The manifestations of allergic diseases depend on the tissues in which mast cell mediators and type 2 cytokines are active, as well as the chronicity of the resulting inflammatory process. Atopic individuals may have one or more types of allergy, the most common forms being allergic rhinitis, asthma, atopic dermatitis, and food allergies. Frequently, an individual will develop more than one atopic disorder. The clinical presentation of atopic dermatitis in babies followed later in childhood by allergic rhinitis and asthma is known as the atopic march, and these three conditions are together called the atopic triad.
The clinical and pathologic features of allergic reactions vary with the anatomic site of the reaction, for several reasons. The point of contact with the allergen can determine the organs or tissues where mast cells and Th2 cells are activated. For example, inhaled antigens cause rhinitis or asthma, and ingested anti gens often cause vomiting and diarrhea. Although there is a propensity for local reactions to depend on the site of allergen entry, many allergens can become widely disseminated whether inhaled or ingested and can cause symptoms throughout the body regardless of the site of entry. Injected antigens, such as drugs, can rapidly cause systemic effects. The concentration of mast cells in various target organs also influences the severity of responses. Mast cells are particularly abundant in the skin and the mucosa of the respiratory and gastrointestinal tracts, and these tissues frequently suffer the most injury in immediate hypersensitivity reactions. The local mast cell phenotype may influence the characteristics of the immediate hypersensitivity reaction. For example, connective tissue mast cells produce abundant histamine and are responsible for wheal-and-flare reactions in the skin.
In the following section, we will discuss the major features of allergic diseases manifested in different tissues.
Systemic Anaphylaxis
Anaphylaxis is a systemic immediate hypersensitivity reaction characterized by edema in many tissues and a decrease in blood pressure secondary to vasodilation and vascular leak. These effects usually result from the systemic presence of anti gen introduced by injection, an insect sting, or absorption across an epithelial surface such as gut mucosa. The allergens that most often cause anaphylaxis include penicillin family antibiotics and proteins in peanuts, soy, sesame, tree nuts, fish, shellfish, milk, eggs, and stinging insect venoms, but there are many other drug, food, and environmental culprits. The allergen activates mast cells in many tissues, resulting in the release of mediators that gain access to vascular beds throughout the body. The decrease in vascular tone and leakage of plasma caused by mast cell mediators can lead to a significant decrease in blood pressure, or shock, called anaphylactic shock, which is often fatal. Mast cell mediators may impair breathing by causing laryngeal edema, bronchoconstriction, and excess bronchial mucus production. There is often diarrhea, as a result of intestinal hypermotility and outpouring of mucus in the gut, and urticarial lesions (hives) in the skin. Anaphylaxis usually occurs within seconds to an hour of exposure to an allergen. In a small minority of patients, a recurrence of symptoms is seen without known reexposure to the allergen, usually within 12 hours but up to 24 to 72 hours after the first episode. This is often called a biphasic anaphylactic reaction. It is not known which mast cell mediators are the most important in anaphylactic shock. The standard of care is epinephrine injection, which can be lifesaving by reversing the bronchoconstrictive and vasodilatory effects of mast cell media tors. Epinephrine also improves cardiac output, further aiding survival from threatened circulatory collapse. While antihistamines and steroids are often given to patients with anaphylaxis, their effectiveness has not been proven and they are only adjunctive to epinephrine.
Asthma
Asthma includes a group of pulmonary diseases characterized by recurrent reversible airflow obstruction and bronchial smooth muscle cell hyperresponsiveness, most often caused by repeated immediate-type hypersensitivity and late-phase reactions (Fig. 1). Patients have paroxysms of bronchocon striction and increased production of thick mucus, which lead to bronchial obstruction and respiratory difficulties. Asthma in adults can coexist with chronic obstructive pulmonary dis ease, and the combination of these diseases can cause severe irreversible airflow obstruction. Affected individuals may have considerable morbidity, and asthma can be fatal. Asthma affects approximately 25 million people in the United States, and the frequency of this disease has increased over the past 30 to 40 years. The prevalence rate is similar in other industrialized countries and higher than in lower-income areas of the world.
Fig1. Histopathologic features of asthma. Atopic asthma results from repeated immediate hypersensi tivity reactions in the lungs with chronic late-phase reactions. A cross-section of a normal bronchus (A) and a cross-section of a bronchus from a patient with asthma (B) are shown. The diseased bronchus has excessive mucus (M) production, many submucosal inflammatory cells (including eosinophils), smooth muscle (SM) hypertrophy, and many more goblet cells than in the normal bronchus (black arrows in insets). (From Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454:445–454. Courtesy G. J. Berry, Stanford University, California.)
Asthma is an “umbrella” diagnosis, in that patients with this diagnosis have many clinical phenotypes that may have different underlying molecular mechanisms (e.g., endotypes). Approximately half of asthma cases are associated with IgE mediated reactions and type 2 inflammation reflecting atopy. In the remaining half of patients, bronchoconstriction may develop upon exposure to cold temperatures or exercise; the underlying mechanism of airway hyperreactivity is unclear in these cases. Among type 2 (or atopic) and nontype 2 (nonatopic) asthmatics, the pathophysiologic process of airway constriction is similar, which suggests that alternative mechanisms of mast cell degranulation (e.g., by locally produced neurotransmitters) or other effector cells may also underlie the disease.
