Immunologic Reactions

Asthma Free Forever

Asthma Free Forever By Jerry Ericson

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The exposure of lung to proteic molecules or molecules that can be carried by endogenous proteins (aptens) may elicit an activation of the immune system (hypersensitivity). The immune response to inhaled antigens is potentially a two-edged sword that may either protect (for example, against infections) or, via a hypersensitivity reaction, harm the host (Table III).

Immediate Hypersensitivity and Asthma

Immediate hypersensitivity is an allergic reaction induced by a specific antigen (allergen), provoked by reex-posure to the same antigen, and is mediated by specific IgE antibodies in genetically susceptible individuals (atopics). In the most extreme systemic form of the reaction, called anaphylaxis, mast cell- and/or basophil-derived mediators can restrict airways leading to asphyxiation and producing potential fatal cardiovascular collapse.

IgE antibodies are cytophilic and bind on the surface of circulating basophils and on mast cells in various tissues.

These cells constitutively express high-affinity surface receptors for the Fc component of IgE (FceRI). Binding and cross-linking of the allergen to surface-receptor bound IgE triggers the immediate release from cytoplasmic granules of mast cells and basophils of preformed (primary) vasoactive mediators of immediate hypersensitivity and also initiates de novo synthesis and release of other (secondary) mediators of hypersensitivity. These last-mentioned mediators are mostly responsible for the late phase reaction characterized by an inflammatory infiltrate of eosinophils, basophils, neutrophils, and lymphocytes, ensuing 4 to 6 hours after mast cell and basophil degranulation.

Allergies may be thought of as Th2-dependent disease because Th2 cells produce IL-4, which is required for IgE production, and IL-5, which stimulates eosinophilic inflammation, a characteristic of many allergic diseases. This reaction differs from delayed-type hypersensitivity, which is mediated by CD4+ Th1 and CD8+ T cells and macrophages with no central role of antibodies.

The inhaled allergens (aeroallergens) are usually proteins associated with biogenic particles sized 2 to 60 mm (Table IV). Such a size allows them to be easily carried, suspended in the atmosphere. The most common and practical classification of the aeroallergens is based on their source. It is possible to distinguish aeroallergens spontaneously derived from sources in nature and aeroallergens generated through domestic or occupational practices.

The natural resource-related aeroallergens (outdoor allergens) show a seasonal fluctuation of their environ-

Table III Immunological Mechanisms of Tissue Injury and Inflammation.

Hypersensitivity reaction

Immediate hypersensitivity IgE-mediated (anaphylaxis)

Immune-complex-mediated hypersensitivity

T-cell mediated hypersensitivity (delayed hypersensitivity)

Time elapsed Specific immune agent

Chemical mediators of tissue injury and inflammation Cell pathology and pathophysiology

Clinical examples

Seconds to minutes IgE

Vasoactive products of mast cells/ basophils (histamine, arachidonate derivatives) Accumulation of neutrophils and eosinophils. Smooth muscle contraction

Anaphylaxis Atopic disorders (allergic rhinitis, hay fever, bronchial asthma)

Hours to days IgG, IgM

Complement and Fc receptor (cytolytic, chemotactic, vasoactive components)

Accumulation of neutrophils, macrophages. Release of lytic lysosomal enzymes Extrinsic allergic alveolitis, serum sickness

2-3 days T-cell reactant

Lymphokines and monokines

Lymphocytes and macrophages; granulomas

Berylliosis, tuberculosis

Table IV Characteristics of Aeroallergens.

Natural resource-related (outdoor aeroallergens) Human activity-related (indoor and occupational aeroallergens)

Patterns of prevalence

Regionally with flora and fauna

Determined by domestic and occupational practice

Period of prevalence

Usually seasonal

Often perennial or prolonged


Difficult or unfeasible

Usually simple and effective

Microscopic appearance

Often recognizable distinctive units

Often amorphous or nondiagnostic


Pollens, fungus spores of Alternaria

House dust, animal allergens, vegetable dusts, fungus spores of Penicillium

mental concentration related to the local flora and fauna. Despite aerobiological techniques that are generally able to detect their presence in the atmosphere, it is quite difficult to avoid exposure to them. Classical examples of this group of aeroallergens are pollens (Table V) and fungus spores of Alternaria species. On the other hand, the indoor aeroal-lergen concentrations show fewer fluctuations and preventive exposure strategies are usually effective. In this group are included house dust mites, animal skin allergens, and spores of Penicillium species (Table IV). All aeroallergens listed in Tables IV and V are potentially able to provoke asthma.

