Allergy

An allergy is an inappropriate immune system response (causing symptoms) to substances that, in most people, cause no response. The response is mainly to harmless substances that come in contact with the respiratory airways, skin, or eye surface. Common allergens are pollen, spores, housedust mites, and animal dander. Certain drugs, and some foods, most commonly dairy products, seafood, strawberries, and cereals, can also cause allergies. In diagnosing an allergy, the individual’s medical history is important. The doctor needs to know if the symptoms vary according to the time of the day or the season, and if there are pets or other likely sources of allergens in the home.

More about allergy

Various conditions caused by inappropriate or exaggerated reactions of the immune system to a wide variety of substances known as allergens. Many common illnesses, such as asthma and hay fever (see rhinitis, allergic), are caused by allergic reactions to substances that, in the majority of people, cause no symptoms. Allergic reactions occur only on second or subsequent exposure to the allergen, after first contact has sensitized the body. It is unclear why only certain people develop allergies, but about one person in eight seems to have an inherited predisposition to them (see atopy).

Types and causes 

The function of the immune system is to recognize antigens (foreign proteins) on the surfaces of microorganisms and to form antibodies (also called immunoglobulins) and sensitized lymphocytes (white blood cells). When the immune system next encounters these antigens, the antibodies and sensitized lymphocytes interact with them, leading to the destruction of the microorganisms. A similar immune response occurs in allergies, except that the immune system forms antibodies or sensitized lymphocytes against harmless substances because these allergens are misidentified as potentially harmful antigens. The inappropriate or exaggerated reactions that are seen in allergies are known as hypersensitivity reactions and can have any of four different mechanisms (which are termed Types I to IV hypersensitivity reactions).

Type 1 hypersensitivity reactions

Most well known allergies are caused by Type I (also known as anaphylactic or immediate) hypersensitivity, in which allergens cause immediate symptoms by provoking the immune system into producing specific antibodies, belonging to a type called immunoglobulin E (IgE), which coat cells (known as mast cells or basophils) that are present in the skin and the lining of the stomach, lungs, and upper respiratory airways. When the allergen is encountered for the second time, it binds to the IgE antibodies and causes the granules in mast cells to release various chemicals, which are responsible for the symptoms of the allergy.

Among the chemicals released is histamine, which causes widening of blood vessels, leakage of fluid into tissues, and contraction of muscles, especially in the airways of the lung. Symptoms can include itching, swelling, sneezing, and wheezing. Particular conditions associated with Type I reactions include asthma, hay fever, urticaria (nettle rash), angioedema, anaphylactic shock (a severe, generalized allergic reaction), possibly atopic eczema, and some food allergies.

Types 2 to 4 hypersensitivity reactions

Because Types II to IV hypersensitivity reactions have different mechanisms to Type I reactions, they are less often implicated in allergies. However, contact allergic dermatitis, in which the skin reacts to prolonged contact with substances such as nickel, is the result of a Type IV hypersensitivity reaction.

Treatment 

Whenever possible, the most effective treatment for allergy of any kind is avoidance of the relevant allergen. Drug treatment for allergic reactions includes the use of antihistamine drugs, which relieve the symptoms. Some antihistamines have a sedative effect, which is useful, for example, in treating itching at night due to eczema; many do not cause drowsiness, making them more suitable for daytime use.

Drugs such as sodium cromoglicate and corticosteroids can be used regularly to prevent symptoms from developing. Hyposensitization can of valuable for a minority of people who suffer allergic reactions to specific allergens such as bee stings.

Treatment involves gradually increasing doses of the allergen to promote formation of antibodies that will block future reactions. Hyposensitization must be carried out under close supervision because a severe allergic reaction can result. (See also delayed allergy.)

Allergy in detail - technical

Summary

Allergy is the term used for a collection of diseases mediated by immunologic mechanisms. Allergic disorders include allergic rhinitis, conjunctivitis, asthma, urticaria, angioedema, food allergy, drug allergy, and anaphylaxis. The prevalence of allergic diseases has been increasing in recent times. They are a major cause of morbidity and decreased quality of life. The development of allergic diseases is influenced by heritable and environmental factors.