One strategy for dividing patients with atopic asthma is the identification of high or low levels of biomarkers reflecting type 2 inflammation. Type 2 high inflammation is most often characterized by elevated blood eosinophils and may also have elevated IL-13, IL-4, and IL-5 production, and/or increased frequency of Th2 cells. Although there is significant heterogeneity of clinical features even among patients with type 2 high or low disease phenotypes, this classification has proved useful to determine which patients are most likely to benefit from new cytokine-directed therapies for asthma, which thus far target type 2 immunity.
The pathophysiologic sequence in atopic asthma is likely initiated by mast cell activation in response to allergen binding to IgE and by Th2 cells reacting to allergens (Fig. 2). The lipid mediators and cytokines produced by the mast cells and T cells lead to the recruitment of eosinophils, basophils, and more Th2 cells. The chronic inflammation in this disease may continue without mast cell activation. There is experimental evidence that other T-cell subsets, including Th1 and Th17 cells and IL-9-secreting T cells, may contribute to the pathologic processes in established disease. Smooth muscle cell hyper trophy and hyperreactivity are thought to result from leukocyte-derived mediators and cytokines. Mast cells, basophils, and eosinophils all produce mediators that constrict airway smooth muscle. The most important of the bronchoconstricting mediators are cysteinyl leukotrienes, including LTC4 and its metabolites. Increased mucus secretion results from the action of cytokines, mainly IL-13, on bronchial epithelial cells.
Fig2. Mediators and treatment of asthma. Targeted asthma therapy is focused on type 2 immunity and is generally targeted at reducing mast cell activation with anti-immunoglobulin E (IgE), inhibiting type 2 cytokine signaling including thymic stromal lymphopoietin (TSLP); interleukin-5 (IL-5), IL-4, and/or IL-13; and countering mediator actions on bronchial smooth muscle by bronchodilators such as inhaled β-adrenergic receptor agonists and leukotriene antagonists. Type 2 inflammatory cytokines are thought to be the major mediators of sustained airway inflammation in atopic asthma, which is an example of a late-phase reaction; corticosteroid therapy is used to inhibit cytokine synthesis, and antibodies are used to block the actions of the cytokines. Currently, type 2 low asthma is an area of active investigation for targeted therapy. LTC4 , Leukotriene C4 ; PAF, platelet-activating factor; TNF, tumor necrosis factor.
Current therapy for asthma has two major goals: prevention and reversal of inflammation, and acute treatment of exacerbations via relaxation of airway smooth muscle (see Fig. 2). Several classes of drugs are in current use to treat asthma, but antiinflammatory agents are now the primary mode. Inhaled corticosteroids block the production of inflammatory cytokines. Corticosteroids also may be given systemically, especially once an attack is underway, to reduce inflammation. With acute symptoms, rescue medications are focused on relaxation of bronchial smooth muscle cells, which is achieved principally by drugs that elevate intracellular cyclic adenosine monophosphate (cAMP) levels in smooth muscle cells, which inhibits contraction. The major drugs used to elevate cAMP are activators of adenylate cyclase, including inhaled β2-adrenergic agonists, which are delivered for prevention or treatment in combination with inhaled corticosteroids. Antagonists specific for the LTC4 receptor on airway smooth muscle cells are effective in preventing asthma symptoms in some patients. Early trials of antibodies targeting type 2 cytokines were not effective, until the strategy of identifying type 2–high patients was introduced into trials. Blood eosinophil count was most often used a biomarker for identification of patients who will benefit from therapy. A humanized mono clonal anti-IgE antibody is an approved therapy that effectively reduces serum IgE levels in patients and improves asthma control. Several monoclonal antibody drugs specific for type 2 cytokines or cytokine receptors have been approved for treatment of asthma, including antibodies specific for IL-5, IL-5 receptor (IL 5R), IL-4R (which is shared by both IL-4 and IL-13 receptors), and TSLP. These biologic drugs are mainly used in patients with severe type 2-high disease that is refractory to other treatments.
Immediate Hypersensitivity Reactions in the Upper Respiratory Tract, Gastrointestinal Tract, and Skin
Allergic rhinitis is perhaps the most prevalent allergic disease and is a consequence of immediate hypersensitivity reactions to common inhaled allergens such as plant pollen or house dust mites. The reaction is localized to the upper respiratory tract, and the pathologic and clinical manifestations include mucosal edema, leukocyte infiltration with abundant eosinophils, mucus secretion, coughing, sneezing, and difficulty breathing. Allergic conjunctivitis, causing red, watery, and itchy eyes, is commonly associated with rhinitis. Focal protrusions of the nasal mucosa, called nasal polyps, filled with edema fluid and eosinophils may develop in patients who have frequent, repetitive bouts of allergic rhinitis. Antihistamines and intranasal steroids are commonly used to treat allergic rhinitis.
