The obvious first step in controlling type I hypersensitivities is to avoid contact with known allergens. Often the removal of house pets, dust-control measures, or avoidance of offending foods can eliminate a type I response. Elimination of inhalant allergens (such as pollens) is a physical impossibility, however, and other means of intervention must be pursued.
Immunotherapy with repeated injections of increasing doses of allergens (hyposensitization) has been known for some time to reduce the severity of type I reactions, or even eliminate them completely, in a significant number of individuals suffering from allergic rhinitis. Such repeated introduction of allergen by subcutaneous injections appears to cause a shift toward IgG production or to induce T-cell-mediated suppression (possibly by a shift to the TH1 subset and IFN-7 production) that turns off the IgE response (Figure 16-12). In this situation, the IgG antibody is referred to as blocking antibody because it competes for the allergen, binds to it, and forms a complex that can be removed by phagocytosis; as a result, the allergen is not available to crosslink the fixed IgE on the mast-cell membranes, and allergic symptoms decrease.
Another form of immunotherapy is the use of humanized monoclonal anti-IgE. These antibodies bind to IgE, but only if IgE is not already bound to FceRI; the latter would lead to his-tamine release. In fact, the monoclonal antibodies are specifically selected to bind membrane IgE on IgE-expressing B cells.
Asthma affects almost 5% of the population of the United States. For reasons that are still unclear, the incidence of asthma recently has increased dramatically in developed countries. Even more alarming is that the severity of the disease also appears to be increasing. The increase in asthma mortality is highest among children, and in the United States the mortality is highest among African-American children of the inner city. In 1999, 7.7 million children had asthma and more than 2000 of them died of the disease. These statistics are increasing each year. In addition to its human costs, asthma imposes high financial costs on society. During 2000, the cost for the treatment of asthma in the United States was more than $12 billion.
Asthma is commonly defined as an inflammatory disease of the airway, and it is characterized by bronchial hyperrespon-
siveness. Atopic individuals, those with a predisposition to the type I hypersensitive response, are most susceptible to the development of bronchial hyperresponsive-ness and asthma, but only 10%-30% of atopic individuals actually develop asthma. The evidence that asthma has a genetic component originally was derived from family studies, which estimated that the relative contribution of genetic factors to atopy and asthma is 40%-60%. While genetic factors are important, further studies have indicated that environmental factors also play a large role. Additionally, asthma is a complex genetic disease, controlled by several genes, so that susceptibility to it is likely to involve the interaction of multiple genetic and environmental factors.
How do we determine which genes contribute to a complex multigenic disease such as this? One approach is the candidate-gene approach, in which a hypothesis suggests that a particular gene or set of genes may have some relation to the disease. After such a gene has been identified, families with apparent predisposition to the disease are examined for polymorphic alle-les of the gene in question. Comparing family members who do or do not have the disease allows correlation between a particular allele and the presence of the disease. The problem with this approach is its bias toward identification of genes already suspected to play a role in the disease, which precludes identification of new genes. A good example of the use of the candidate-gene approach is the identification of a region on chromosome 5, region 5q31-33, that appears to be linked to the development of asthma. Using a candidate-gene approach, this region was investigated because it includes a cluster of cytokine genes, among them the genes that encode IL-3, -4, -5, -9, and -13, as well as the gene that encodes granulocytemacro-phage colony-stimulating factor. IL-4 is thought to be a good candidate gene, since it induces the Ig class-switch to IgE. Several groups of investigators have examined this region in different populations and concluded that there is a polymorphism associ-
These antibodies are humanized by the genetic engineering of the genes encoding the H and L chains; mouse framework regions are replaced with human framework sequences and
the end result is a mouse/human chimeric monoclonal that is not likely to be recognized as foreign by the human immune system. When injected into people suffering from allergy, these antibodies can bind free IgE as well as down-regulate IgE production in B cells. This results in lower serum IgE concentration which, in turn, reduces the sensitivity of basophils. This form of immunotherapy is useful in treating many forms of allergies, especially crippling food allergies.
Another approach for treating allergies stems from the finding that soluble antigens tend to induce a state of anergy by activating T cells in the absence of the necessary co-stimulatory signal (see Figure 10-15). Presumably, a soluble
Hyposensitization treatment of type I allergy. Injection of ragweed antigen periodically for 2 years into a ragweed-sensitive individual induced a gradual decrease in IgE levels and a dramatic increase in IgG. Both antibodies were measured by a radioimmunoassay. [Adapted from K. Ishizaka and T. Ishizaka, 1973, in Asthma Physiology, Immunopharmacology and Treatment, K. F. Austen and L. M. Lichtenstein (eds.), Academic Press]
ated with predisposition to asthma that maps to the promotor region of IL-4. Additionally, two alleles of IL-9 associated with atopy have been identified.
