Atopic Asthma and the Immune System

Ken May

Fall 1996

Asthma is a chronic disease that plagues approximately 4 to 5 percent, or 10 million members, of the American population (McFadden et al. 1928). Clinically, this illness is characterized by reversible airway obstruction, bronchial hyperresponsiveness, and chronic inflammation of bronchial mucosa. At the cellular level, asthmatic patients show a marked lung infiltration of proinflammatory cells, especially eosinophils and T lymphocytes, and a significant lack of neutrophils and macrophages (Corrigan et al. 501; Abbas et al. 290; McFadden et al. 1928-9). Atopic asthma, found in some 66% to 75% of asthma patients (McFadden et al. 1928; Abbas et al. 501), is a type of asthma that is caused in part by a predisposition to atopy, which is the hypersensitivity to certain antigens called allergens. Atopic individuals produce abnormally high levels of the antibody IgE in response to these allergens, express more high affinity IgE receptors than normal individuals, and have more of these receptors occupied by IgE (Corrigan et al. 501; Abbas et al. 279,289). Atopic asthma is also accompanied by the characteristic inflammatory components that are present in all forms of asthma.

The development of atopic asthma in an individual has both genetic and environmental components. Genetic research currently implicates at least two key genes in the predisposition to asthma. One major gene cluster located on chromosome 5 codes for a group of cytokines that mediate inflammatory immune responses (IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, and GM-CSF). Gene linkage studies have connected this gene cluster (particularly IL-4) with both IgE production and manifestation of the asthmatic phenotype. Another potential "asthmatic" gene, located on chromosome 11, involves a mutation in the ß chain of Fcbeen linked with atopy (Holgate et al. 29; Bradding 305).

Environmental influences are also critical to the acquisition of atopic asthma. Despite having a genetic predisposition for asthma, the actual expression of asthmatic symptoms in an individual requires the initial sensitization to an environmental allergen (Sporik et al. 502). Sensitization to allergens may occur as early as in the developing fetus. Such intrauterine exposure results from allergens passing directly across the placenta or via maternal cells carrying allergens into the fetal bloodstream (Holgate et al. 30). More definitive research has been done with regards to sensitization in early childhood. One longitudinal study strongly correlates development of atopic asthma with childhood sensitization to inhaled house-dust mite allergen (Der p I). This allergen is present in large quantities in the average house, particularly in mattresses and carpets, where very early exposure (to a newborn) is likely to occur. Other aeroallergens, derived from cat dander, cockroach, and grass pollen, have also been linked to early sensitization (Sporik et al. 502-6; Utell and Looney 49).

One model for the development of asthma proposes that initial sensitization to environmental allergens occurs in infancy or early childhood through a "competition" between T lymphocyte subsets. Upon initial exposure to an allergen, an individual's CD4+ T helper cells begin to differentiate into Th1 or Th2 cells (Holt 44-5). Th1 cells mediate phagocytic immune responses to intracellular microbes, while Th2 cells mediate IgE-dependent immune responses to allergens (Abbas et al. 207-8). In addition to mediating immune responses, each of these T cell subsets produces cytokines that inhibit the proliferation of the other subset. Th1 cells produce high levels of IFN-\ which inhibits Th2 cell growth. Th2 cells, conversely, produce IL-10 which inhibits Th1 cell growth, and IL-4 which promotes IgE production (a vital component of atopy). In response to an allergen, these mutually antagonistic cell populations will competitively grow, and one subset will become dominant and differentiate into memory cells that will determine future responses to the allergen. When the Th1 subset is dominant, the individual is able to inhibit IgE production, which effectively protects against atopy. This IgE suppression may also be enhanced by allergen-specific CD+8 T cells that secrete IFN-\. However, if the Th2 subset is dominant, IgE production is increased and the individual becomes atopic for the allergen (Holt 44-45; Corrigan et al. 504).

