Case 19

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 19

A married couple in your practice is planning their first pregnancy. They are both asthmatics, on regular inhalant therapy. They have both been hospitalized twice and one of them was intubated once for exacerbations. They are concerned to know the likelihood of a genetic predisposition, environmental factors, and so on, that might affect development of asthma in their child. You discuss these issues and the classic presentation and diagnosis of asthma.

QUESTIONS FOR GROUP DISCUSSION

1. In very general terms, what are the two main causes of airway obstruction in asthma (see Etiology).

2. Recent studies have attempted to unravel the complexities underlying genetic association and susceptibility to asthma using positional cloning. What is chromosomal linkage? What is the assumption in this approach?

3. Discuss the criteria that have been used to identify atopic individuals. List various gene clusters that are linked to polymorphic genes whose allelic expression is, in turn, associated with atopy in individuals.

4. What is a FEV₁? Explain its role in the diagnosis of asthma.

5. Describe the test used to measure airway hyperresponsiveness to confirm a diagnosis of asthma.

6. Explain the rationale for speculation that the presence of a dog in a family or a rural lifestyle is protective for allergic diseases.

7. Under what circumstances do high levels of IgE correlate with a particular allelic form of FcεR1-β in some Australian aborigines parasitized with helminths?

8. Explain why recent studies are focusing on the role of polymorphisms in the interleukin [IL]-4Rα component of the receptors for IL-4 and IL-13 as a contributory factor in the genetics of asthmatic disorders.

9. Inhaled glucocorticoids and or leukotriene receptor blockade is the presently accepted therapy for asthma. What are leukotrienes? How are they generated? What are the roles of phospholipase A₂ and phospholipase C in leukotriene production?

10. Explain why chemokine receptor antagonists are under investigation as possible therapeutic agents for the treatment of asthma.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Given the fact that both husband and wife are chronic asthmatics, their offspring would be at high risk for developing asthma. Although there is a major genetic component to the underlying cause of asthma, the inherited pattern cannot be classed as autosomal, X-linked, or recessive.

Recent studies using positional cloning have attempted to address the issue of genetic associations. Positional cloning is a technique that attempts to identify polymorphic genes located close to known positions (markers) on chromosomes. The assumption is that the allelic forms of polymorphic genes, relevant for developing allergies, will be common to atopic individuals. Various criteria have been used to identify atopic individuals, including levels of IgE antibodies, a diagnosis of asthma, atopic dermatitis, and so on. On the basis of these studies, common allelic forms of polymorphic genes have been identified because of their link to known gene clusters (markers) on chromosome 2 (close to the interleukin [IL]-1 cluster), chromosome 5 (cytokine gene cluster), chromosome 6 (major histocompatibility complex genes), chromosome 11 (FcεR1-β receptor for IgE), chromosome 12 (near the interferon gamma [IFNγ] gene cluster), and chromosome 13 (cysteinyl leukotriene 2 receptor), as well as several other chromosomes. Nevertheless there are still hundreds of genes encoded within the clusters of interest. Several cytokines encoded within the cytokine gene cluster on chromosome 5 have been implicated in allergic responses (e.g., IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor).

Implications/Analysis of Clinical History

A common clinical presentation in infants and children is wheezing, coughing, and shortness of breath as a result of airway obstruction. About 50% of children who are genetically predisposed to asthma have at least one wheezing illness before entering primary school. Many, however, will have one wheezing episode before the age of 1 year. Most of these wheezing incidents are triggered by a viral infection of the respiratory tract. It is important to rule out other causes of wheezing, which include cystic fibrosis, anatomic anomalies, and so on. In adults, the clinical presentation is similar to that described for infants/children, but nonasthmatic causes of wheezing need to be ruled out. In adults this includes emphysema, chronic bronchitis, upper airway obstruction, and so on.