Asthma is an inflammatory disease caused by repeated immediate hypersensitivity reactions in the lung leading to a variable degree of airflow obstruction, bronchial hyper-responsiveness, and airway inflammation.

Although the fraction of patients suffering from allergic asthma is increasing for various and still unknown reasons, there is a subpopulation of asthmatic patients with no per sonal or family history of allergy, with negative skin tests, and with normal serum levels of IgE. These patients are said to have idiosyncratic asthma.

For many patients, the allergic asthma has its roots in infancy, and both genetic factors (atopy) and environmental factors (viruses, allergens, and occupational exposures) contribute to its inception and evolution.

The avoidance of allergens—when it is possible—should be the first recommendation in the treatment of allergic asthma. The diagnosis of asthma should be clearly established and the baseline severity of the disease classified to help establish the recommended course of pharmacological therapy (Tables VI and VII). An early diagnosis and treatment can reduce the decline in lung function and airway remodeling. Remodeling entails thickening of the airway walls, with increases in submucosal tissue, the adventitia, and smooth muscle. These features differ in asthma and chronic obstructive pulmonary diseases, in allergic and non-allergic asthma, and with the severity of asthma. The precise

Table V Pollen Allergens from Various Sources for Which the Entire Coding Sequences

Have Been Cloned.




Field crops

Common name

Scientific name

Pollen allergen

Short ragweed

Ambrosia artemisiifolia

Amb a 1, Amb a 2, Amb a 5, Amb a 6

Western ragweed

Ambrosia psilostachya

Amb p 5

Giant ragweed

Ambrosia trifida

Amb t 5

Parietaria judaica

Par j 1, Par j 2

Bermuda grass

Cynodon dactylon

Cyn d 1, Cyn d 7, Cyn d 12

Orchard grass

Dactylis glomerata

Dac g 2, Dac g 3

Velvet grass

Holcus lanatus

Hol l 1, Hol l 5

Perennial ryegrass

Lolium perenne

Lol p 1, Lol p 2, Lol p 3, Lol p 5

Lolium italicum

Lol i 1

Canary grass

Phalaris aquatica

Pha a 1, Pha a 5

Timothy grass

Phleum pretense

Phl p 1, Phl p 2, Phl p 5, Phl p 6, Phl p 7, Phl p 11, Phl p 13

Kentucky blue grass

Poa pratensis

Poa p 2, Poa p 9

Johnson grass

Sorghum halepence

Sor h 1


Triticum aestivum

Tri a 2


Zea mays

Zea m 1, Zea m 11


Hordeum vulgare

Hor v 9


Oryza sativa

Ory s 1


Alnus glutinosa

Aln g 1, Aln g 4

White birch

Betula verrucosa

Bet v 1, Bet v 2, Bet v 3, Bet v 4, Bet v 5


Carpinus betulus

Car b 1

Japanese cypress

Chamaecyparis obtuse

Cha o 1, Cha o 2


Corylus avellana

Cor a 1

Japanese cedar

Cryptomeria japonica

Cry j 1, Cry j 2

Cupressus arizonica

Cup a 1

Cupressus sempervirens

Cup s 1

Juniperus ashei

Jun a 1, Jun a 2, Jun a 3

Juniperus oxycedrus

Jun o 2

Juniperus oxycedrus

Jun o 2

Eastern red cedar

Juniperus virginiana

Jun v 1, Jun v 3


Ligustrum vulgare

Lig v 1


Syringea vulgaris

Syr v 1

Annual dog's mercury

Mercurialis annua

Mer a 1


Olea europea

Ole e 1, Ole e 2, Ole e 3, Ole e 6, Ole e 8


Brassica rapa

Bra r 1, Bra r 2

Oilseed rape

Brassica napus

Bra n 1, Bra n 2


Helianthus annuus

Hel a 2

Table VI Classification of Asthma Severity [2].



