most abundant mediator produced in mast cells by the cyclooxygenase pathway. It causes intense bronchospasm as well as increased mucus secretion. • Platelet-activating factor (PAF). PAF (Chapter 3) is a lipid mediator produced by some mast cell populations but it is not derived from arachidonic acid. It causes platelet aggregation, release of histamine, broncho- spasm, increased vascular permeability, and vasodila- tion. Its role in immediate hypersensitivity reactions is not well established. Cytokines. Mast cells are sources of many cytokines, which may play an important role at several stages of immediate hypersensitivity reactions. The cytokines include: TNF, IL-1, and chemokines, which promote leu- kocyte recruitment (typical of the late-phase reaction); IL-4, which amplifies the TH2 response; and numerous others. The inflammatory cells that are recruited by mast cell- derived TNF and chemokines are additional sources of cytokines and of histamine-releasing factors that cause further mast cell degranulation. These mediators are responsible for the manifesta- tions of immediate hypersensitivity reactions. Some, such as histamine and leukotrienes, are released rapidly from sensitized mast cells and are responsible for the intense immediate reactions characterized by edema, mucus secre- tion, and smooth muscle spasm; others, exemplified by cytokines, including chemokines, set the stage for the late- phase response by recruiting additional leukocytes. Not only do these inflammatory cells release additional waves of mediators (including cytokines), but they also cause epi- thelial cell damage. Epithelial cells themselves are not passive bystanders in this reaction; they can also produce soluble mediators, such as chemokines.

Answer 3

Atopic asthma is caused by a TH2 and IgE response to environmental allergens in genetically pre- disposed individuals. Airway inflammation is central to disease pathophysiology and causes airway dysfunction partly through the release of potent inflammatory media- tors and partly through remodeling of the airway wall. As the disease becomes more severe, there is increased local secretion of growth factors, which induce mucus gland hypertrophy, smooth muscle proliferation, angiogenesis, fibrosis and nerve proliferation. Varying combinations of these processes help explain the different asthma subtypes, their response to treatment and their natural history over a person’s lifetime. The contributions of the immune response, genetics and environment are discussed separately below, although they are closely intertwined. TH2Responses,IgEandInflammation. Afundamentalabnor- mality in asthma is an exaggerated TH2 response to nor- mally harmless environmental antigens (Fig 15-10). TH2 cells secrete cytokines that promote inflammation and stimulate B cells to produce IgE and other antibodies. These cytokines include IL-4, which stimulates the produc- tion of IgE; IL-5, which activates locally recruited eosino- phils; and IL-13, which stimulates mucus secretion from bronchial submucosal glands and also promotes IgE pro- duction by B cells. The T cells and epithelial cells secrete chemokines that recruit more T cells and eosinophils, thus exacerbating the reaction. As in other allergic reactions (Chapter 6), IgE binds to the Fc receptors on submucosal mast cells, and repeat exposure to the allergen triggers the mast cells to release granule contents and produce cyto- kines and other mediators, which collectively induce the early-phase (immediate hypersensitivity) reaction and the late- phase reaction. The early reaction is dominated by bronchoconstric- tion, increased mucus production, variable degrees of vasodilation, and increased vascular permeability. Bron- choconstriction is triggered by direct stimulation of sub- epithelial vagal (parasympathetic) receptors through both central and local reflexes triggered by mediators pro- duced by mast cells and other cells in the reaction. The late-phase reaction is dominated by recruitment of leuko- cytes, notably eosinophils, neutrophils, and more T cells. Although TH2 cells are the dominant T cell type involved in the disease, other T cells that contribute to the inflam- mation include TH17 (IL-17 producing) cells, which recruit neutrophils. Many mediators produced by leukocytes and epithelial cells have been implicated in the asthmatic response. The long list of “suspects” in acute asthma can be ranked based on the clinical efficacy of pharmacologic intervention with antagonists of specific mediators. • Mediators whose role in bronchospasm is clearly sup- ported by efficacy of pharmacologic intervention are: (1) leukotrienes C4, D4, and E4, which cause prolonged bronchoconstriction as well as increased vascular per- meability and increased mucus secretion, and (2) acetyl- choline, released from intrapulmonary parasympathetic nerves, which can cause airway smooth muscle constric- tion by directly stimulating muscarinic receptors. • A second group includes agents present at the “scene of the crime” but whose actual role in acute allergic asthma seems relatively minor on the basis of lack of efficacy of potent antagonists or synthesis inhib- itors: (1) histamine, a potent bronchoconstrictor; (2) pros- taglandin D2, which elicits bronchoconstriction and vasodilatation; and (3) platelet-activating factor, which causes aggregation of platelets and release of serotonin from their granules. These mediators might yet prove important in certain types of chronic or nonallergic asthma. • Finally, a large third group comprises the “suspects” for whom specific antagonists or inhibitors are not avail- able or have been insufficiently studied as yet. Several promising focused therapies for asthma that target the IL-13/IL-4 signal transduction pathways are in develop- ment, including anti-IL-13 monoclonal antibodies and IL-4 receptor antagonists. Other targets include IL-1, TNF, IL-6, chemokines (e.g., eotaxin, also known as CCL11), neuropeptides, nitric oxide, bradykinin, and endothelins It is thus clear that multiple mediators contribute to the acute asthmatic response. Moreover, the composition of this “mediator soup” might vary among individuals or different types of asthma. The appreciation of the impor- tance of inflammatory cells and mediators in asthma has led to greater emphasis on anti-inflammatory drugs, such as corticosteroids, in its treatment.

