Hypersensitivity is a condition in which an exaggerated or augmented immune response occurs that is harmful to the host. Hypersensitivity requires a presensitized state. For example, in a given individual, such reactions typically occur after the second encounter with that specific antigen (allergen).

In 1963, Coombs and Gell classified hypersensitivity into four types: Types I, II, III (antibody mediated), and IV (T cell mediated).

Type I: Immediate Hypersensitivity (Allergy)

Type I hypersensitivity manifests itself in tissue reactions occurring within seconds after the antigen combines with specific IgE antibody. Its symptoms may manifest as a systemic anaphylaxis (eg, after intravenous administration of heterologous proteins) or as a local reaction (eg, an atopic allergy involving rhinitis such as occurs with hay fever).

The general mechanism of immediate hypersensitivity involves a series of steps. An antigen induces the formation of IgE antibody, which binds firmly by its Fc portion to high affinity IgE receptors on mast cells, basophils, and possibly eosinophils. Sometime later, an individual experiences a second exposure to same antigen. This second exposure results in the cross-linking of the cell bound IgE molecules and the release of pharmacologically active mediators. Cyclic nucleotides and calcium are essential in the release of mediators.

Pharmacologic mediators of type I hypersensitivity are listed as follows:

1. Histamine—Histamine exists in a preformed state in platelets and in granules of mast cells, basophils, and eosinophils. The release of histamine causes vasodilation, increased capillary permeability, and smooth muscle contraction (eg, bronchospasm). Antihistamine drugs can block histamine receptor sites and are relatively effective in allergic rhinitis. Histamine is one of the primary mediators of a type I reaction.

2. Prostaglandins and leukotrienes—Prostaglandins and leukotrienes are newly formed mediators derived from arachidonic acid via the cyclooxygenase pathway. Prostaglandins induce edema and bronchoconstriction. Leukotriene B4 is a chemoattractant that activates and recruits leukocytes to the site of injury. Leukotrienes C4 and D4 cause vasodilation and vascular permeability. These mediators, along with TNF-α and IL-4, are referred to as secondary mediators of a type I reaction.

A. Atopy

Atopic hypersensitivity disorders exhibit a strong familial predisposition and are associated with elevated IgE levels. Predisposition to atopy is clearly genetic, but the symptoms are induced by exposure to specific allergens. These antigens are typically environmental (eg, respiratory allergy to pollens, ragweed, or house dust) or foods (eg, intestinal allergy to shellfish). Common clinical manifestations include hay fever, asthma, eczema, and urticaria. Many patients experience immediate-type reactions to skin tests (injection, patch, scratch) involving the offending antigen.

B. Treatment and Prevention of Anaphylactic Reactions

Treatment aims to reverse the action of mediators by maintaining the airway, providing artificial ventilation if necessary, and supporting cardiac function. Epinephrine, antihistamines, and corticosteroids are often given. However, the best prevention relies on the identification of the antigen (detected by skin test or IgE antibody serology) and subsequent avoidance.

Type II: Hypersensitivity

 Type II hypersensitivity involves the binding of IgG antibodies to cell surface antigens or extracellular matrix molecules. Antibody directed at cell surface antigens can activate complement to damage the cells. The result may be complement mediated lysis, which occurs in hemolytic anemia, ABO transfusion reactions, and Rh hemolytic disease.

Drugs such as penicillin can attach to surface proteins on red blood cells and initiate antibody formation. Such autoimmune antibodies may then combine with the cell surface, and cause hemolysis. In Goodpasture syndrome, antibody is generated to the basement membranes of the kidney and lung. This results in complement activation, leukocyte chemotaxis, and severe membrane damage. In some cases, antibodies to cell surface receptors alter cell function without cell injury (eg, in Graves disease, an autoantibody binds to the thyroid stimulating hormone receptor, which generates stimulation of the thyroid, and hyperthyroidism).