Once sensitization to an allergen has occurred, all subsequent exposures to that allergen will elicit a hypersensitive immune response, as seen in asthma. The immune response begins with the binding, processing, and presentation of the allergen by dendritic cells in the lungs. In non asthmatic individuals, the bronchial epithelium provides a protective barrier against inhaled allergens that prevents these particles from reaching the antigen presenting dendritic cells beneath the epithelial layer. In asthmatic patients however, it has been demonstrated that the bronchial epithelium is unusually permeable to certain allergens, allowing access to the subepithelial dendritic cells. Bronchial epithelial cells in asthmatic individuals have also been shown to secrete GM-CSF, which enhances the proliferation and antigen-presenting capabilities of dendritic cells. The result of these aberrations in the bronchial epithelium is the increased presentation of allergen to hypersensitivity-mediating T cells (Mori et al. 817-818).

The immune response to inhaled allergen is mediated by two major pathways, each associated with a distinct phase in the asthmatic reaction (see Fig.1 at end of paper). Because both of these pathways are initiated by specific Th2 cell recognition of processed allergen, the T cell is considered to be the central orchestrator of all immune responses against the allergen (Corrigan et al. 503; Kay, Corrigan, and Frew 107s). The initial response to allergen exposure is called the early phase asthmatic response (occurring 4 to 6 minutes after exposure), and is mediated by the IgE antibody network. Though such humoral immunity is directly controlled by B cells, antibody production cannot occur without the critical second signal provided by T cell help (Abbas et al. 189). Upon activation by allergen, the Th2 cell secretes IL-4 which induces the isotype-switching and production of allergen-specific IgE by B lymphocytes. IgE binds to the allergen, and this complex in turn binds to certain high affinity IgE receptors (Fcal. 421).

After binding to the mast cell, these allergen-IgE complexes cross-link with each other, which stimulates the mast cell to release its intracellular granules (Sutton et al. 421). Such degranulation is also stimulated by histamine releasing factors secreted by T cells (Wilson et al. 86). Mast cell granule products, including histamine, leukotrienes, tryptase, prostoglandin, and platelet-activating factor, are major contributors to the clinical manifestations of asthma. These products produce the immediate bronchoconstriction, vasodilation (resulting in bronchial edema), mucus secretion, and tissue destruction that characterize an early phase asthmatic response. However, despite their initial potency, these mast cell granule-mediated responses are short-lived and comprise only the initial acute phase of the asthmatic process (Holgate et al. 31; Redington et al. 23-31,36; McFadden and Gilbert 1929-30).

IgE cross-linking also stimulates mast cells to secrete various inflammatory cytokines (see Fig.2), including IL-4, IL-5, and TNF-ÿ (all originally thought to be exclusively produced by T cells). IL-4 further amplifies the IgE-mediated pathway, and along with TNF-ÿ, increases the expression of certain vascular endothelial (and epithelial) cell adhesion molecules (E-selectin, ICAM-1, VCAM-1) that recruit eosinophils, T cells, and other inflammatory cells. IL-5 also aids in recruiting and activating eosinophils. This mast cell cytokine production mediates the beginning of the late phase asthmatic response (4 to 6 hours after exposure), which is marked by the initial recruitment of inflammatory cells to the site of allergen exposure before Th2 cells ever arrive. (Drazen et al. 1-2; Holgate 30-31; Okayama et al. 1796-1797,1806; Redington et al. 36, 42-43).

The bronchial epithelium also plays a role in the IgE-mediated response to allergen. It has been demonstrated that bronchial epithelial cells in many asthmatics express a low-affinity IgE receptor (Fcexpression of pro-inflammatory adhesion molecules (Campbell et al. 506-8). Furthermore, such direct IgE binding to the bronchial epithelium stimulates these cells to produce IL-8, which serves as a powerful eosinophil attractant when complexed with IgA (Holgate et al. 32).

