Friday, 23 August 2013


A. Overview. Under some circumstances, immune responses produce damaging and sometimes fatal results, known collectively as hypersensitivities. 
Hypersensitivity reactions differ from protective immune responses in that they are exaggerated or inappropriate and damaging to the host. Hypersensitivity reactions are classified by the immune mechanism.

B. Type I hypersensitivity reaction (also known as immediate hypersensitivity) occurs upon the reaction of allergen (an antigen that elicits an allergic response) with specific IgE antibody that is bound to high affinity receptors on the surface of mast cells and basophils.

1. Sensitization phase. Initial contact with the allergen leads to proliferation and differentiation of the specific TH and B-cell populations. This is known as sensitization and does not generate allergic symptoms. After sensitization, IgE associates with mast cells and allergic reactions can be elicited upon reexposure to the allergen. All normal individuals can make IgE specific for a variety of different antigens; however, some individuals (atopic) are more prone to developing IgE and experiencing allergic responses. The tendency to develop IgE-mediated responses does appear to have a genetic component. The pattern of inheritance is not yet understood, although MHC-linked genes appear to be involved in some cases.

2. Activation phase. Cross-linking and clustering of the mast cell–bound IgE by the presence of allergen leads to the rapid release of mast cell granules containing many preformed inflammatory mediators (histamine, proteases, and TNF-a "Tumor necrosis factor alpha") and the synthesis of longer acting agents (leukotrienes, prostaglandins, and cytokines) that mediate the late phase response. The initial degranulation occurs within minutes, whereas the late phase response usually begins within 4 to 6 hrs and can last 24 hrs. Direct activation of mast cells via non–IgE-mediated events can also lead to the clinical features resulting from rapid mast cell degranulation. Complement components (C3a and C5a) act directly on mast cells, as do some food additives and certain drugs (e.g., aspirin, angiotensin-converting-enzyme [ACE] inhibitors, opioids) in some sensitive patients.

3. Effector phase. The symptoms of the type I hypersensitivity reactions are due to the inflammatory mediators released by the activated mast cells.
a. Histamine binds rapidly to a variety of cells via histamine receptors; H1 and H2 receptors are chiefly involved in the type I hypersensitivity reaction. Histamine binds to H1 receptors on smooth muscles (airway constriction, gastric muscular contractions) and endothelial cells (vascular permeability). Binding of histamine to H2 receptors, chiefly present at mucosal surfaces, results in increased mucous secretion and increased gastric acid production.
b. Cytokines and chemotactic factors are important for the growth and differentiation of leukocyte cell types, such as TH2s and eosinophils, as well as recruitment of leukocytes, including eosinophils and neutrophils.
c. Leukotrienes and prostaglandins, which are both synthesized as part of the late phase response, lead to prolonged constriction of smooth muscle (bronchoconstriction) and continued vascular permeability.

4. Clinical presentations of type I hypersensitivities
a. Allergic rhinitis is the most common atopic disorder worldwide. Airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and conjunctiva, resulting in degranulation of these mast cells, increased mucous secretion, localized vasodilation, and increased vascular permeability. Typical respiratory allergens include grass, tree, and weed pollens; fungal spores; dust mite allergens; and pet dander.
b. Asthma is a syndrome characterized by a generalized but reversible airway obstruction, bronchial hyperresponsiveness, and airway inflammation. Asthma cannot be explained solely based on IgE-mediated mast cell processes; however, most cases occur in patients who also show immediate hypersensitivity to defined environmental allergens. Airway inflammation plays a major role in the pathogenesis of asthma; recruitment of inflammatory cells, particularly eosinophils, can ultimately lead to remodeling of the respiratory tissue.
c. Food allergies are caused by the intake of certain foods that then interact with sensitized mast cells of the GI tract. Mast cell degranulation and mediator release leads to smooth muscle contraction (nausea and vomiting) and increased mucous and acid secretion. Typical food allergens include nuts, eggs, milk, and shellfish. In some cases, the food can be absorbed systemically, leading to mast cell degranulation in the skin (hives or atopic urticaria) or anaphylaxis from systemic mast cell degranulation.
d. Anaphylaxis is due to a generalized degranulation of IgE-sensitized mast cells following allergen exposure and is characterized by bronchospasm and cardiovascular collapse. Common allergens associated with anaphylaxis include bee and wasp stings, certain foods, and drugs (most notably, penicillin).