Type III: Immune Complex Hypersensitivity

 When antibody combines with its specific antigen, immune complexes are formed. Normally, these immune complexes are promptly removed, but occasionally, they persist and are deposited in tissues. In persistent microbial or viral infections, immune complexes may be deposited in organs (eg, the kidneys), resulting in tissue and organ dysfunction. In autoimmune disorders, “self” antigens may elicit antibodies that bind to organ antigens or are deposited in organs and tissues as complexes, especially in the joints (arthritis), kidneys (nephritis), and blood vessels (vasculitis). Finally, environmental antigens such as fungal spores and certain drugs can cause immune complex formation with similar tissue and organ damage.

Wherever immune complexes are deposited, they can activate complement. Once complement is activated, macro phages and neutrophils migrate to the site and inflammation and tissue injury ensue. There are two major forms of immune complex-mediated hypersensitivity. One type of immune complex-mediated hypersensitivity is produced locally and is called Arthus reaction. This reaction occurs when a low dose of antigen is injected into the skin. This induces the production of IgG antibodies and complement activation. In addition, mast cells and neutrophils are stimulated to release their mediators that enhance vascular permeability. This reaction usually occurs within 12 hours. Another example of type III hypersensitivity involves a systemic immune complex disease such as acute poststreptococcal glomerulonephritis.

Acute poststreptococcal glomerulonephritis is a well-known immune complex disease. Its onset takes place several weeks after a group A β-hemolytic streptococcal infection, particularly of the skin, and often occurs with infection due to nephritogenic types of streptococci. The complement level is typically low, suggesting an antigen–antibody reaction with consumption of complement. Lumpy deposits of immunoglobulin and complement component, C3, are observed along the glomerular basement membrane. These membranes can be stained by immunofluorescence and visualized under UV microscopy. This type of pattern reveals antigen–antibody complexes. It is likely that streptococcal antigen–antibody complexes are filtered out by glomeruli, fix complement, and attract neutrophils. This series of events results in an inflammatory process that damages the kidney.

Type IV: Cell-Mediated (Delayed) Hypersensitivity

 Cell-mediated hypersensitivity is a T cell–mediated response. The interaction of an antigen with specifically sensitized T cells results in T cell proliferation, release of potent inflammatory cytokines (IFN-γ and IL-2), and activation of macro phages. This inflammatory response most often begins 2 or 3 days after contact with the antigen and typically lasts for several days.

A. Contact Hypersensitivity

 Contact hypersensitivity occurs after sensitization with simple chemicals (eg, nickel, formaldehyde), plant materials (poison ivy, poison oak), topically applied medications (eg, sulfonamides, neomycin), some cosmetics, soaps, and other substances. In all cases, small molecules enter the skin and then, acting as haptens, attach to body proteins to serve as complete antigens. Cell-mediated hypersensitivity is induced, particularly in the skin. When the skin again comes in contact with the offending agent, the sensitized person develops erythema, itching, vesication, eczema, or necrosis of skin within 12–48 hours. Avoidance of the inciting material will prevent recurrences. A skin test may identify the antigen in question. Langerhans cells in the epidermis, which interacts with CD4 T h1 cells, appears to play a role in driving this response.

B. Tuberculin-Type Hypersensitivity

Delayed hypersensitivity to antigens of microorganisms occurs in many infectious diseases and it has been used as an aid in diagnosis. The tuberculin reaction is a good example of a delayed-type hypersensitivity (DTH) response. When a small amount of tuberculin is injected into the epidermis of a patient previously exposed to Mycobacterium tuberculosis, there is little immediate reaction. Gradually, however, induration and redness develop and reach a peak in 24–72 hours. Mononuclear cells, especially CD4 Th1 cells, accumulate in the subcutaneous tissue. A positive skin test indicates that the person has been infected with the microorganism but does not imply the presence of current disease. However, a recent change of skin test response from negative to positive suggests recent infection and possible current activity.

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مواضيع ذات صلة

The Immunoglobulin Domain and Variations

Deficiencies of the Immune Response

Cytokines

Complement Deficiencies and Pathogen Evasion

Complement Pathways

T Cells

Antibody Responses

Immunoglobulin Genes and Generation of Diversity

Immunoglobulin Classes

Immunofluorescence

Chemiluminescence

Enzyme Immunoassay