IMMUNOLOHY

LESSON 27: HYPERSENSITIVITY REACTIONS

Learning Objectives
In this lesson you will learn

Type I Hypersensitivity Type II Hypersensitivity Type III Hypersensitivity Type IV Hypersensitivity

Tissue Injury Initiated by Immune Responses Well even immune system has two faces. One of the Hero as it helps the body against foreign invasions and protects it and the second image of a villain as sometimes in doing so it harms our own cells and tissues The immune response to an antigen is potentially a two-edged sword which may either protect or harm the host. Of course, the paramount biological effects of the immune response are the humoral and cellular recognition and elimination of infectious agents and other foreign antigens. Nevertheless, reexposure of some previously sensitized individuals to the same antigen may bring about an exaggerated (hypersensitive) or misdirected immune response that results in local tissue injury or in systemic manifestations, including shock or death. Immune responses that result in tissue injury or other pathophysiological changes are called hypersensitivity (allergic/ immunopathological) reactions.
The ensuing tissue injury may be caused by:

resulting in an immediate local or systemic reaction (anaphylaxis). IgE antibodies are cytophilic and bind to circulating and tissue mast cells and basophils that constitutively express highaffinity surface receptors for the Fc component of IgE. Binding and cross-linking of the allergen to surface-receptor bound IgE triggers the immediate release from cytoplasmic granules of mast cells and basophils of preformed (primary) vasoactive mediators of immediate hypersensitivity and also initiates de novo synthesis and release of other (secondary) mediators of hypersensitivity. Immediate-type hypersensitivity reactions may occur locally or systemically and may cause mild symptoms or lead to sudden death from anaphylactic shock. Common clinical examples of immediate hypersensitivity include allergic rhinitis, allergic asthma, atopic (familial predisposed) dermatitis, and systemic anaphylaxis. Food allergies, including allergy to peanuts and tree nuts, are said to account for the majority of fatal or near fatal anaphylactic reactions in the U.S. Also, it is estimated that about 2% of all recipients of penicillin in this country become sensitized to penicillin and that more than 100 deaths each year are attributable to penicillin anaphylaxis. Disorders included with type I hypersensitivity reactions are the atopic diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and allergic [extrinsic] asthma and some cases of urticaria and GI food reactions and systemic anaphylaxis. The incidence of asthma has increased markedly, although the causes are largely unknown. Recently, a marked increase in type I reactions has been noted in relation to exposure to watersoluble proteins in latex products (eg, rubber gloves, dental dams, condoms, tubing for respiratory equipment, catheters, and enema tips with inflatable latex cuffs), particularly among medical personnel and patients exposed to latex and children with spina bifida and urogenital birth defects. Common reactions to latex are urticaria, angioedema, conjunctivitis, rhinitis, bronchospasm, and anaphylaxis. As a rule, patients with atopic diseases (including atopic dermatitis) have an inherited predisposition for developing IgE antibody-mediated hypersensitivity to inhaled and ingested substances (allergens) that are harmless to people who are not atopic. Except in atopic dermatitis, IgE antibodies usually mediate hypersensitivity. Although IgE-mediated food allergy may contribute to symptoms of atopic dermatitis in infants and young children, it is largely independent of allergic factors in older children and adults, even though most patients continue to have specific allergies.

1. Release of vasoactive substances (PRIMARY AND SECONDARY MEDIATORS) 2. Phagocytosis or lysis of cells 3. Activation of the inflammatory and cytolytic components of the complement system 4. Release from recruited inflammatory cells of proteolytic enzymes, cytokines, and other mediators of tissue injury and inflammation. Gell and Coombs described four types of hypersensitivity reactions as follows

Type I (Anaphylaxis) Type II (Antibody dependent/ Cytotoxic) Type III (Immune-complex initiated)

Type IV (Cell mediated/Delayed). An immune-mediated disease may be the expression of only one or several types of hypersensitivity reactions.