Diagnosis often involves documenting responses to allergen such as in skin testing, radioallergosorbant allergen testing, or bronchial provocation testing. Allergic disorders share the common pathology of inflammation of affected tissues. Allergy requires sensitization to an allergen and response on reexposure to that same allergen. Pathogenesis involves production and release of cytokines, chemokines, and lipid mediators which cause tissue damage and recruit inflammatory cells. Current therapies include allergen avoidance, antihistamines, leukotriene modifiers, corticosteroids, phosphodiesterase inhibitors, humanized monoclonal anti-IgE, and immunotherapy.

Introduction

Allergy encompasses a wide variety of disorders that share immunologic mechanisms. For centuries, patients had allergic symptoms but the causative agent for sensitivity to allergens was unknown. Allergic symptoms were first described by Leonardo Bottallo in sixteenth century Europe. Wyman identified ragweed as the trigger of the ‘autumnal catarrh’ and Blackely identified hay fever as being initiated by grass pollen in the 1870s. Twenty years later Behring described the adverse skin reactions to tubercle bacillus as ‘hypersensitivity’.

Portier and Richet attempted to confer immunity to sea anemone toxin by injecting dogs with subsequent doses of toxin. They employed the term ‘anaphylaxis’ (denoting antiprotection) in 1902 to describe a lethal reaction after the dogs received the second dose of the toxin. Von Pirquet used the term ‘allergy’ in 1906 to describe the skin reaction to cowpox vaccine at 24 h post-vaccination. His definition of allergy described an organism’s alteration by contact with an organic agent. Four years later, Noon observed reactions to pollen extracts on abraded skin and began immunotherapy with these extracts. Dale and Laidlaw produced respiratory distress and anaphylaxis in animals by histamine infusion in 1919. Another major discovery was the identification of cytokines. This class includes chemokines that are important in the recruitment of inflammatory cells.

In 1921, Prausnitz and Kustner demonstrated that a factor could be transferred to a nonsensitized person’s skin and confer sensitivity. This factor was called ‘reagin’ by Coca and Cooke. In 1966, Ishizaka’s discovery of IgE established a scientific basis for the specific reactions. Concurrently, S G O Johannson independently identified a protein in multiple myeloma that was also elevated in allergic patients. Subsequently, the WHO determined that both proteins were IgE.

In 1968, Gell and Coomb described four classes of immunologic reactions. These classes are IgE-mediated immediate hypersensitivity (e.g., anaphylactic shock), IgG- or IgM-mediated cytotoxic reactions (e.g., immune hemolytic anemia), immune complexmediated reactions (e.g., serum sickness), and delayed hypersensitivity (e.g., contact dermatitis). Allergic diseases can be mediated by any of these mechanisms. Allergic disorders include allergic rhinitis, conjunctivitis, asthma, urticaria, angioedema, food allergy, drug allergy, and anaphylaxis.

Etiology

Atopy refers to the tendency of patients to be sensitive to allergens. Atopic diseases include eczema, allergic rhinitis, and asthma. Over the past century, genetics has been thought to affect allergic disease occurrence. The incidence of allergic disease in patients with an allergic family history is higher than in those without one. Atopy is thought to be autosomally transmitted and multigenic. It is probably a complex trait influenced by both heritable and environmental factors. Environmental exposures likely have effects on gene expression and the development of allergic disease. The hygiene hypothesis proposes that in Western countries the developing immune system is deprived of environmental microbial antigens that stimulate Th1 cells. This lack of stimulation increases the presence of atopic disease. Other factors such as diet and exposure to high pollen counts at birth may also increase allergic disease.

Linkage studies for allergy and asthma have produced 420 distinct chromosomal regions with linkage to asthma or related traits. The lack of distinct phenotypes, the inexact definitions of allergic diseases, and the presumed influence of numerous genes have made positional cloning with linkage studies problematic. The linkages reproduced most frequently are on 6p, 5q, 12q, and 13q. Linkage on 14q and 7p was identified in founder populations in Iceland and Finland. Chromosome 2q14–2q32, which includes the IL-1 gene, has been linked to asthma. Candidate gene analysis is a promising technique.