Days with symptoms

Nights with symptoms

For adults and children aged > 5 years who can use a spirometer or peak flow meter

FEV1 or PEF % predicted of normal

PEF variability (%)

Severe Persistent 4 Continual Frequent

Moderate Persistent 3 Daily > 1/week

Mild persistent 2 > 2/week, but < 1 time/day > 2/month

Mild intermittent 1 < 2/week < 2/month

Table VII Medications Used in Different Levels of Asthma Severity [4].



Daily medication

Quick relief medication

Severe persistent Moderate persistent

Mild persistent

Mild intermittent

High-dose inhaled steroids (ICS) and long-acting inhaled b2-agonist

If needed, add oral steroids!

Low-to-medium-dose ICS and long-acting b2-agonist (preferred)

Medium-dose ICS (another preferred option for children aged < 5 years)

Low-to-medium-dose ICS and either leukotriene modifier or theophylline

Low-dose inhaled steroids (preferred)

Cromolyn, leukotriene modifier, or (except for children aged < 5 years) nedocromil or sustained release theophylline to serum concentration of 5-15 ||g/mL

No daily medicine needed

Short-acting inhaled b2-agonist, as needed; oral steroids may be required

Short-acting inhaled b2-agonist, as needed; oral steroids may be required

Short-acting inhaled ß2-agonist, as needed; oral steroids may be required

Short-acting inhaled ß2-agonist, as needed; oral steroids may be required

mechanisms underlying the remodeling process are under intense study.

The diagnosis of asthma is established by demonstrating reversible airway obstruction. Reversibility is traditionally defined as a 15 to 20 percent or greater increase in FEVj after b-adrenergic agonist administration. When the spirometry results are normal at presentation, the diagnosis can be made by showing heightened airway responsiveness to challenge with methacoline.

In the past decade, the treatment of asthma has emphasized long-term suppression of airway inflammation plus relief of symptoms with quick-acting bronchodilators (primarily aerosolized b-agonists). Inhaled corticosteroids are the most effective agents available for the symptomatic control of asthma and improvement in pulmonary function, but their potential side effects when used in escalating doses have led to the use of adjunctive therapies. Concomitant treatments with long-acting b-agonists, theophylline, and leukotriene antagonists have all been shown to help control asthma while minimizing the doses of inhaled corticosteroids that are needed.

Nevertheless, whether used alone or in combination with other therapies, corticosteroids do not consistently abrogate airway inflammation in patients with asthma. For this reason, other approaches that modulate IgE-associated immunologically mediated inflammatory responses are in use or under development. Allergen immunotherapy can be effective in many, but not all, patients [3]. Immunotherapy can be administered by subcutaneous injection, topically to the nasal mucosa, or sublingually. When given by injection, exceptionally severe, potentially fatal, anaphylactic reactions have been reported, and hence it is best if a specialist prescribes immunotherapy.

DNA vaccines and other molecular methods of down-regulating antigen-specific Th2-mediated responses are currently being studied. Agents directed at diminishing the production of IgE through effects on interleukin-4 or on IgE itself have also been evaluated. One such compound is a soluble recombinant interleukin-4 receptor that can be delivered in nebulized form.

Another compound, a recombinant humanized monoclonal antibody that forms complexes with free IgE (rhuMAB-E25, or omalizumab), blocks the interaction of IgE with mast cells and basophils. Several clinical studies have been performed in adults and children with moderate-to-severe allergic asthma to evaluate the efficacy and safety of this agent. Treatment with omalizumab was well tolerated and showed clinical benefit in terms of a reduction in the frequency and number of asthma exacerbation episodes and lower usage of corticosteroids and other medications to control disease, along with improved quality of life.

The efficacy of these therapies emphasizes the important contribution of allergic inflammatory mechanisms in the pathophysiology of asthma in many patients [5].

