eMedicine Specialties > Allergy and Immunology > Allergy Pathogenesis

Hypersensitivity Reactions, Immediate

Author: Miriam K Anand, MD, Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd
Coauthor(s): John M Routes, MD, Professor of Pediatrics, Medical College of Wisconsin; Chief, Section of Allergy and Clinical Immunology, Department of Pediatrics, Children's Hospital of Wisconsin
Contributor Information and Disclosures

Updated: Jun 16, 2009

Introduction

Background

The immune system is an integral part of human protection against disease, but the normally protective immune mechanisms can sometimes cause detrimental reactions in the host. Such reactions are known as hypersensitivity reactions, and the study of these is termed immunopathology. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the most commonly known classification system. It divides the hypersensitivity reactions into the following 4 types:

• Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–mediated release of histamine and other mediators from mast cells and basophils.
• Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface antigens, with subsequent complement fixation.
• Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in postcapillary venules, with subsequent complement fixation.
• Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by antibodies.

Some authors believe this classification system may be too general and favor a more recent classification system proposed by Sell et al. This system divides immunopathologic responses into the following 7 categories:

• Inactivation/activation antibody reactions
• Cytotoxic or cytolytic antibody reactions
• Immune-complex reactions
• Allergic reactions
• T-cell cytotoxic reactions
• Delayed hypersensitivity reactions
• Granulomatous reactions

This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions (see Pathophysiology). In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reactions.

Allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, some types of drug reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from anaphylactoid reactions that involve IgE-independent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast dye, opiates, or vancomycin and appear similar clinically by resulting in urticaria or anaphylaxis.

Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure.

The focus of this article is allergic reactions in general. Although some of the clinical manifestations listed previously are briefly mentioned, refer to the articles on these topics for more detail. For example, see Allergic and Environmental Asthma; Anaphylaxis; Food Allergies; Rhinitis, Allergic; and Urticaria.

Pathophysiology

TH1 cells produce interferon gamma, interleukin (IL)–2, and tumor necrosis factor-beta and promote a cell-mediated immune response (eg, delayed hypersensitivity reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to promote the production of antigen-specific IgE. Therefore, TH2 cells play an important role in the development of immediate hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio. Interestingly, the cytokines produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells. Current evidence suggests that Tregs may also actively inhibit TH2 responses to allergens.¹

The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is either inhaled or ingested and is then processed by the dendritic cell, an antigen-presenting cell. The antigen-presenting cells then migrate to lymph nodes, where they prime naive TH cells (TH0 cells) that bear receptors for the specific antigen.

TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of allergen sensitization, the TH0 cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center B cells) and possibly to histamine-primed dendritic cells, both of which cause them to develop into TH2 cells. These primed TH2 cells then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of antigen-specific IgE antibodies.

For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen and present it to the TH2 cells on the major histocompatibility class II molecules found on B-cell surfaces. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class switching from immunoglobulin M production to antigen-specific IgE production (see Image 1).

The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils. Reexposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:

Preformed mediators

• Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion.
• Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation.
• Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be important in storing the preformed proteases and may play a role in the production of alpha-tryptase.
• Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, can cause significant tissue damage in the later phases of allergic reactions.

Newly formed mediators

• Arachidonic acid metabolites
  • Leukotrienes - Produced via the lipoxygenase pathway
    • Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability
    • Leukotrienes C4 and D4 - Potent bronchoconstrictors, increase vascular permeability, and cause arteriolar constriction
    • Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability
    • Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of anaphylaxis
  • Cyclooxygenase products
    • Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator, coronary and pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer of histamine release from basophils
    • Prostaglandin F2-alpha - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet aggregation inhibitor
    • Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction
• Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils.
• Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release.
• Bradykinin: Kininogenase released from the mast cell can act on plasma kinins to produce bradykinin. Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not been clearly demonstrated.

Cytokines

• IL-4: IL-4 stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis.
• IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for histamine and leukotriene release.
• IL-6: IL-6 promotes mucus production.
• IL-13: This cytokine has many of the same effects as IL-4.
• Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other cytokines by T cells.