Candidate genes encode biochemical markers that affect allergic diseases. Many of these genes control IgE and cytokine production. Candidate genes include one loci on 5q near the gene cluster for IL-4, IL-5, IL-9, and IL-13. Polymorphisms of the IL-9 gene are associated with human asthma. 11q13, which encodes the b chain of the high-affinity IgE receptor has been linked to asthma. Polymorphisms of the IL-4 receptor a chain are associated with atopic asthma. PHF11, present in the locus for total IgE on 13q14, is expressed in many immune-related tissues. It is associated with total IgE and has been linked with asthma in multiple genome screens. The ADAM33 gene on 20p13 encodes a disintegrin and metalloprotease. This gene was mapped in 2002 as an asthma and airway hyperresponsiveness gene by Van Eerdewegh and co-workers. A cluster of single nucleotide polymorphisms (SNPs) was identified in the ADAM33 gene and demonstrated significant associations with asthma. Howard and co-workers reproduced the association seen by Van Eerdewegh’s group and lent support to the potential role of ADAM33 in asthma susceptibility (see Genetics: Gene Association Studies).

Pathology

Allergic inflammation is present in all allergic diseases. Most tissues exhibit vasodilation and increased vascular permeability. Eosinophils, neutrophils, CD4þ T cells, and basophils eventually infiltrate the site of allergy. Asthma is a disorder which also involves an increase in mucous glands, mucus hypersecretion, smooth muscle hypertrophy, and airway remodeling. Recruitment of eosinophils is a prominent feature of allergic diseases (see Leukocytes: Eosinophils). Eosinophils migrate across blood vessels into tissues by binding endothelial cell adhesion molecules. Major basic protein, lipid mediators, and cytokines enable the eosinophil proinflammatory effects. Eosinophils may also repair damage to mucosal surfaces with fibrogenic growth factor and matrix metalloprotease. This repair mechanism may result in remodeling of airway tissue as seen in asthma.

Mast cells are present in tissues throughout the body. Features of an allergic reaction vary with the anatomic site. The site of allergen contact determines the tissue or organ involved. The concentration of mast cells at the site determines the severity. The wheal and flare is the typical cutaneous allergic response. When allergen binds to specific IgE on mast cells, mast cell mediators are released and cause local blood vessel dilation. These vessels leak fluid and macromolecules and produce redness and swelling (known as the wheal). Dilation of vessels on the edge of the swelling causes redness (known as the flare).

Clinical Features

Patients with allergic rhinitis typically experience rhinorrhea, congestion, sneezing, and itchy nose. Patients also may report postnasal drip and associated eye, ear, and throat symptoms. Patients commonly exhibit reactions to dust mite, animal dander, molds, and pollens. Small molecular weight chemicals can also react with self-proteins and become allergens. Reactivity to allergens can be determined by immediate hypersensitivity skin testing. Drops of allergen are placed into the dermis by various methods. Most skin testing employs a prick device composed of metal or plastic to introduce allergen into the skin. Allergen binds IgE and the mast cells in the skin release histamine to produce the wheal and flare response. The skin response can be compared to controls of saline (negative control) and histamine (positive control).

Radioallergosorbant allergen testing (RAST) quantitates allergenspecific IgE in a patient’s serum. RAST is usually reserved for patients who have a contraindication to skin testing or are taking medications that either interfere with testing (antihistamines) or interfere with treatment should a reaction occur (beta blockers or ace inhibitors). Nasal cytology can reveal the presence or absence of inflammatory cells, especially eosinophils. Adjunct tests such as rhinoscopy and rhinomanometry can provide further characterization of the nasal airway (see Allergy: Allergic Rhinitis).

Patients with asthma report symptoms of wheezing, shortness of breath, cough, and chest tightness. These patients’ airways show hyperresponsiveness with reversibility. Patients may experience asthmatic symptoms in response to allergens, infections, exercise, nonsteroidal anti-inflammatory drugs, gastroesophageal reflux disease, stress, and irritants. Lung function can be assessed by spirometry before and after treatment with bronchodilators. Bronchial hyperresponsiveness can be investigated with bronchial provocation testing such as with methacholine or exercise challenge testing (see Asthma: Overview).