Type I Hypersensitivity (Anaphylaxis) Type I or immediate-type hypersensitivity is an allergic reaction induced by specific antigen (called allergen), provoked by reexposure to the same antigen (by contact, inhalation, ingestion, injection), mediated by specific IgE antibodies, and produced by the cellular release of histamine and other vasoactive mediators,

Type II Hypersensitivity (Antibody-Dependent) In type II hypersensitivity, the antibodies (Ab) produced during the immune response recognize and bind to antigens (Ag) which are structural components of cell surfaces or other tissue components. The Ag can be intrinsic (innately part of the host

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tissues) or extrinsic (absorbed onto host tissue surfaces during exposure). IgG and IgM antibodies bound to these antigens form in situ complexes that activate the CLASSICAL PATHWAY of complement and generate mediators of acute inflammation at the site. The result is opsonization of the surface or creation of a membrane defect (MAC formation and deposition) leading to cell lysis and death. Transfusion reactions, reactions to certain drugs and autoimmune hemolytic anemia are examples of Ab mediated complement dependent reactions. In some cases formation of the immune complexes does not lead to activation of the complement system. In such circumstances binding of the antibodies to cell surfaces still leads to cell injury : Ab dependent cell mediated cytotoxicity (ADCC). In yet another form of physiologic deregulation, the antibodies produced bind to cell surface receptors. Binding of the antibodies to them can prevent or mimick occupancy of the physiologic ligand. In myastenia gravis anti acetyl-choline receptor antibodies block neuromuscular transmission resulting in muscle weakness. Examples of cell injury in which antibody reacts with antigenic components of a cell are Coombs-positive hemolytic anemias, antibody-induced thrombocytopenic purpura, leukopenia, pemphigus, pemphigoid, Goodpastures syndrome, and pernicious anemia. These reactions occur in patients receiving incompatible transfusions, in hemolytic disease of the newborn, and in neonatal thrombocytopenia, and they also may play a part in multisystem hypersensitivity diseases (eg, SLE). The mechanism of injury is best exemplified by the effect on RBCs. In hemolytic anemias, the RBCs are destroyed either by intravascular hemolysis or by macrophage phagocytosis, predominantly within the spleen. In vitro studies have shown that in the presence of complement some complement-binding antibodies (eg, the blood group antibodies anti-A and anti-B) cause rapid hemolysis; others (eg, anti-LE antibodies) cause a slow cell lysis; still others do not damage cells directly but cause their adherence to and destruction by phagocytes. In contrast, Rh antibodies on RBCs do not activate complement, and they destroy cells predominantly by extravascular phagocytosis. Examples in which the antigen is a component of tissue are early acute (hyperacute) graft rejection of a transplanted kidney, which is due to the presence of antibody to vascular endothelium, and Goodpastures syndrome, which is due to reaction of antibody with glomerular and alveolar basement membrane endothelium. In experimental Goodpastures syndrome, complement is an important mediator of injury, but the role of complement has not been clearly determined in early acute graft rejection. Examples of reactions due to haptenic coupling with cells or tissue include many of the drug hypersensitivity reactions (eg, penicillin-induced hemolytic anemia). Antireceptor hypersensitivity reactions alter cellular function as a result of the binding of antibody to membrane receptors. In many diseases (eg, myasthenia gravis, Graves disease, insulinresistant diabetes), antibodies to cell membrane receptors have been reported. In animal models of myasthenia gravis, the