The actions of the above mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

• Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema is swelling of the affected area; it tends to be painful rather then pruritic.
• Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal congestion, rhinorrhea, and itchy or watery eyes.
• Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus production, and inflammation of the airways, resulting in chest tightness, shortness of breath, and wheezing.
• Anaphylaxis: Systemic release of the above mediators affects more than one system and is known as anaphylaxis. In addition to the foregoing symptoms, the GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea. Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock. Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat swelling and asphyxiation.

Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These effects can last a few hours and usually resolve within 24-48 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) can result in chronic allergic inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. This can result in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgE–mediated responses.

Frequency

United States

• The prevalence of atopic diseases had increased significantly in the 1980s and 1990s in industrialized societies.
• Allergic rhinitis is the most prevalent allergic disease; it affects approximately 17-22% or more of the population.
• Asthma is estimated to affect more than 20 million people. Ninety percent of asthma cases in children are estimated to be allergic, compared with 50-70% in adults.
• Atopic dermatitis had also increased in prevalence in the 1980s and 1990s; prevalence in the United States is likely similar to that in Europe (see below, International).
• The prevalence of anaphylaxis is approximately 1-3% in industrialized countries.

International

• The estimated prevalence of atopic dermatitis among school children in various European countries is 15-20%.
• Asthma, as with other atopic diseases, was previously increasing in prevalence.^2,3  Data from a recent study from England suggest that the prevalence of asthma, allergic rhinitis, and atopic dermatitis may be stabilizing.⁴  Hospital admissions for anaphylaxis, however, have increased by 600% over the past decade in that country and by 400% for food allergy. Admission rates for urticaria increased 100%, and admission rates for angioedema increased 20%, which suggests that these allergic diseases may be increasing in prevalence.
• Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations compared with rural populations. This was initially thought to be related to environmental pollution, but the results from studies of asthma prevalence before and after the unification of Germany contradict this theory.⁵
  
  
  • The prevalence of asthma in East Germany prior to 1990 was lower than in West Germany, despite the fact that East Germany had more air pollution.
  • Over the 10 years after unification, the prevalence of asthma in the former East Germany has increased and is now comparable with that of former West Germany.
  • In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic disease.
  • These findings have led to the hygiene hypothesis, which proposes that early exposure to infectious agents helps direct the immune system toward a TH1 cell–predominant response that, in turn, inhibits the production of TH2 cells. A TH1 response does not lead to allergies, while a cleaner, more hygienic environment may lead to TH2 predominance and more allergies.

Mortality/Morbidity

• Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively rare. In 1995, 5579 people died from asthma in the United States. Approximately 500 people die annually from anaphylaxis in the United States.
• Allergic diseases are a significant cause of morbidity. In 1990, the economic impact of allergic diseases in the United States was estimated to be $6.4 billion from health care costs and lost productivity. Children with untreated allergic rhinitis do worse on aptitude tests than their nonatopic peers.

Race

• Any differences in the prevalence of allergic diseases with respect to race seem to be more related to environmental factors than to true racial differences. For example, in the United States, the prevalence of asthma is 2.5 times higher in African Americans than in whites. Asthma is more prevalent in inner-city populations, and this may explain the difference.

Sex

• Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in boys during the first decade of life; after puberty, prevalence is higher in females. The male-to-female ratio of children who have atopic disease is approximately 1.8:1.
• Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.

Age

• In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.
• Food allergies and subsequent anaphylaxis are more prevalent in children. Some children may outgrow their allergies to certain foods, or their reactions may diminish over time. However, anaphylaxis from food and other triggers is still a threat in adults. Some food allergies, such as allergy to peanuts, may last a lifetime.
• Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma later in life (beginning in adolescence) and can also have asthma that is more severe.

Clinical

History

History findings vary depending on which organ systems are affected.