Implications/Analysis of Laboratory Investigations

The initial assessment is the pulmonary function test to determine the baseline level of airflow obstruction. Although more sophisticated equipment and techniques are available in some laboratories, simple spirometry is available in most laboratories. This test is used to obtain two measures (1) FEV₁, which is the volume of air that is forcefully exhaled in 1 second, and (2) FVC (forced vital capacity), which is the maximal volume of air that can be forcefully exhaled. The ratio of FEV₁/FVC is expressed as a percentage.

Individuals are retested 10 minutes after inhalation of a bronchodilator (e.g., albuterol) to determine reversibility of the FEV₁, a basic characteristic of asthma. An improvement in FEV₁ of 12% is considered significant. Because asthma has both an inflammatory and a bronchospastic component, a bronchodilator will not necessarily result in an increase in the FEV₁ if the airways are only inflamed. Results of these tests can be used to assess response to pharmacologic intervention. Individuals suspected of having exercise-induced asthma can be tested in a similar manner, repeating spirometry after exercise on a treadmill or other exercise unit.

Additional Laboratory Tests

Airway hyperresponsiveness may be assessed to confirm a diagnosis of asthma when the FEV₁ is not reversible and physical findings and clinical histories are insufficient to make a diagnosis. In this approach, a provocation challenge (e.g., with methacholine in aerosol form) is done. Spirometry results before and after the provocation challenges are compared. Asthmatics respond to provocation challenge with a 20% fall in FEV₁ at a lower concentration of methacholine. In other words, they are hyperreactive to methacholine. This is a more sensitive test than reversibility using a bronchodilator.

DIAGNOSIS

On the basis of the tests performed, a diagnosis of asthma may be made.

THERAPY

Long-term asthma control has traditionally been achieved with inhaled glucocorticoids. In recent years, however, therapeutic interventions have focused on blocking leukotriene receptor binding sites. For many patients, optimal therapy requires a combination of both inhaled corticosteroids and leukotriene receptor blockade. Leukotrienes are the end products of a biochemical cascade triggered by the action of 5-lipoxygenase on arachidonic acid. Leukotrienes (LTC4, LTD4, and LTE4) play an important role in the pathophysiology of asthma in that they mediate bronchoconstriction, chemotaxis of inflammatory cells, mucus production, and mucosal edema.

Arachidonic Acid: Precursor of Leukotrienes

Arachidonic acid is released from the No. 2 position of membrane-bound glycerophospholipids (e.g., phosphatidylinositol) by the action of phospholipase A₂ (PL-A₂). Arachidonic acid may also be released from the No. 2 position of 1-2 diacylglycerol (DAG) by DAG lipase. DAG is generated after the hydrolysis of phosphatidylinositol bisphosphate by phospholipase C (PL-C). Activation of PL-A₂ and PL-C occurs after the ligand interaction with a plasma membrane receptor on cells. A variety of different receptor/ligand interactions can trigger these signaling cascades, and these, in turn, may vary with the cell type (e.g., neutrophils). (Prostaglandins are produced after the action of cyclooxygenase 1 on arachidonic acid.) Cells do not synthesize the arachidonic (fatty) acid and so it, or its precursor linoleic acid, must be derived from the diet.

ETIOLOGY: ASTHMA

Asthma is a multifactorial disease with a marked inflammatory component and bronchial smooth muscle spasm, both of which can lead to airway obstruction. Inflammatory cells and mucus accumulate in the airway (Fig. 19-1). In susceptible individuals this inflammation causes recurrent episodes of wheezing, dyspnea, and cough, particularly at night and in the early morning. Airway obstruction is generally reversible with appropriate pharmacologic therapy. However, in some cases there is evidence for only partial reversibility, suggesting that structural remodeling of the airway may develop in the long term.

FIGURE 19-1 Lung tissue from asthmatic patient. The bronchi show hyaline thickening of the basement membrane with hypertrophy of underlying smooth muscle. Note the inflammatory infiltrate (eosinophils) and epithelial cells and eosinophilic mucinous material in the bronchial lumen. (Hematoxylin & eosin, ×200.)

