Allergic Reaction: Physiologic Overview

Allergic Reaction: Physiologic Overview

An allergic reaction is a manifestation of tissue injury resulting from interaction between an antigen and an antibody. Allergy is an inappropriate and often harmful response of the immune system to normally harmless substances. In this case, the substance is termed an allergen. Atopy refers to allergic reactions characterized by the action of IgE antibodies and a genetic predisposition to allergic reactions.When the body is invaded by an antigen, usually a protein that the body’s defenses recognize as foreign, a series of events occurs in an attempt to render the invader harmless, destroy it, and remove it from the body. When lymphocytes respond to the antigen, antibodies (protein substances that protect against antigens) are produced. Common allergic reactions occur when the immune system of a susceptible person responds aggressively to asubstance that is normally harmless (eg, dust, weeds, pollen, dander). Chemical mediators released in allergic reactions may produce symptoms ranging from mild to life-threatening.The many cells and organs of the immune system secrete various substances important in the immune response. These parts of the immune system must work together to ensure adequate defense  against  invaders  (ie,  virus,  bacteria,  other  foreign  substances) without destroying the body’s own tissues by an overly aggressive reaction.

FUNCTION AND PRODUCTION OF IMMUNOGLOBULINS

Antibodies formed by lymphocytes and plasma cells in response to an immunogenic stimulus constitute a group of serum proteins called immunoglobulins. Grouped into five classes (IgE, IgD, IgG, IgM, and IgA), antibodies can be found in the lymph nodes, tonsils, appendix, and Peyer’s patches of the intestinal tract or circulating in the blood and lymph. Each antibody molecule is composed of two identical heavy (H) chains and two identical light (L) chains. Each chain contains one variable region and one or more constant regions. The constant regions determine the class (IgE, IgD, etc.) of each antibody and allow each class of antibody to interact with specific effector cells and molecules. The variable regions contain antigen-binding sites (Porth, 2002). Antibodies are capable of binding with a wide variety of antigens, which include macromolecules and small chemicals (Abbas & Lichtman,2001). Antibodies of the IgM, IgG, and IgA classes have definite and well-established protective functions. These include neutralization of toxins and viruses and precipitation, agglutination, and lysis of bacteria and other foreign cellular material.         Immunoglobulins of the IgE class are involved in allergic disorders and some parasitic infections, evidenced by elevation of IgE levels. IgE-producing cells are located in the respiratory an intestinal mucosa. Two or more IgE molecules bind together to an allergen and trigger mast cells or basophils to release chemical mediators, such as histamine, serotonin, kinins, slow-reacting substance of anaphylaxis (SRS-A), and the neutrophil factor,which produces allergic skin reactions, asthma, and hay fever.

Antibodies combine with antigens in a special way, likened to keys fitting into a lock. Antigens (the keys) only fit certain anti-bodies (the locks). Hence, the term “specificity” refers to the spe-cific reaction of an antibody to an antigen. There are many variations and complexities in these patterns. The strength with which one antigen-binding surface of an antibody binds to one epitope, an immunologically active site on an antigen, is knownas the affinity of the interaction (Abbas & Lichtman, 2001).

Antibody molecules are bivalent; that is, they have two com-bining sites. Therefore, the antibody easily becomes a cross-link between two antigen groups, causing them to clump together (ag-glutination). By this action, foreign invaders are cleared from the bloodstream. Agglutination is the means for determining blood group in laboratory tests.

Role of B Cells

The B cell, or B lymphocyte, is programmed to produce one spe-cific antibody. On encountering a specific antigen, a B cell stim-ulates production of plasma cells, the site of antibody production. The result is the outpouring of antibodies for the purpose of de-stroying and removing the antigen.

Role of T Cells

The T cell, or T lymphocyte, assists the B cells in producing an-tibodies. T cells secrete substances known as lymphokines that encourage cell growth, promote cell activation, direct the flow of cell activity, destroy target cells, and stimulate the macrophages. Macrophages present the antigen to the T cells and initiate the immune response. They also digest antigens and assist in remov-ing cells and other debris. The antigen-binding site of a T cell has a structure much like that of an immunoglobulin. It recognizes epitopes through complementary interactions. Unlike a specific antibody, a T cell does not bind free antigens (Parslow, Stites, Terr & Imboden, 2001).

FUNCTION OF ANTIGENS

Antigens are divided into two groups: complete protein antigens and low-molecular-weight substances. Complete protein antigens, such as animal dander, pollen, and horse serum, stimulate a com-plete humoral response. Low-molecular-weight substances, such as medica-tions, function as haptens (incomplete antigens), binding to tis-sue or serum proteins to produce a carrier complex that initiates an antibody response. The term “hapten” is derived from the Greek word haptien (to fasten). The proteins or other immuno-gens that haptens are fastened to are known as carriers (Parslow et al., 2001).