IgE-mediated food allergies are immediate hypersensitivity reactions to ingested foods that lead to the release of mediators from intestinal mucosal and submucosal mast cells of the gastro intestinal tract, including the oropharynx. The resulting clinical manifestations include pruritus; tissue edema; enhanced peristalsis; increased epithelial fluid secretion; and symptoms of oropharyngeal swelling, vomiting, and diarrhea. Rhinitis, urticaria, and mild bronchospasm are also often associated with allergic reactions to food, suggestive of systemic antigen exposure, and anaphylaxis may occasionally occur. Individuals may be sufficiently sensitive to these allergens that severe systemic reactions can occur in response to small accidental ingestions. Allergies to foods, including cow’s milk, eggs, peanuts, tree nuts, shellfish, fish, soy, and wheat, are extremely common across the world. Of note, there are also non classical food allergies that are not caused by IgE generated against food protein allergens, including eosinophilic esophagitis and food protein induced enterocolitis syndrome. Both can be managed in part by food avoidance, although a monoclonal antibody drug specific for IL-4RA has recently been approved to treat eosinophilic esophagitis.
Common allergic reactions in the skin include urticaria and atopic dermatitis. Urticaria, or hives, is an acute wheal-and-flare reaction induced by mast cell mediators and occurs in response to direct local contact with an allergen or after an allergen enters the circulation. It may be associated with infections, reactions to therapeutic drugs, foods, physical contact with allergens, and some systemic autoimmune disorders. Because the reaction that ensues is mediated largely by histamine, antihistamines can attenuate this response and are the mainstay of therapy. Urticaria may persist for several hours or days (though individual urticaria do not last more than 24 hours), but if it persists for more than 6 weeks it is defined as chronic.
Atopic dermatitis (commonly called eczema) is a common skin disorder characterized by acute flares of itchy red exudative papules and chronically dry, scaly skin. It can be part of the atopic march discussed earlier but can also occur in isolation. Atopic dermatitis is rarely associated with filaggrin mutations that result in defective skin barrier function. As a result, in those cases, there is increased exposure to environmental anti gens and activation of keratinocytes to secrete cytokines that promote type 2 immune responses. Patients with eczema go on to develop chronic late-phase reactions in the skin. As may be expected for a cytokine-mediated response, the late-phase inflammatory reaction is not inhibited by antihistamines but can be treated with corticosteroids, which inhibit cytokine synthesis. Multiple anti-cytokine therapies are approved for the treatment of atopic dermatitis including anti-IL-4R v. IL-4RA again, anti IL-13, anti-IL31R and topical and oral inhibition of JAK signaling (downstream of cytokine receptors and upstream of STATs).
Specific Immunotherapy (Desensitization) for Allergic Diseases
In addition to therapy aimed at the consequences of immediate hypersensitivity that we have discussed, clinical allergists often try to reduce the onset of allergic reactions by altering the allergen-specific immune response in the patient. Several empirical immunotherapy protocols have been used, which induce multiple immunologic alterations that may account for the clinical benefit. In one approach, called desensitization, or specific allergen immunotherapy, small quantities of the allergen are repeatedly administered subcutaneously or sublingually. As a result of this treatment, specific IgE levels decrease and IgG titers often rise, perhaps further inhibiting IgE production by neutralizing the antigen and by antibody feedback. It is possible that desensitization may work by inducing specific T-cell tolerance, by changing the predominant phenotype of antigen-specific T cells from Th2 to Th1, by inducing production of nonallergy isotypes of IgG specific for the allergen, or by inducing allergen-specific regulatory T cells; however, there is no clear evidence to support any of these hypotheses. The beneficial effects of desensitization may occur in a matter of hours, much earlier than changes in IgE levels. Although the precise mechanism is not known, this approach has been effective in preventing acute anaphylactic responses to protein antigens (e.g., insect venom) or vital drugs (e.g., penicillin). Many people with more common chronic atopic conditions, such as allergic rhinitis, may also benefit from desensitization therapy. In addition, there is increasing clinical familiarity with, and evidence to support, using oral immunotherapy, to reduce reactions to single or multiple foods in patients with IgE-mediated food allergies.
As mentioned earlier, epidemiologic and clinical trial data have shown that exposure of high-risk infants 4 to 11 months of age to peanut- containing foods reduces the risk of developing peanut allergy later in life. These results have led to the reversal of standard clinical recommendations, from peanut avoidance to peanut exposure, for all children at risk for developing peanut allergy (e.g., children with severe eczema or egg allergy). In the trials, prevention of the allergy is by early-life exposure correlated with the induction of nonallergenic IgG4 antibodies specific for the peanut allergens, but it is not known if this or other mechanisms are the basis of tolerance induction, and it is not known if this approach of early-life exposure will be effective for other food allergens. A preparation of powdered peanuts taken orally on an ongoing basis, once safely initiated with an allergist, has been shown to reduce the risks for severe allergic reactions to peanuts in children older than 4 years with a known peanut allergy and is approved for use in children 4 to 17 years of age.