• Anaphylaxis
  • Patients may report dizziness, faintness, diaphoresis, and pruritus. Difficulty breathing can result from angioedema of the pharyngeal tissue and from bronchoconstriction. Patients may also report GI symptoms, including nausea, vomiting, diarrhea, and abdominal cramping. Patients may experience uterine cramping or urinary urgency. Patients can have a sudden onset of respiratory and/or circulatory collapse and go into anaphylactic shock.
  • Symptoms usually begin within minutes of allergen exposure (eg, drug administration, insect sting, food ingestion, allergen immunotherapy) but can recur hours after the initial exposure (late-phase reaction).
  • Patients may not be able to identify the allergen either because they are unaware of the allergy (eg, first reaction to insect sting) or because they were unaware of exposure to the allergen (eg, a patient who is allergic to peanuts who eats a processed food containing peanut protein).
  • Particular attention should be given to new or recently changed medications. A history specific for insect stings or new environmental exposures should be obtained. If applicable, a food history should also be obtained.
• Allergic rhinoconjunctivitis
  • Symptoms consist of itchy, runny nose and eyes and itching of the palate and inner ear. Patients may also report postnasal drip, which can cause sore throat, coughing, or throat clearing.
  • Rhinoconjunctivitis usually results from exposure to aeroallergens and can be seasonal or perennial. Airborne allergens typically also cause ocular symptoms consisting of itchy eyes, tearing, or redness of the eyes.
  • Repeated exposure to the allergen can result in chronic allergic inflammation, which causes chronic nasal congestion that can be further complicated by sinusitis.
• Allergic asthma
  • Allergen exposure results in bronchoconstriction, and patients may report shortness of breath (eg, difficulty getting air out), wheezing, cough, and/or chest tightness.
  • Long-term allergen exposure can cause chronic changes of increased difficulty breathing and chest tightness, and the patient may give a history of repeated rescue inhaler use or reduced peak flows.
• Urticaria/angioedema
  • Diffuse hives or wheals may occur and cause significant pruritus; individual wheals resolve after minutes to hours, but new wheals can continue to form.
  • Acute urticaria (lasting <6 wk) can be caused by foods, drugs, or contact allergens.
  • Chronic urticaria lasts longer than 6 weeks. Although many causes are possible, often, a cause is not found.
  • Angioedema is localized tissue swelling that can occur in soft tissues throughout the body. Patients may report pain at the site of swelling instead of pruritus, which occurs with urticaria.
  • Angioedema of the laryngopharynx can obstruct the airway, and patients may report difficulty breathing. Stridor or hoarseness may be present. Angioedema of the laryngopharynx can be life threatening.
• Atopic dermatitis
  • This condition is an eczematous cutaneous eruption more common in children than in adults; it can be exacerbated by allergen exposure, especially food allergies, in some patients.
  • Patients report significant pruritus that causes scratching, which produces the lesions. Superinfection can occur, particularly in severely excoriated or cracked lesions.
• GI involvement
  • Patients may report nausea, vomiting, abdominal cramping, and diarrhea after ingestion of the offending food.
  • Note that other mechanisms (eg, lactose intolerance) commonly cause these symptoms.
  • Eosinophilic esophagitis and gastritis are newly recognized syndromes that may be allergic in nature.

Physical

Physical examination findings vary with the organ system involved.

• Anaphylaxis
  • Vital signs should be monitored closely because patients can quickly progress to circulatory and/or respiratory failure. Tachycardia may precede hypotension. Patients who are hypotensive have a reflex tachycardia, but bradycardia can also occur in 5%. Flushing and tachycardia are usually the first and are invariant symptoms of anaphylaxis.
  • Patients may have urticaria, angioedema, or both. Angioedema of the airway and throat can result in respiratory failure or asphyxiation; therefore, this must be closely monitored.
  • Patients may be wheezing during the respiratory examination, which is secondary to bronchoconstriction.
  • Confusion and alteration of mental status can occur.
• Allergic rhinoconjunctivitis
  • Patients may sneeze or have frequent throat clearing and/or cough from postnasal drip.
  • Sclera may be injected, and patients may have dark rings under the eyes (ie, allergic shiners).
  • Nasal mucosa can be boggy and pale, usually with clear drainage.
  • The pharynx may have a cobblestone appearance from postnasal mucus drainage.
  • The patient may have frontal or maxillary sinus tenderness from chronic nasal congestion or infection.
• Allergic asthma
  • Findings can vary depending on the patient and the severity of symptoms. Patients may be coughing or appear short of breath. Wheezing may be present, but it might not be heard in patients with milder symptoms or, if the asthma is severe, patients may not move enough air to produce wheezing. 
  • Breaths may be shallow or the patient may have a prolonged expiratory phase.
  • Cyanosis of the lips, fingers, or toes may occur with severe asthma caused by hypoxemia.
• Urticaria/angioedema
  • Urticaria is usually represented by wheals with surrounding erythema. Wheals from allergic causes usually last a few minutes to a few hours. Wheals due to cutaneous vasculitis may last up to 24 hours and may leave postinflammatory hyperpigmentation upon healing.
  • Angioedema is localized swelling of the soft tissues that can occur anywhere but is particularly concerning if pharyngeal or laryngeal tissues are involved.
• Atopic dermatitis
  • The physical examination findings can vary with the severity of the disease. In less severe cases, skin can appear normal, dry, or with erythematous papules. In more severe cases, patients can have extremely dry, cracked, and, sometimes, crusted lesions.
  • In infants, the head and extensor surfaces are more involved, whereas in older children and adults, the flexural surfaces tend to be affected.