In an allergic reaction, the production of antigen-specific IgE antibodies requires active communication between macrophages, T cells, and B cells. When the allergen is absorbed through the respiratory tract, gastrointestinal tract, or skin, allergen sensitiza-tion occurs. The macrophage processes the antigen and presents it to the appropriate T cell. B cells that are influenced by the cell mature into an allergen-specific IgE immunoglobulin-secreting plasma cell that synthesizes and secretes antigen-specific IgE antibody.

FUNCTION OF CHEMICAL MEDIATORS

Mast cells, which have a major role in IgE-mediated immediate hypersensitivity, are located in the skin and mucous mem-branes. When mast cells are stimulated by antigens, powerful chemical mediators are released that cause a sequence of physi-ologic events resulting in symptoms of immediate hypersensi-tivity (Fig. 53-1). There are two types of chemical mediators: primary, which are preformed and found in mast cells or ba-sophils, and secondary, which are inactive precursors formed or released in response to primary mediators. The most prevalent known primary and secondary mediators are described next. Table 53-1 summarizes the actions of primary and secondary chemical mediators.

Primary Mediators

IgE-mediated inflammation occurs when an antigen binds to the IgE antibodies that occupy certain receptors on mast cells. Within minutes, this binding causes the mast cell to degranulate, releasing certain preformed mediators. A two-phase response results. There is an initial immediate effect on blood vessels, smooth muscle, and glandular secretion. This is followed a few hours later by cellular infiltration of the involved site. This type of inflammatory response is commonly known as an immediate hypersensitivity response (Parslow et al., 2001).

HISTAMINE

Histamine plays an important role in the immune response. His-tamine is released from mast cell granules where it is stored. Max-imal intensity is reached within about 15 minutes after antigen contact (Parslow et al., 2001). The effects of histamine release in-clude erythema; localized edema in the form of wheals; pruritus; contraction of bronchial smooth muscle, resulting in wheezing and bronchospasm; dilation of small venules and constriction of larger vessels; and increased secretion of gastric and mucosal cells, resulting in diarrhea. Histamine action results from stimulation of histamine-1 (H₁) and histamine-2 (H₂) receptors found on dif-ferent types of lymphocytes, particularly T-lymphocyte suppres-sor cells and basophils. H₁ receptors are found predominantly on bronchiolar and vascular smooth muscle cells. H₂ receptors are found on gastric parietal cells.

Certain medications are categorized by their action at these re-ceptors. Diphenhydramine (Benadryl) is an example of an anti-histamine, which is a medication displaying an affinity for H₁receptors; cimetidine (Tagamet) and ranitidine (Zantac) are ex-amples of other pharmacologic agents that target H₂ receptors to inhibit gastric secretions in peptic ulcer disease.

EOSINOPHIL CHEMOTACTIC FACTOR OF ANAPHYLAXIS

Preformed in the mast cells, this chemotactic factor, which affects movement of eosinophils (granular leukocytes) to the site of al-lergens, is released upon degranulation to inhibit the action of leukotrienes and histamine.

PLATELET-ACTIVATING FACTOR

Platelet-activating factor (PAF) is responsible for initiating platelet aggregation at sites of immediate hypersensitivity reac-tions. It also causes bronchoconstriction and increased vascular permeability. PAF also activates factor XII, or Hageman factor, which induces the formation of bradykinin.

PROSTAGLANDINS

Prostaglandins, composed of unsaturated fatty acids, producesmooth muscle contraction as well as vasodilation and increased capillary permeability. The fever and pain that occur with in-flammation are due in part to the prostaglandins.

Secondary Mediators

LEUKOTRIENES

Leukotrienes are chemical mediators that initiate the inflamma-tory response. They are metabolites released by mucosal mast cells. They collectively make up what was once termed “slow-reacting substance of anaphylaxis” (SRS-A). Leukotrienes cause smooth muscle contraction, bronchial constriction, mucus secretion in the airways, and the typical wheal and flare reaction of the skin (Parslow et al., 2001). Compared with histamine, leukotrienes are 100 to 1,000 times more potent in causing bronchospasm. Many manifestations of inflammation can be attributed in part to leukotrienes. Medications categorized as leukotriene antagonists or modifiers (zileuton [Zyflo], zafirlukast [Accolate], montelukast [Singulair]) block the synthesis or action of leukotrienes and pre-vent the signs and symptoms associated with asthma.

BRADYKININ

Bradykinin is a polypeptide with the ability to cause increasedvascular permeability, vasodilation, hypotension, and contraction of many types of smooth muscle, such as the bronchi (Parslow et al., 2001). Increased permeability of the capillaries results in edema. Bradykinin stimulates nerve cell fibers and produces pain.

SEROTONIN

Serotonin is released during platelet aggregation, acting as a po-tent vasoconstrictor and causing contraction of bronchial smooth muscle.