Urticaria is localized edema in skin or mucous membranes. Patients have pale to pink wheals that are extremely pruritic. These lesions are transient and usually resolve within 24 h. Angioedema involves local edema in deeper areas of skin or mucous membranes. These lesions are often painful. Urticaria/ angioedema can be triggered by temperature, sun, direct pressure, medication, infections, foods, or systemic diseases.

Atopic eczema is a skin disorder with pruritis, erythematous macules or papules, and xerosis. Lesions may become excoriated with crust and exudates. Skin tends to be dry and more permeable to allergens and bacteria. Chronic irritation may cause lichenification of the skin and scaling patches or papules. Young children typically have lesions on the face, scalp, and extensor surfaces. Older children and adults have flexor surface involvement.

Food allergy is most frequent in young children. Symptoms may include urticaria, angioedema, rash, flushing, rhinitis, wheezing, or anaphylaxis after ingestion of the allergenic food. Some patients experience the oral allergy syndrome which is usually confined to the oropharynx. Symptoms may consist of pruritis and angioedema of the tongue, lips, palate, and throat. Patients with birch pollen-induced rhinitis may develop oral allergy symptoms after eating raw potato, carrot, apple, celery, or hazelnut. Patients with ragweed pollen-induced rhinitis may develop symptoms after eating melons or bananas. Major food allergens in children are milk, egg, peanuts, soybeans, wheat, fish, and tree nuts. Major food allergens in adults are peanuts, tree nuts, fish, and shellfish. Conformational and sequential food epitopes are responsible for food allergy. Patients with IgE to sequential epitopes react to all forms of a food and tend to have persistent allergy, whereas those with IgE to conformational epitopes tolerate small amounts of food after heating or partial hydrolysis because these conformational epitopes are destroyed. These patients tend to have clinical tolerance. Prick skin testing for foods can be performed as described previously. Negative prick skin tests have a high negative predictive value. Positive skin tests are not conclusive. RAST may also be performed to aid in diagnosis.

Drug allergy reactions most commonly consist of urticaria, morbilliform rash, or anaphylaxis. Skin testing for drug allergy is not standardized and the predictive value of this technique is unclear. Anaphylaxis is an immediate generalized systemic allergic reaction in response to an allergen. Symptoms may include flushing, pruritis, urticaria, angioedema, wheezing, shortness of breath, chest tightness, abdominal pain, nausea, vomiting, diarrhea, laryngeal edema, arrhythmia, myocardial infarction, and hypotension. Serum tryptase can be measured within 6 h of a reaction to determine if mast cell degranulation has occurred during the reaction. Serum histamine and urinary LTE4 may be quantitated to provide evidence of anaphylaxis.

Pathogenesis

Immunology plays a large role in allergic diseases. T lymphocytes are the major effector cells of these immune responses (see Leukocytes: T cells). CD4þ lymphocytes are present in two predominant types, Th1 and Th2 cells. Th1 are helper cells that produce IL-2 and interferon gamma (IFN-g) and promote cellmediated reactions. Th2 are helper cells that produce IL-4, IL-5, IL-6, IL-10, and IL-13 and are involved in humoral immunity and allergic inflammation. Th2 cytokines augment antibody production (especially IgE), enhance eosinophil production, and are associated with allergic and antibody-driven responses (Figure 1). Th1 and Th2 cells suppress each other. Patients with an allergic phenotype generate responses to allergens that favor Th2 responses.

Another type of T cell is the regulatory T cell (T reg). Thymus-derived CD4þCD25þ regulatory cells are termed naturally occurring T regs. Adaptive T regs are T-cell populations induced by in vitro or in vivo manipulation. Active T-cell suppression by T regs promotes immunologic tolerance, but the mechanism of this suppression is controversial. There is a potential role for T regs in the control or prevention of Th2 responses. CD4þCD25þ T cells and IL-10- producing T regs have been shown in humans to prevent T-cell activation by allergens and are possibly deficient in atopic patients. T regs may also secrete the immunosuppressive cytokines IL-10 and TGF-b. IL-10 inhibits macrophage activation and antagonizes IFN-g while TGF-b inhibits T- and B-cell proliferation.