Immune-Complex-Mediated Hypersensitivity and Extrinsic Allergic Alveolitis (EAA)

When large amounts of antigen enter the bloodstream and bind to antibody, circulating immune complexes are noted. If antigen is in excess, small complexes form; because these are not easily cleared by the phagocytic cells, they can cause complement activation and tissue damage.

Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis (EAA), is a complex syndrome of varying intensity, clinical presentation, and natural history, rather than a single uniform disease. It can progress to disabling or even fatal end-stage lung disease. The only truly effective treatment is early recognition and control of exposure. Although patients produce antibody exuberantly, the immunopathogenesis involves also cellular immunity— notably, CD8+ cytotoxic lymphocytes, multinucleate giant-cell granulomas, and ultimately interstitial fibrosis. Many causative agents have been recognized in occupational dusts or mists, but most current new cases arise from residential exposure to pet birds (pigeons and parakeets), contaminated humidifiers, and indoor molds. Pathologically, acute HP is characterized by poorly formed noncaseating interstitial granulomas and mononuclear cell infiltration in a peribronchial distribution with prominent giant cells.

The subacute, or intermittent, form produces more well-formed noncaseating granulomas. There is bronchiolitis with or without organizing pneumonia, and interstitial fibro-sis. Chronic forms reveal the additional findings of chronic interstitial inflammation and alveolar destruction (honeycombing) associated with dense fibrosis. Cholesterol clefts or asteroid bodies are present within or outside granulomas.

Most patients have circulating immunoglobulin G (IgG) antibodies that are specific for the offending antigen. The antibody will react with a specific antigen to form a precipitate. Surprisingly, approximately 50 percent of asymptomatic people exposed to the sensitizing antigen also will develop these precipitating antibodies.

The late onset of symptoms, about 4 to 8 hours after antigen inhalation, suggests that the disease mechanism may resemble an Arthus-type skin reaction following intradermal skin tests that has the same kinetics. An antibody-dependent inflammatory process has been suggested for both. The Arthus skin histology demonstrates deposition of immune complexes and complement with an influx of neutrophils, similar to lung histology of biopsies taken during the acute phase. Generally biopsies are taken from patients with more long-standing lung disease and show a lymphocytic infil trate, with minimal evidence for immune complexes or complement. Therefore the pathogenesis of EAA is thought to be a hypersensitivity reaction against inhaled antigens with involvement of both humoral and cellular immune responses.

The symptoms and physical findings are nonspecific. Serum IgG contains high titers of specific antibody to the offending antigen. Pulmonary function tests show restrictive and diffusion defects with hypoxemia, especially after exercise. Occasionally, small-airway disease causes obstruction. Radiographic changes vary according to the stage of the disease and are best evaluated by means of high-resolution computed tomography. In typical cases, the history of a known exposure and the presence of a characteristic interstitial lung infiltrate with serologic confirmation of IgG antibody to the offending antigen suffice for diagnosis. In more obscure cases, observation of changes after a natural environmental exposure, along with BAL and lung biopsy, might be indicated.

Early response to the antigen is characterized by an increase in neutrophils in the alveoli and small airways followed by an influx of mononuclear cells. These cells release proteolytic enzymes, prostaglandins, and leukotrienes. In addition the production and release of inter-leukins, cytokines, growth factors, and various other mediators from T lymphocytes and macrophages play an important role in HP pathogenesis.

Most syndromes are occupation-related and symptom prevalence can be up to 16 percent of exposed subjects, with significant morbidity. In addition to its clinical and economic importance, the disease has considerable research potential as a model of inflammatory lung disease in which the populations at risk can be identified, the relevant antigens purified, and the immunological and clinical consequences of antigen exposure monitored. Many of the pathological characteristics of HP overlap with other lung diseases and may therefore provide a means to identify common mechanisms of pathogenesis.