Causes

Atopy is defined as the genetic predisposition to form IgE antibodies in response to exposure to allergens. Therefore, a genetic predisposition exists for the development of atopic diseases. Mutations of specific alleles on the long arm of chromosome 5 have been associated with higher levels of IL-4 and IgE and are known as IL-4 promoter polymorphisms. Impaired function of Treg cells may also contribute to the development of atopic diseases.

Environmental issues also play an important role, although the role exposure at an early age to certain antigens might play in either the progression to or the protection from the development of an allergic response remains unclear. Some studies have shown that children in day care and those with older siblings may be less likely to develop allergic disease. The environment certainly can help determine the allergens to which the patient will be exposed. For example, children in inner cities are more likely to be sensitized to cockroaches than children in rural areas. Similarly, dust mites, a potent allergen, are primarily found in humid climates, and those who have never been exposed to such a climate are less likely to be allergic to mites.

• Allergic reactions
  • Reactions can be elicited by various aeroallergens (eg, pollen, animal dander), drugs, or insect stings.
  • Other possible causes are latex allergy and food allergy.
• Allergens
  • Allergens can be complete protein antigens or low–molecular-weight proteins capable of eliciting an IgE response.
  • Pollen and animal dander represent complete protein antigens.
  • Haptens are low–molecular-weight (inorganic) antigens that are not capable of eliciting an allergic response by themselves. They must bind to serum or tissue proteins in order to elicit a response. This is a typical cause of drug hypersensitivity reactions. Note that all drug hypersensitivity reactions are not mediated by IgE. In addition to anaphylactoid reactions, drug reactions can be caused by cytotoxicity and immune-complex formation and by other immunopathologic mechanisms.
• Foods
  • The most common food allergens are peanuts, tree nuts, finned fish, shellfish, eggs, milk, soy, and wheat.
  • Certain foods can cross-react with latex allergens. These foods include banana, kiwi, chestnut, avocado, pineapple, passion fruit, apricot, and grape.
• Hymenoptera
  • Bee, wasp, yellow jacket, hornet, and fire ant stings can cause IgE-mediated reactions.
  • While anaphylaxis is the most serious reaction, localized swelling and inflammation can also occur and do not by themselves indicate increased risk of a subsequent life-threatening reaction.
  • At least 50 Americans die each year from anaphylaxis caused by a stinging insect.
• Anaphylactoid reactions
  • Non–IgE-mediated mast cell and basophil degranulation can occur from a variety of substances. Although the mechanisms are different, the clinical manifestations can appear the same.
  • Causes can include radiocontrast dye, opiates, and vancomycin (eg, red man syndrome).
  • Patients can be pretreated with glucocorticosteroids and both H1 and H2 antihistamines prior to exposure to iodinated radiocontrast dye. This, together with the use of low-osmolal nonionic dye, reduces the risk of a repeat reaction to approximately 1%.
  • Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can also cause reactions by causing release of leukotrienes via the 5-lipoxygenase pathway of arachidonic acid metabolism. Patients susceptible to this syndrome can develop acute asthma exacerbation, nasal congestion, urticaria, or angioedema after ingestion. However, note that in rare cases, patients can have what are thought to be true IgE-mediated anaphylactic reactions to a specific NSAID. In these cases, no cross-reactivity occurs with other NSAIDs.

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