IgE-mediated allergic responses occur through numerous steps. First, a patient is exposed to an allergen. Then antigen-presenting cells internalize the allergen which is then processed and presented to Th2 cells by class II MHC molecules. T-cell receptors bind the presented allergen thus activating the Th2 cells. The activated cells produce IL-4. Atopic patients have more allergen-specific IL-4 secretory T cells in circulation than nonatopics and produce more IL-4 per cell. B cells, in turn, are stimulated by IL-4 to class-switch to produce IgE, specific to the allergen. Approximately 20% of an exposed population will generate specific IgE to an allergen. This IgE binds to receptors on mast cells. When the patient is subsequently exposed to the allergen, the allergen binds the IgE already present on the mast cell surfaces and cross-links the antibodies.

Antibody cross-linking of mast cells activates a variety of responses. The early phase of immediate hypersensitivity occurs within minutes and involves the release of preformed mediators from granules. These mediators include biogenic amines (histamine), enzymes (tryptase, chymase), carboxypeptidase, cathepsin G, acid hydrolases, and tumor necrosis factor alpha (TNF-a) (see Leukocytes: Mast Cells and Basophils). Histamine causes endothelial cells to contract and allow plasma to leak into tissue. Endothelial cells also produce prostacyclin and nitric oxide which promote vascular smooth muscle relaxation and lead to vasodilation. Bronchial smooth muscle constriction is also caused by histamine.

Antibody cross-linking also triggers the initiation of several pathways which lead to cytokine, prostaglandin, and leukotriene production. Arachadonic acid is converted to prostaglandin D2 and the cysteinyl leukotrienes (LTC4, LTD4, LTE4) (see Lipid Mediators: Leukotrienes). These mediators are responsible for vascular leak, bronchoconstriction, inflammation, and tissue damage. These substances lead to inflammatory changes hours after exposure, referred to as the late-phase response. The late phase involves recruitment and infiltration of the mucosa with neutrophils, eosinophils, basophils, and Th2 cells. TNF-a activates endothelial expression of adhesion molecules E-selectin and ICAM-1 and promotes cell infiltration. IL-3 promotes mast cell proliferation. IL-5 stimulates eosinophil production and activation (see Interleukins: IL-5). The chemokines eotaxin and monocyte chemotactic protein-5 from epithelial cells recruit eosinophils. IL-4 and IL- 13 induce Th2 differentiation. While mast cells are responsible for the majority of leukotriene production in the early response, basophils and eosinophils produce most of the leukotrienes in the late-phase response.

Animal Models

Mouse models have been used in the study of allergy because mice are readily available, have a well-characterized immune system, and strains are genetically characterized. Knockout mice can be used to evaluate the role of a cell type or mediator.Many allergists propose that allergic rhinitis and asthma may represent a continuum of inflammation and should be considered as a united allergy airway disorder. Mouse models have been used to investigate this concept. Mice were systemically sensitized with allergen (most often ovalbumin) and then challenged with airway allergen. The inflammatory response in the mouse nose resembles human allergic rhinitis. Nasal mucosal thickening can be seen on imaging. Experimental asthma in mice also mimics human asthma. Bronchial hyperresponsiveness can be documented by plethysmography. Most of the inflammation in mice is seen in the lower airways where the minority of allergen is deposited. This may indicate increased sensitivity in the lower airways. Inhaled allergen causes an increase in allergen-specific IgE and eosinophils in the blood and increases bone marrow eosinopoiesis. Currently, it is unclear why sensitization causes symptoms in the nose, the lower airway, or both. There may be a genetic cause so studying different strains of mice may be useful.

Mouse models have also been used in the study of atopic eczema. Mice have been sensitized epicutaneously with ovalbumin on shaved skin. Elevated serum total and specific IgE and IgG1 and increased dermal IL-4, IL-5, and IFN-g were observed. Deficiencies of these cytokines decreased the eczematous phenotype. For example, IL-4-deficient mice showed Th1- biased skin inflammation with decreased eosinophils and eotaxin mRNA in the dermal infiltrate. IL-5- deficient mice similarly had less pronounced epidermal and dermal thickening and the dermal infiltrate lacked eosinophils. IFN-g-deficient mice showed only slight dermal thickening. The necessity of certain lymphocytes in eczema was demonstrated. ab T cells are essential since T-cell receptor a-chain-deficient mice did not develop a dermal infiltrate or induction of IL-4 or IgE. Mice that lack gd T cells showed no change in infiltrate. Likewise, mice that lack B cells still develop an infiltrate and elevated IL-4.