5. Clinical tests for allergies and intervention. Sensitivity is normally assessed by the introduction of small amounts of allergen into the skin either via skin prick (scratch test) or intradermal injection, followed by assessment for the wheal and flare (swelling and redness) reaction within 30 mins. Alternatively, allergen-specific serum IgE can be measured by radioallergosorbent test (RAST) or the enzyme-linked immunosorbent assay (ELISA). Skin tests and antigen-specific IgE blood tests are not always an accurate assessment for food allergies.

6. Treatments
a. For some patients, the easiest means to control allergies or asthma is to avoid exposure to known allergens or asthma triggers.
b. Modulation of the immunologic response or desensitization by injection of small amounts of allergen can lessen the hypersensitivity reaction to those specific allergens. Desensitization is thought to occur via a stimulation of TH1 cells rather than TH2 cells and, in some cases, a production of increased amounts of IgG rather than IgE. Recent desensitization clinical trials using oral introduction of allergen shows promise, particularly with respect to food allergies, and is thought to occur via the stimulation of TREG cells. Sublingual immunotherapy (SLIT, currently used in Europe for desensitization to environmental allergies) and specific oral tolerance induction (SOTI, used in investigational studies) are not currently approved by the U.S. Food and Drug Administration (FDA) and are considered experimental.
c. Another strategy in the treatment of severe, persistent, allergic asthma uses an anti-IgE monoclonal antibody (omalizumab) to inhibit the binding of IgE to the mast cell.
d. Mast cell stabilization. Cromolyn sodium (sodium cromoglycate) renders mast cells more resistant to triggering and activation.
e. Mediator antagonists. Antihistamines (ethanolamines, most notably diphenhydramine) are H1-receptor competitive antagonists of histamine. Cimetidine and ranitidine competitively inhibit histamine H2 receptors. Specific treatments for asthma will be discussed later. Epinephrine acts through its alpha-agonist and beta-agonist effects and is the most important drug for the treatment of anaphylaxis.

C. Type II hypersensitivities are antibody mediated and are due to the production of IgM or IgG antibodies directed to foreign antigens associated with cell surfaces. The targeted cell is either damaged or destroyed by complement activation, either direct lysis or opsonization; antibody-dependent, cellmediated cytotoxicity via NK cells or eosinophils; or opsonization by antibody, followed by phagocytosis by neutrophils and macrophages. Certain drugs, as well as blood group antigens (e.g., ABO incompatible transfusion reactions or Rh hemolytic disease), may act as type II hypersensitivity antigens.
1. Type II drug reactions. Drugs acting as haptens may become associated with cells or other components of the body and initiate antibody formation. When associated with the surface of red blood cells, drugs (e.g., penicillins, cephalosporins, and quinidine) can result in hemolytic anemia. Other drugs (e.g., quinine) more often attach to platelets and produce thrombocytopenia. The sensitization phase of a type II hypersensitivity reaction to a drug requires approximately 7 to 10 days after the initiation of drug therapy, at which point, antibody production will be sufficient for cell lysis and inflammation. Subsequent exposure to the drug will result in symptoms more rapidly (approximately 3 days or less). Withdrawing the drug typically resolves the symptoms.
2. The Rhesus blood group (Rh antigen) is a protein antigen, most often the D polypeptide; anti-Rh antibodies are the leading cause of hemolytic disease of the newborn (HDN). During pregnancy of an Rh-negative mother with an Rh-positive child, the mother may become sensitized to the D antigen of the child’s blood. Sensitization usually occurs at or near delivery and does not affect the source child. However, subsequent Rh-positive children may develop HDN when maternal IgG, including anti-D antigen antibodies, are passed across the placenta into the neonate during the third trimester. Rh-negative women are administered RhoD immune globulin (RhoGAM) during the latter part of pregnancy and within 72 hrs of delivery of an Rh-positive child in an effort to prevent sensitization. The passive immunization with the anti-RhoD antibodies acts by binding fetal blood cells that may be in the maternal circulation.