The second pathway in an asthmatic immune response is the direct Th2 cell-mediated eosinophil recruitment and infiltration of the lungs in the late phase asthmatic response. This recruitment phase is begun by IgE-activated mast cells (as described above) and is greatly enhanced by the eventual arrival of Th2 cells to the site of allergen exposure (Holgate et al. 31; Makino et al. 19). In addition to IL-4, Th2 cells secrete IL-3, IL-5, and GM-CSF, all of which result in the migration of eosinophils to the region of allergen exposure. As seen in mast cells, these cytokines promote the expression of certain adhesion molecules by local endothelial cells to increase eosinophil binding, and also function in eosinophil activation, differentiation, and survival (Drazen et al. 1-2; Redington et al. 31-2; Corrigan et al. 502-6). The bronchial epithelium has also been shown to secrete IL-8, GM-CSF, and RANTES, which all act as eosinophil attractants and activators (Davies et al. 428-29; Wang, Devalia, et al. 27-28).

Eosinophils recruited to the site of allergen exposure become the major effector cells of the late phase asthmatic response. The effects of eosinophil action are manifold. The most significant result of the eosinophil response in asthma is the damage and death of the bronchial epithelium, which is directly correlated with increased airway hyperresponsiveness. This toxic effect is mediated by several eosinophil granule products, including major basic protein, eosinophil cationic protein, and eosinophil peroxidase. Eosinophils also release certain chemical mediators, such as platelet activating factor and leukotriene-4, which increase bronchoconstriction, vasodilation, and bronchial hyperresponsiveness. Furthermore, eosinophils secrete several cytokines (IL-3, IL-5, GM-CSF) that are thought to function in a self-promoting autocrine manner (Makino 17-19; Corrigan 502-3; Kay and Corrigan 58; Drazen et al. 2). Because of their late entrance into the immune response and the significant damage caused to bronchial epithelium, eosinophil effector mechanisms are responsible for the long-term bronchial inflammation and chronic symptoms of asthma (Corrigan et al. 505).

It is apparent from these immunological effects and from personal experience that asthma is a serious, and potentially life-threatening disease, whose management is a major goal of medicine. One of the most effective and widely used clinical treatments for atopic asthma is inhaled corticosteroids. These drugs function as anti-inflammatory agents, aimed at reducing the edema, leukocyte infiltration, and bronchial hyperresponsiveness that are characteristic of the late-phase asthmatic response. The anti-inflammatory action of corticosteroids takes several forms. The major anti-inflammatory effect is the inhibition of the cytokines responsible for mediating asthmatic atopy, particularly those cytokines that recruit asthmatic effector cells. Inhaled corticosteroids inhibit cytokine production primarily at the molecular level. Proposed mechanisms for this molecular intervention include inhibition of cytokine gene transcription, breakdown of cytokine mRNA, and inhibition of cytokine receptor synthesis (Wang, Devalia, et al. 35). Corticosteroids also alleviate asthma by acting as vasocontrictors, which decrease airway edema and mucus secretion (Hanania et al. 196). Finally, these drugs may actually promote the repair of damaged epithelium, including regeneration of epithelial cilia (Duddridge et al. 489).

The specific inhaled corticosteroid that I use to control my asthma is called beclomethasone dipropionate (BDP) (sold as Vanceril). This particular steroid inhibits the production of several pro-inflammatory cytokines by bronchial epithelial cells. Several studies have shown that IL-8, GM-CSF, and RANTES expression by bronchial epithelia are all down-regulated during treatment with BDP. Since these cytokines regulate eosinophil chemotaxis and activation, BDP treatment results in significantly decreased numbers of activated eosinophils in the bronchial epithelium and decreased bronchial hyperresponsiveness (Wang, Trigg, et al. 1025,1032; Davies et al. 428-29; Wang, Devalia, et al. 27,35). This effective elimination of eosinophils from the site of allergen exposure prevents these cells from inflicting much of their damage on bronchial epithelium and reduces eosinophil-mediated swelling. In addition to eosinophils, BDP may also decrease mast cell populations and damaged bronchial epithelial cell numbers in the lung (determined from bronchial aspirate)(Duddridge et al. 495). Finally, though BDP has not been shown to decrease lung T cell numbers, this corticosteroid does inhibit T cell activation, as evidenced by decreased expression of the activation markers CD25 and HLA-DR following BDP treatment (Wilson et al. 86,89).