Numerous animal models have been utilized in food allergy. Rats and mice have been used to assess foodinduced anaphylaxis. Animals ingested ovalbumin by gavage or in drinking water and were subsequently challenged intraperitoneally. The route, dose, and age of the animal were shown to influence sensitization. Rats and swine sensitized to allergens and subsequently challenged orally, demonstrated alterations in small intestinal pathology. Tolerance is dose-dependent for specific antigens. Mice fed ovalbumin or peanuts required a 50-fold higher dose of peanuts to develop tolerance; low doses of peanuts were more likely to induce sensitization. The importance of an intact mucosal barrier was shown when mice, fed a novel dietary protein while their gastrointestinal tracts were inflamed, developed sensitization and high serum IgE.

Allergic conjunctivitis has been studied in guinea pigs, rats, and mice. Mice exposed to ragweed by topical contact with conjunctival and nasal mucosa developed signs of allergic conjunctivitis and ragweedspecific IgE. Regulators of vascular permeability are important in allergic conjunctivitis. Substance P has been shown to be a mediator of allergic conjunctivitis and acts through NK1 receptors on blood vessels to produce conjunctival hyperpermeability. Nitric oxide has been shown to play a major role in regulating vascular permeability and stimulating prostaglandin E2 production. T-cell adhesion molecules are integral in allergic conjunctivitis. Guinea pig models with ovalbumin have shown that the integrin very late activation antigen-4 (VLA-4) plays a critical role in eosinophil infiltration. Other mice studies showed that antibodies against the integrin intercellular adhesion molecule-1 (ICAM-1) and its ligand leukocyte function-associated antigen-1 (LFA-1) inhibited clinical and histological signs of conjunctivitis. The significance of IL-1 for inflammatory changes in conjunctivitis was demonstrated using an IL-1 receptor antagonist in mice exposed to cat dander antigens. Studies in rats using ovalbumin showed that IFN-g suppresses the development of allergic conjunctivitis during the induction phase.

Management and Current Therapy

One of the cornerstones of allergy treatment is avoidance. Avoiding or reducing allergen exposure prevents or minimizes the body’s response to allergen. Environmental control measures help one decrease exposure. For example, patients with house dust-mite allergy can encase their mattresses and pillows in special covers to minimize exposure to dust mites while asleep. One study showed that in inner-city children with atopic asthma, a comprehensive environmental intervention decreased exposure to indoor allergens and reduced asthma-associated morbidity. Avoiding allergic foods or drugs can prevent reactions (Figure 2). Depending on one’s sensitivities, allergen avoidance may range from simple to extremely difficult. Other therapies available to treat allergic disorders include antihistamines, leukotriene modifiers, corticosteroids, phosphodiesterase inhibitors, humanized monoclonal anti-IgE, and immunotherapy.

H1-antihistamines have been used for decades for the relief or prevention of allergic symptoms. Antihistamines have recently received the designation of inverse agonists because they stabilize the inactive form of the H1 histamine receptor. First-generation antihistamines have marked sedation; second-generation antihistamines that are relatively nonsedating have also been identified. Antiallergic activities include inhibiting the release of mast cell mediators probably through direct inhibition of Caþ channels. Anti-inflammatory effects include inhibiting cell adhesion molecule expression and inhibiting inflammatory cell chemotaxis (e.g., eosinophil chemotaxis). These inhibitions probably involve the downregulation of NF-kB, a transcription factor that regulates adhesion proteins and proinflammatory cytokines. Antihistamines have established roles in the treatment of allergic rhinitis and urticaria. A potential role exists for the treatment of anaphylaxis or asthma.