HYPERSENSITIVITY

Although the immune system defends the host against infections and foreign antigens, immune responses can themselves cause tis-sue injury and disease. An immune response to an antigen may result in sensitivity to challenge with that antigen; hypersensi-tivity is a reflection of excessive or aberrant immune responses(Abbas & Lichtman, 2001).

A hypersensitivity reaction is an abnormal, heightened reaction to any type of stimuli. It usually does not occur with the first ex-posure to an allergen. Rather, the reaction follows a re-exposure after sensitization in a predisposed individual. Sensitization initi-ates the humoral response or buildup of antibodies. To promote understanding of the immunopathogenesis of disease, hypersen-sitivity reactions have been classified into four specific types of reactions (Fig. 53-2). Most allergies are identified as either type I or type IV hypersensitivity reactions.

Anaphylactic (Type I) Hypersensitivity

The most severe form of a hypersensitivity reaction is anaphy-laxis. This systemic reaction is characterized by edema in manytissues, including the larynx, and is often accompanied by hy-potension (Abbas & Lichtman, 2001). Type I or anaphylactic hy-persensitivity is an immediate reaction beginning within minutes of exposure to an antigen. This reaction is mediated by IgE anti-bodies rather than IgG or IgM antibodies. Type I hypersensitiv-ity requires previous exposure to the specific antigen. In turn, the plasma cells produce IgE antibodies in the lymph nodes, where helper T cells aid in promoting this reaction. The IgE antibodies bind to membrane receptors on mast cells found in connective tissue and basophils. 

During re-exposure, the antigen binds to ad-jacent IgE antibodies, activating a cellular reaction that triggers degranulation and the release of chemical mediators (histamine, leukotrienes, and eosinophil chemotactic factor of anaphylaxis [ECF-A]).

Primary chemical mediators are responsible for the symptoms of type I hypersensitivity because of their effects on the skin, lungs, and gastrointestinal tract. When chemical mediators con-tinue to be released, a delayed reaction may occur lasting for up to 24 hours. Clinical symptoms are determined by the amount of the allergen, the amount of mediator released, the sensitivity of the target organ, and the route of allergen entry. Type I hyper-sensitivity reactions may include both local and systemic anaphylaxis.

Cytotoxic (Type II) Hypersensitivity

Type II, or cytotoxic, hypersensitivity occurs when the system mistakenly identifies a normal constituent of the body as foreign. This reaction may be a result of a cross-reacting antibody, possi-bly leading to cell and tissue damage. Type II hypersensitivity involves the binding of either IgG or IgM antibody to the cell-bound antigen. The result of antigen–antibody binding is activa-tion of the complement cascade and destruction of the cell to which the antigen is bound.

A type II hypersensitivity reaction is associated with several disorders. For example, in myasthenia gravis, the body mistak-enly generates antibodies against normal nerve ending receptors. In Goodpasture syndrome, antibodies against lung and renal tis-sue are generated, producing lung damage and renal failure.

A type II hypersensitivity reaction resulting in red blood cell de-struction is associated with drug-induced immune hemolytic ane-mia, Rh-hemolytic disease of the newborn, and incompatibility reactions in blood transfusions.

Immune Complex (Type III) Hypersensitivity

Type III, or immune complex, hypersensitivity involves immune complexes formed when antigens bind to antibodies. These com-plexes are then cleared from the circulation by phagocytic action. When these type III complexes are deposited in tissues or vascu-lar endothelium, two factors contribute to injury: the increased amount of circulating complexes and the presence of vasoactive amines. As a result, there is an increase in vascular permeability and tissue injury. The joints and kidneys are particularly suscep-tible to this type of injury. Type III hypersensitivity is associated with systemic lupus erythematosus, rheumatoid arthritis, certain types of nephritis, and some types of bacterial endocarditis. These are discussed elsewhere in this text.

Delayed-Type (Type IV) Hypersensitivity

Type IV, or delayed-type hypersensitivity, also known as cellular hypersensitivity, occurs 24 to 72 hours after exposure to an aller-gen. It is mediated by sensitized T cells and macrophages. An ex-ample of this reaction is the effect of an intradermal injection of tuberculin antigen or purified protein derivative (PPD). Sensitized T cells react with the antigen at or near the injection site. Lym-phokines are released and attract, activate, and retain macrophages at the site. These macrophages then release lysozymes, causing tis-sue damage. Edema and fibrin are responsible for the positive tu-berculin reaction.

An example of a type IV hypersensitivity reaction is contact dermatitis resulting from exposure to allergens such as cosmetics, adhesive tape, topical medications, medication additives, and plant toxins. The primary exposure results in sensitization. Re-exposure causes a hypersensitivity reaction composed of low-molecular-weight molecules (haptens) that bind with proteins or carriers and are then processed by Langerhans cells in the skin. The symptoms that occur include itching, erythema, and raised lesions.