Despite the remarkable anti-inflammatory effectiveness of inhaled beclomethasone dipropionate, recent studies have revealed several harmful systemic side effects, particularly associated with high dose usage. These side effects range from the relatively minor oral candidiasis and hoarseness to the more problematic adrenal suppression, decreased bone density, osteoporosis, cataract formation, hyperglycemia and other metabolic changes, skin thinning, and behavioral changes (Hanania et al. 196-204; Nicolaizik et al. 625,627-8). It must be noted, however, that many of these side effects are somewhat unsubstantiated or even contradicted by reliable studies. For example, two recent studies find no evidence for the reputed decreases in bone density or overall growth (Allen et al. 967; Hopp et al. 189).

Since increased BDP dosage has been directly correlated with improved lung function and asthma control, many treatment regimens employ frequent high doses of BDP (800-1000 µg/day), especially in patients with serious asthmatic symptoms (Hanania et al. 197). Practically speaking, the proven anti-inflammatory effects of beclomethasone dipropionate and other inhaled corticosteroids far outweigh the low incidence of side effects observed, especially considering that my usual dosage is 84 µ/day. As a matter of precaution, numerous studies recommend that patients use as low a dose of steroid as possible to contain asthmatic symptoms (Hanania et al. 204; Nicolaizik et al. 628). As an interesting side note, in my research for this paper, I came across many references to a new inhaled corticosteroid called fluticasone propionate (FP). Several of these studies compared the anti-asthmatic effects of FP with BDP to assess relative efficacy, and found that one dose of FP is at least as effective as two doses of BDP in controlling bronchial hyperresponsiveness (Bootsma et al. 1044; Fabbri et al. 817; Booth et al. 45). In addition, another study found that FP use had markedly less side effects than BDP use, specifically with regards to growth rate (Wolthers and Pedersen 673-675). With further evidence, I may consult my allergy doctor concerning a change in therapy strategies from inhaled BDP to FP to minimize my risk (however small) of harmful side effects.

Atopic asthma is a serious inflammatory lung disease which has both genetic and environmental components to its development. After initial sensitization, the typical immune response to inhaled allergen is composed of two distinct pathways. The IgE-mediated pathway activates mast cells and the bronchial epithelium, and is responsible for the acute symptoms of an early asthma attack. The Th2 cell-mediated pathway of eosinophil recruitment results in the more long-term, sustained effects of chronic asthma. Together, these pathways form an intricate web of cellular interaction. Through the use of cytokines, granule-derived mediators, and antibodies, the many cell types implicated in the pathogenesis of asthma communicate and regulate one another to produce a beautiful, yet deadly amplification system for the symptomatic effects of asthma. The management of these effects, through the use of inhaled corticosteroids (such as BDP), has been a significant achievement of modern medicine. However, the persistence of incomplete asthma control and drug side effects necessitate further advances before I can breathe easily.

Figure 1: Two Major Immune Pathways Mediating Atopic
(adapted from J.M. Drazen et al. 2; and C.J.
Corrigan and A.B. Kay 505)

Table 1: Cytokines Mediating Immune Pathways in Atopic
(from mainly from A.E. Redington et al. 32;
J.M. Drazen et al.; and others)

Cytokine: Secreted from: Effect:
IL-3 Th2 cells, mast cells, eosinophils eosinophil recruitment, survival, and activation
IL-4 Th2 cells, mast cells B cell isotype switching to IgE, upregulates expression of endothelial adhesion molecules (ICAM-1, VCAM-1, E-selectin), eosinophil recruitment
IL-5 Th2 cells, mast cells, eosinophils eosinophil recruitment, survival, and activation
IL-8 bronchial epithelium, mast cells T cell and eosinophil recruitment
GM-CSF Th2 cells, bronchial epithelium, mast cells, eosinophils eosinophil recruitment, survival, and activation (autocrine effect when produced by eosinophils)
TNF-a Th2 cells, mast cells upregulates expression of endothelial adhesion molecules
RANTES bronchial epithelium eosinophil recruitment, activation, and factor release



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