The cysteinyl leukotrienes and LTB4 are products of arachadonic acid metabolism by 5-lipoxygenase. Leukotrienes cause airway inflammation and obstruction by affecting mucus production, smooth muscle contraction, and vascular permeability. They may also affect airway remodeling. The effects of leukotrienes are most likely mediated through the CysLT1 receptor. The CysLT1 receptor antagonists montelukast, pranlukast, and zafirlukast block the actions of LTC4, LTD4, and LTE4. A nonselective antagonist of the CysLT1 and CysLT2 receptors is not yet clinically available. Zileuton is a 5-lipoxygenase inhibitor and decreases the production of leukotrienes. Leukotriene modifiers are useful in allergic rhinitis and asthma. Leukotriene modifiers inhibit an important part of the inflammatory cascade and decrease eosinophil survival, goblet cell hyperplasia, mucus release, collagen deposition, and airway smooth muscle proliferation.

Corticosteroids block the production of inflammatory cytokines (see Corticosteroids: Therapy). They may be given topically at the site of inflammation (nose, lungs, or skin) or delivered systemically. Glucocorticoids are the most potent therapy for treating all allergic disorders. They are liposoluble hormones that enter the cell and bind a cytoplasmic glucocorticoid receptor (see Corticosteroids: Glucocorticoid Receptors). This receptor translocates to the nucleus and binds a glucocorticoid-response element in the promoter region of target genes. The glucocorticoid receptor can also bind transcription factors like NF-kB and AP-1 and prevent these factors from binding their DNA-response elements. Glucocorticoids control airway inflammation by inhibiting transcriptional activity of genes encoding proinflammatory molecules such as cytokines, chemokines, adhesion molecules, and mediator-synthesizing enzymes. They may suppress histone acetylation and stimulate histone deacetylation. They may also interfere with signal transduction pathways, such as MAP kinase enzymatic cascades involved in the regulation of transcription factors.

Theophylline is a nonselective phosphodiesterase inhibitor with a narrow therapeutic ratio and significant drug interactions and has been used exclusively in asthma (see Bronchodilators: Theophylline). Inhibitors of phosphodiesterase type 4 have recently been developed. These inhibitors increase the intracellular concentration of CAMP and exhibit a broad range of anti-inflammatory effects on effector cells. Blocking the PDE4B receptor subtype appears responsible for anti-inflammatory properties of these agents. Cilomast and roflumilast are PDE4 inhibitors that are in late phase III clinical trials. Roflumilast has demonstrated more selectivity and a superior therapeutic ratio (Figure 3).

The humanized monoclonal anti-IgE omalizumab is a new therapy which decreases the amount of IgE available for reactions and downregulates the number of IgE receptors on mast cells. This therapy is currently available for the treatment of severe asthma. Its use in food allergy is being investigated.

Patients with allergic rhinitis and/or asthma who are (Figure 4) poorly controlled on medications may find immunotherapy (allergy shots) a feasible alternative. Immunotherapy involves administering injections of allergens to which a patient is sensitive. Increasing doses of allergen are given weekly until the patient is at a maintenance dose. This maintenance dose is continued monthly for 3 to 5 years. Patients receive relief from nasal allergy symptoms and their asthma may improve. The mechanisms of immunotherapy are not well defined. Immunotherapy may induce specific T-cell tolerance or a shift from a Th2 to a Th1 phenotype. Possibly, the Th2 response is inhibited, Th1 response is upregulated, or both. Immunotherapy also increases the production of IL-10 and TGF-b by T cells including T regs. IgG is also produced in response to antigen instead of the typical IgE. Allergen-specific IgG or blocking antibodies may compete with IgE for allergen and inhibit IgE activation of mast cells. IgG can also bind epitopes on allergen that are not recognized by IgE. This IgG binding may prevent cross-linking of IgE. Allergen-IgG complexes on antigen-presenting cells might impair antigen processing or the co-stimulation of T cells and render patients anergic. Immunotherapy is a type of desensitization, where small amounts of allergen are given until the patient tolerates the allergen. The same theory is used in treatment of drug allergies by giving increasing doses of drug until a therapeutic dose is tolerated.