Environmental Factors

In the western world there has been a general increase in the incidence of allergic diseases in association with improved public health. There is speculation that allergic diseases are a consequence of the absence of the habitual bacterial and parasitic infections with which we co-evolved. This is supported by epidemiologic data indicating that rural lifestyles tend to be protective for allergic diseases and that in nonfarming households the presence of a dog is protective.

Interestingly, the gene encoding CD14 is located within the chromosome 5 cytokine cluster. CD14 forms part of the receptor for lipopolysaccharide (LPS), a bacterial cell wall component and major stimuli of nonspecific inflammation. The segregation of CD14 with the cytokine cluster on chromosome 5 suggests that these act in concert. For example, CD14 triggers an inflammatory response that is then downregulated by cytokines (e.g., IL-10) expressed in that cluster.

Asthma and Gene Polymorphism

Polymorphism within the gene encoding the receptor for the Fc region of IgE (FcεR1-β) is linked with high levels of IgE in some Australian aborigines parasitized with helminths. Engagement of FcεR1-β provides the major trigger for production of allergic mediators by mast cells. Interestingly, linkage of a particular FcεR1-β allele at this gene locus to atopy (high IgE levels) is seen only when the gene was inherited from the mother. If that allele is inherited from the father, that particular allelic form of FcεR1-β does not result in high levels of IgE.

This may reflect a maternal-fetal interaction through the placenta and/or breast milk (which explains early-onset irritable airways during the period of passive immunoglobulin acquisition from the mother). For later-onset disease, genomic imprinting may be in operation, where genes from one parent are preferentially expressed in comparison to genes from the other parent, as a result of the inactivation of either the maternal or paternal allele of a particular locus. This imprinting has also been observed where there is evolutionary conflict between maternal and paternal genes, such as in genes controlling fetal growth.

Role of Th2 Cytokines in Asthma

Recent data have documented unequivocally the important role of IL-13, as well as IL-4, in allergy and asthma. Both cytokines not only share significant structural homology but also share IL-4Rα as a receptor component. Although abundant data implicate IL-4 in Th2 development and isotype switching to IgE, it is clear that IL-4–independent (IL-13–dependent) pathways exist. T cells, eosinophils, mast cells, and NK cells have all been shown to secrete IL-13 in vitro.

More recently it has been shown that IL-13 mediates a nonoverlapping (with IL-4) role in mucus overproduction and eosinophilia seen in the bronchial airways of asthmatics. (IL-13 also plays a role in intestinal worm expulsion.)

Not surprisingly, more recent studies are focusing on the role of polymorphisms in the IL-4Rα chain as contributory factors to the genetics of asthmatic disorders. One polymorphism identified so far maps within the ITIM (immunoreceptor tyrosine-base inhibition motif) of this receptor molecule. In general, ITIMs are linked to inhibitory signaling cascades.

Role of Chemokines in Asthma

Any discussion of the immunogenetics of allergy/asthma must include consideration of chemokine biology. Chemokines and their receptors (seven-transmembrane G protein–coupled receptors) are essential for leukocyte trafficking from the circulation to inflamed tissues. (Chemokines are small secreted proteins that bind to receptors on cells, with the resulting effect being the movement of that cell toward the highest concentration of that chemokine.)

There is high promiscuity in this family, with many ligands binding different receptors and vice versa. Recently it has been shown that Th1 and Th2 cells express different chemokine receptors (CXCR3, CCR5 on Th1; CCR3, CCR4, and CCR8 on Th2). Thus, there is speculation that antagonists of these receptors (on Th2 cells) might be fruitful for treatment of allergic disorders. In asthma, recruitment of eosinophils to the airway might be targeted by blockade of chemokines implicated in this attraction (RANTES [CCL5] or eotaxin [CCL11]).

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