D. Type III hypersensitivity reactions are mediated by immune complexes of foreign antigen together with IgG, or occasionally IgM antibodies. The presence of the immune complexes results in activation of complement, including the generation of chemotactic and vasoactive factors. The classic immune complex allergic disorders include the Arthus reaction, serum sickness, and hypersensitivity pneumonitis (farmer’s lung).
1. Arthus reactions are localized cutaneous inflammatory reactions due to the immune complexes and inflammation that form in dermal blood vessels following the localized injection of large amounts of antigen into a sensitized individual. Antigen sources for Arthus reactions include drug injections (e.g., b-lactam–based antibiotics, heparin, incidental foreign proteins in injectable products such as fetal calf serum), vaccines, insect stings, and spider bites. Arthus reactions are characterized by an edematous and erythematous reaction, occurring within 3 to 8 hrs at the site of the antigen injection. The reaction will resolve without intervention, although hemorrhagic ulceration at the site is not uncommon. A limited form of Arthus reaction occurs commonly at the site of allergy desensitization and usually subsides in less than 24 hrs.
2. Serum sickness is a systemic immune complex reaction that occurs after injection of large quantities of foreign material. The antigen–antibody complexes deposit in small blood vessels, where complement-generated inflammation gives rise to the clinical features: fever, joint pain, urticaria, and splenomegaly. Typical antigens for serum sickness include heterologous antiserum (e.g., antivenin for snake, scorpion, and spider bites), antitoxins, intravenous human gamma globulin, and intravenous drugs. After initial injection, symptoms of primary serum sickness begin to appear as the antibody response develops (usually 7 to 10 days). In patients already sensitized to the antigen, symptoms appear more quickly (usually 2 to 4 days after injection). Complications of serum sickness are rare, and the symptoms usually resolve as the antibody response increases and the immune complexes are more efficiently removed from the body. Treatment is largely symptomatic.
3. Inhalation of antigenic particles or fumes can result in a hypersensitivity pneumonitis due to antigen–antibody complexes and the subsequent inflammation that forms in the lungs. Inhalation of environmental fungal spores or other organic particles, especially Aspergillus spores in farmer’s lung, appears to generate both IgE and IgG to the inhaled antigens as well as TH1 cells. The combination of the IgE- and IgG-mediated reactions, together with the action of proinflammatory cytokines, leads to tissue damage, inflammation, and the typical symptoms, which could be described as asthma symptoms superimposed with fever, cough, and sometimes chronic lung damage. Avoidance of antigen exposure is an important feature of management; repeated episodes lead to bronchial wall weakening and pulmonary fibrosis. High-dose systemic corticosteroid therapy is necessary to resolve the acute allergic inflammation and prevent long-term lung damage.

E. Type IV hypersensitivities (delayed-type hypersensitivities) are mediated by specific effector T cells. Examples of type IV hypersensitivities include the immune response to some infections (tuberculosis) and contact dermatitis, most often associated with metals or haptenic chemicals.
1. One of the best known examples of a type IV hypersensitivity is the tuberculin skin test (Mantoux skin test). Injection of purified protein derivative (PPD) into the skin of an individual previously infected with Mycobacterium tuberculosis recruits and activates those cells currently or previously employed in response to the tubercule bacillus (i.e., T cells and macrophages). A positive tuberculin skin test will present with redness and a palpable induration at 48 to 72 hrs after administration.

2. Many chemical substances, natural and synthetic, can be the source of contact hypersensitivity, which is typically a type IV hypersensitivity reaction. Common allergens include metals (nickel and chromate), plastics, rubber, lanolin, latex, plant chemicals, and medications such as neomycin and phenothiazines. The plant oil urushiol is the immunogenic hapten that is responsible for the contact dermatitis associated with poison ivy. The reaction is characterized by a red rash within a few days of contact, bumps, patches of weeping blisters on the skin, swelling of the area, and intense itching. Effective treatment focuses on suppressing the T-cell response: topical steroids such as triamcinolone or clobetasol. If the affected area involves more than 20% of the body or is particularly severe, systemic corticosteroid therapy may be required. Inhalation of the allergen when the plants are burned can lead to severe allergic respiratory issues.

3. Celiac disease, also known as gluten-sensitive enteropathy, is considered an autoimmune disorder that is triggered by a cell-mediated, adaptive immune response to ingested gluten, such as that found in wheat gluten and related proteins in rye and barley. In genetically susceptible individuals (i.e., HLA-DQ2 or -DQ8), gliadin, gluten’s main antigen, associates with host proteins.
Development of the symptoms of the disease is associated with TH and TC lymphocytic infiltration in the gut epithelial membrane and lamina propria, expression of proinflammatory cytokines, and production of IgA and IgG antibodies directed against the gluten as well as host components (e.g., tissue transglutaminase). Inflammation, villous atrophy, and crypt hyperplasia in the small intestine are all characteristic of celiac disease. Extraintestinal symptoms can include bone and skin disease, anemia, endocrine disorders, and neurological deficits. Gluten-free diet is the only effective intervention for celiac disease.

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