Unmethylated CG dinucleotides, or CpG motifs, are responsible for the immunostimulatory effect of bacterial DNA and induce a Th1 type response in humans. Synthetic oligodeoxynucleotides mimic the bacterial DNA immunostimulatory sequences. These synthetic nucleotides can be conjugated to allergen to produce an allergen vaccine that is more immunogenic but less allergenic than allergen alone. These vaccines are currently under clinical trials.

Recently, there has been an interest in pharmacogenetics. This field recognizes that medications may work more efficaciously in certain patients because of their genetic makeup. Single nucleotide polymorphisms (SNPs) may signal a change in proteins or amino acids in an individual. These changes may alter a drug’s target, uptake, metabolism, or excretion. A polymorphism in Gly 16 promotes bronchodilator resistance while the Arg 16 polymorphism potentiates a greater response to bronchodilators. An alternatively spliced form of glucocorticoid receptor b is present with higher frequency in corticosteroid-resistant patients. A polymorphism in the 5-lipoxygenase promoter decreases the response to the 5-lipoxygenase inhibitor zileuton. Pharmacogenetics is an exciting area that may shape the future of treatment for allergic diseases.

Further Reading

Abbas AK and Lichtman AH (2003) Cellular and Molecular Immunology, 5th edn. Philadelphia: Saunders.

Adelman DC, Casale TB, and Corren J (2002) Manual of Allergy and Immunology, 4th edn. Philadelphia: Lippincott Williams & Wilkins.

Broide DH (2001) Molecular and cellular mechanisms of allergic disease. Journal of Allergy and Clinical Immunology 108: S65–S71.

Cakebread JA, et al. (2004) The role of ADAM33 in the pathogenesis of asthma. Springer Seminars in Immunopathology 25: 361–375.

Creticos PS, Chen Y, and Schroeder JT (2004) New approaches in immunotherapy: allergen vaccination with immunostimulatory DNA. Immunology and Allergy Clinics North America 24: 569–581.

Groneberg DA, et al. (2003) Animal models of allergic and inflammatory conjunctivitis. Allergy 58: 1101–1113.

Gutermuth J, et al. (2004) Mouse models of atopic eczema critically evaluated. International Archives of Allergy and Immunology 135: 262–276.

Hallstrand TS and Henderson WR (2002) Leukotriene modifiers. Medical Clinics of North America 86: 1009–1033.

Hellings PW and Ceuppens JL (2004) Mouse models of global airway allergy: what have we learned and what should we do next? Allergy 59: 914–919.

Helm RM and Burks AW (2002) Animal models of food allergy. CurrentOpinion in Allergy and Clinical Immunology 2: 541–546.

Holgate ST (2004) Pharmacogenetics: the new science of personalizing treatment. Current Opinion in Allergy and Clinical Immunology 4: 37–38.

Joad J and Casale TB (1988) Histamine and airway caliber. Annals of Allergy 61: 1–7. Kay AB (2001) Allergy and allergic diseases: first of two parts. New England Journal of Medicine 344(1): 30–37.

Kim DS and Drake-Lee AB (2003) Allergen immunotherapy in ENT: historical perspective. Journal of Laryngology & Otology 117: 940–945.

Lipworth BJ (2005) Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365: 167–175.

Morgan WJ, et al. (2004) Results of a home-based environmental intervention among urban children with asthma. New England Journal of Medicine 351: 1068–1080.

Pelaia G, et al. (2002) Molecular mechanisms of corticosteroid action in chronic inflammatory airway diseases. Life Sciences 72: 1549–1561.

Robinson DS, Larche M, and Durham SR (2004) Tregs and allergic disease. Journal of Clinical Investigation 114: 1389–1397.

Sampson HA (2004) Update on food allergy. Journal of Allergy and Clinical Immunology 113(5): 805–819.

Shearer WTand Li JT (2003) Primer on allergic and immunologic diseases. Journal of Allergy and Clinical Immunology 111(2): S441–S778.

Simons FER (2004) Advances in H1-antihistamines. New England Journal of Medicine 351: 2203–2217.

Till SJ, et al. (2004) Mechanisms of immunotherapy. Journal of Allergy and Clinical Immunology 113(6): 1025–1034.

Weiss ST and Raby BA (2004) Asthma genetics 2003. Human Molecular Genetics 13: R83–R89.