Prevalence varies by region, climate, and farming practices. Most patients recover completely after the inciting exposure ceases. The sources of antigen causing HP are diverse even though the clinical presentation of the different allergens is similar. This suggests that although the antigen is specific for each syndrome, the subsequent hypersensitiv-ity pathway reactions are common. For this simple reason it could be argued that there can be no disease-specific antigen. There are however, some nonspecific agents common to the alveolitis-associated antigens. These are generally derived from organic material, or from organisms growing on organic waste. The agents are about one micron in diameter, which is the correct aerodynamic size to reach and deposit soluble antigen in the alveoli, where the disease process is most evident. These particles generally have adjuvant activity.

On the basis of the antigens we can distinguish several syndromes. Farmer's lung, first described by Campbell in 1932, is a hypersensitivity pneumonitis caused by the inhalation of thermophilic actinomycetes that grow in moldy hay or straw (Saccharopolyspora rectivirgula, Micropolyspora faeni, and Aspergillus umbrosis). Bird fancier's (breeder's) lung is caused by inhaling transuded serum and secretory proteins on feather dust (bloom) and in bird droppings. There is also described a humidifier fever caused by antigens dispersed by contaminated water from recirculating air-conditioning systems that harbor the protozoan Naegleria gruberi. Isocyanate alveolitis is an example of occupational exposure to a bioactive inorganic molecule that can cause HP [6].

T-Cell-Mediated Reaction or Delayed-Type Hypersensitivity (DTH) and Berylliosis

The delayed-type hypersensitivity reactions develop when antigen activates sensitized CD4+ T cells of the Th1 subset and CD8+ cells, both of which secrete cytokines that activate macrophages and induce inflammation. Berylliosis is a classic example of T-cell-mediated immune lung injury.

Beryllium (Be) is a lightweight metal with excellent thermal and electrical conductivity. Initially used in the manufacture of fluorescent lamps, beryllium is now widely used in the ceramics, nuclear weapons, computer, and aerospace industries. It is also a common component of many household appliances. Inhalation of beryllium has been associated with two pulmonary syndromes, which are an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD), or berylliosis.

In the acute beryllium disease, the metal acts as a direct chemical irritant causing a nonspecific inflammatory reaction (acute chemical pneumonitis). Because of strict regulation of acceptable exposure levels, acute berylliosis rarely occurs.

CBD continues to be observed in industries where beryllium is manufactured and processed and where workers are exposed to beryllium fumes or dust. Its clinical and histopathological features are similar to those of other gran-ulomatous diseases such as sarcoidosis.

The histopathologic findings in this disease are primarily diffuse alveolar damage. Although CBD may affect multiple organs, the lung usually is most severely involved. Exer-tional dyspnea is the most common presenting complaint, followed by cough and chest pain; less common symptoms include weakness, weight loss, fevers, and arthralgias. The diagnosis of CBD may be suggested by a history of significant exposure to beryllium, consistent radiographic findings, and abnormal pulmonary function tests. Confident diagnosis, however, requires demonstration of granulomas in tissue, immunologic evidence that granuloma formation is caused by beryllium hypersensitivity, and a proliferative response of lymphocytes obtained by bronchoalveolar lavage to beryllium. This last test, known as the bron-choalveolar lymphocyte transformation test, is highly accurate and can diagnose CBD before onset of clinical symptoms or pulmonary function abnormalities. Most beryllium is excreted in the urine, and the pulmonary half-life ranges from several weeks to 6 months. Relatively insoluble chemical forms of beryllium may be retained for years.

The key to the pathogenesis of CBD is a delayed-type hypersensitivity reaction in which beryllium most likely functions as a hapten and acts as a class II restricted antigen, stimulating local proliferation and accumulation in the lung of beryllium-specific T cells. Following inhalation of beryllium, large numbers of CD4+ lymphocytes accumulate in the lungs. These helper T cells demonstrate a marked pro-liferative response as a result of exposure to beryllium. Beryllium not only has antigen-specific effects but also acts in a nonspecific inflammatory manner to promote the cellular events leading to granuloma formation. It may induce changes in lung permeability and the production of proin-flammatory cytokines and growth factors that lead to granuloma formation and maintenance. As the disease progresses, the granulomas become organized and eventually form small, fibrous nodules; progressive impairment of pulmonary function occurs [7].

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