Answer 4

Asthma may be categorized as atopic (evidence of allergen sensitization and immune activation, often in a patient with allergic rhinitis or eczema) or non-atopic (no evidence of allergen sensitization). In either type, episodes of bronchospasm can have diverse triggers, such as respi- ratory infections (especially viral infections), exposure to irritants (e.g., smoke, fumes), cold air, stress, and exercise. There is some evidence that sub-classifying asthma accord- ing to its clinical features and underlying biology is clini- cally useful. One example is early-onset allergic asthma associated with TH2 helper T cell inflammation, a feature seen in about half of the patients. This form of asthma responds well to corticosteroids. However, there is no current consensus as to definitions and diagnostic criteria. Asthma may also be classified according to the insert cintent here. Atopic c Asthma. This most common type of asthma is a classic example of IgE-mediated (type I) hypersensitivity reaction, discussed in detail in Chapter 6. The disease usually begins in childhood and is triggered by environ- mental allergens, such as dusts, pollens, cockroach or animal dander, and foods, which most frequently act in synergy with other proinflammatory environmental cofac- tors, most notable respiratory viral infections. A positive family history of asthma is common, and a skin test with the offending antigen in these patients results in an imme- diate wheal-and-flare reaction. Atopic asthma may also be diagnosed based on high total serum IgE levels or evidence of allergen sensitization by serum radioallergosorbent tests (called RAST), which can detect the presence of IgE anti- bodies that are specific for individual allergens. Non-Atopic Asthma. Individuals with non-atopic asthma do not have evidence of allergen sensitization and skin test results are usually negative. A positive family history of asthma is less common in these patients. Respiratory infec- tions due to viruses (e.g., rhinovirus, parainfluenza virus and respiratory syncytial virus) are common triggers in non-atopic asthma. Inhaled air pollutants, such as smoking, sulfur dioxide, ozone, and nitrogen dioxide, may also con- tribute to the chronic airway inflammation and hyperreac- tivity in some cases. As already mentioned, in some instances attacks may be triggered by seemingly innocuous events, such as exposure to cold and even exercise. Drug-Induced Asthma. Several pharmacologic agents pro- voke asthma. Aspirin-sensitive asthma is an uncommon type, occurring in individuals with recurrent rhinitis and nasal polyps. These individuals are exquisitely sensi- tive to small doses of aspirin as well as other nonsteroidal anti-inflammatory medications, and they experience not only asthmatic attacks but also urticaria. Aspirin (and other non-steroidal anti-inflammatory drugs) triggers asthma in these patients by inhibiting the cyclooxygenase pathway of arachidonic acid metabolism, leading to a rapid decrease in prostaglandin E2. Normally prosta- glandin E2 inhibits enzymes that generate proinflamma- tory mediators such as leukotrienes B4, C4, D4 and E4, which are believed to have central roles in aspirin-induced asthma. Occupational Asthma. This form of asthma may be trig- gered by fumes (epoxy resins, plastics), organic and chemi- cal dusts (wood, cotton, platinum), gases (toluene), or other chemicals (formaldehyde, penicillin products). Only minute quantities of chemicals are required to induce the attack, which usually occurs after repeated exposure. The underlying mechanisms vary according to stimulus and include type I reactions, direct liberation of bronchocon- strictor substances, and hypersensitivity responses of unknown origin.

Immunology and asthma Flashcards

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