Another approach to identifying genes associated with a particular disease is a random genomic search. In this method, the entire genome is scanned for polymorphisms associated with the disease in question. Using the random genomic approach, a British study (Lympany et al., 1992) identified a linkage between a polymorphism on chromosome 11—more specifically, region 11 q13—associated with atopy in British families. This region maps to the vicinity of the p subunit of the high-affinity IgE receptor (FceRIp). This association is exciting, since we know how important IgE is in mediating type I reactions. However, some caution in interpreting these results is necessary. This study looked at associations between polymorphisms and atopy, but most individuals who are atopic do not develop asthma. Therefore this association, while important in identifying factors in developing atopy, may not be relevant to the development of asthma.
More recently, a large genome-wide screen for loci linked to asthma susceptibility was conducted in ethnically diverse populations that included Caucasians, Hispanics, and African-Americans. This study, published by a large collaborative group from medical centers throughout the United States identified many candidate loci associated with asthma. One locus on chromosome 5 coincided with the already identified region at 5q31-33. Interestingly, however, this locus was associated with asthma in Caucasians but not in Hispanics or African-Americans. Similarly, some loci appeared to have a high correlation with asthma in Hispanics only, and other loci were identified as unique to African-Americans. Another interesting conclusion was that the association between chromosome 11q and atopy did not appear to be correlated with asthma. This could indicate that asthma and atopy have different molecular bases. More important, it suggests that genetic linkage to atopy should not be confused with genetic linkage to asthma. Overall, this study identified several genes linked to asthma and found that the number and relative importance of these genes may differ among ethnic groups. This suggests that genetic differences as well as differences in environment may be the underlying basis of the differences observed in the prevalence as well as the severity of the disease among ethnic groups in the United States.
It is well documented that a higher than average percentage of African-American inner-city children have serious complications with asthma. This has raised the question whether there is a genetic predisposition for asthma in African-Americans. Recently, however, a report from Rosenstreich and colleagues has indicated an important environmental linkage to asthma in the inner city. This group assessed the role of allergies to the cockroach in the development of asthma; they found that a combination of cockroach allergy and exposure to high levels of cockroach allergen can help explain the high frequency of asthma-related health problems in inner-city children. These data also point to defects in the public-health systems in large cities. Clearly, a concerted effort by public agencies to eradicate insect infestations would benefit the health of those who live in inner-city communities.
antigen is internalized by endocytosis, processed, and presented with class II MHC molecules, but fails to induce expression of the requisite co-stimulatory ligand (B7) on antigen-presenting cells.
Knowledge of the mechanism of mast-cell degranulation and the mediators involved in type I reactions opened the way to drug therapy for allergies. Antihistamines have been the most useful drugs for symptoms of allergic rhinitis. These drugs act by binding to the histamine receptors on target cells and blocking the binding of histamine. The H1 receptors are blocked by the classical antihistamines, and the H2 receptors by a newer class of antihistamines.
Several drugs block release of allergic mediators by interfering with various biochemical steps in mast-cell activation and degranulation (Table 16-4). Disodium cromoglycate (cromolyn sodium) prevents Ca2+ influx into mast cells. Theophylline, which is commonly administered to asthmatics orally or through inhalers, blocks phosphodiesterase, which catalyzes the breakdown of cAMP to 5'-AMP. The resulting prolonged increase in cAMP levels blocks degranulation. A number of drugs stimulate the p-adrenergic system by stimulating p-adrenergic receptors. As mentioned earlier,
Mechanism of action of some drugs used to treat type I hypersensitivity
Antihistamines Block H1 and H2 receptors on target cells
Cromolyn sodium Blocks Ca2+ influx into mast cells
Theophylline Prolongs high cAMP levels in mast cells by inhibiting phosphodiesterase, which cleaves cAMP to 5'-AMP*
Epinephrine Stimulates cAMP production by binding
(adrenalin) to p-adrenergic receptors on mast cells*
Reduces histamine levels by blocking conversion of histidine to histamine and stimulates mast-cell production of cAMP*
*Although cAMP rises transiently during mast-cell activation, degranulation is prevented if cAMP levels remain high.
epinephrine (also known as adrenaline) is commonly administered during anaphylactic shock. It acts by binding to p-adrenergic receptors on bronchial smooth muscles and mast cells, elevating the cAMP levels within these cells. The increased levels of cAMP promote relaxation of the bronchial muscles and decreased mast-cell degranulation. A number of epinephrine analogs have been developed that bind to selected p-adrenergic receptors and induce cAMP increases with fewer side effects than are seen with epineph-rine. Cortisone and various other anti-inflammatory drugs also have been used to reduce type I reactions.
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