production of antibodies by immunization to the acetylcholine receptor has resulted in the typical muscle fatigue and weakness noted in humans. In humans, this antibody also is demonstrable in serum and on muscle membranes. In addition, when serum or the IgG fraction from patients with myasthenia gravis is transfused into nonhuman primates, a self-limiting myasthenic syndrome is produced. This antibody prevents the binding of endogenously produced acetylcholine to its receptor, thereby preventing muscle activation. In some diabetic patients with extreme insulin resistance, antibodies to insulin receptors have been shown, thus preventing the binding of insulin to its receptor. In patients with Graves disease, an antibody to the thyroid-stimulating hormone (TSH) receptor has been identified that simulates the effect of TSH on its receptor, resulting in hyperthyroidism. Antibody-mediated cytotoxicity reactions occur when an antibody-coated cell is injured by killer cells. Techniques are available for determining B- and T-cell subsets of circulating lymphocytes. Another subset does not have B- or T-cell markers; these are called null cells and include killer and natural killer cells. The killer cells bind to cells coated with IgG by their Fc receptors and can destroy the target cell. Natural killer cells do not require antibody coating of the cell for recognition and can lyse tumor cells, virus-infected cells, and fetal cells. These mechanisms have been shown in animal models and in in vitro studies of hypersensitivity, but their role in human disease is not established.

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Type III Hypersensitivity (Immune Complex Initiated) In type III hypersensitivity, soluble immune complexes form in the circulation and deposit in various tissues where they may trigger the classical pathway of complement activation. Mediators of acute inflammation are generated at sites of immune complex deposition. Conditions in which immune complexes (ICs) appear to play some role are serum sickness due to serum, drugs, or viral hepatitis antigen; SLE; RA; polyarteritis; cryoglobulinemia; hypersensitivity pneumonitis; bronchopulmonary aspergillosis; acute glomerulonephritis; chronic membranoproliferative glomerulonephritis; and associated renal disease. In bronchopulmonary aspergillosis, drug- or serum-induced serum sickness, and some forms of renal disease, an IgE-mediated reaction is thought to precede the type III reaction. The standard animal models of type III reactions are the local Arthus reaction and experimental serum sickness. In the Arthus reaction (typically a local skin reaction), animals are first hyperimmunized to induce large amounts of circulating IgG antibodies and then are given a small amount of antigen intradermally. The antigen precipitates with the excess IgG and activates complement, so that a highly inflammatory, edematous, painful local lesion rapidly appears (by 4 to 6 h) and may progress to a sterile abscess containing many polymorphonuclear cells, and then to tissue necrosis. A necrotizing vasculitis with occluded arteriolar lumina can be seen microscopically. No lag time precedes the reaction because antibody is present already.

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In experimental serum sickness, a large amount of antigen is injected into a nonimmunized animal. After a lag time, antibody is produced; when the antibody reaches a critical level (10 to 14 days in humans), antigen-antibody complexes form and are deposited in endothelial vessels, where they produce widespread vascular injury characterized by the presence of polymorphonuclear leukocytes. When vasculitis occurs, a fall in serum complement can be detected, and antigen, antibody, and complement can be found in the areas of vasculitis. The antigen-antibody complexes, however, cannot induce injury by themselves, but rather require the presence of increased vascular permeability, such as occurs in IgE-mediated (type I) reactions and when complement is activated to enhance vascular deposition of the IC.

release interleukin-1, which promotes the proliferation of helper T cells. Helper T cells release interferon-gamma and interleukin2, which together regulate delayed hypersensitivity reactions centered around macrophage activation and T-cell mediated immunity. Activated cytotoxic T cells destroy target cells, such as allografts, on contact. Natural killer cells can kill target cells directly, in the absence of prior immunization and without MHC restriction, and by antibody-dependent cellular cytotoxicity (ADCC). Activated macrophages express increased phagocytic, bacteriocidal, and cytocidal activity and, when confronted with certain intracellular pathogens, undergo granulomatous transformation into epithelioid and multinucleated giant cells. Some clinical conditions in which type IV reactions are believed to be important are contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, some forms of drug sensitivity, thyroiditis, and encephalomyelitis after rabies vaccination. Evidence for the last two is based on experimental models, and in human disease on the appearance of lymphocytes in the inflammatory exudate of the thyroid and brain.

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Type IV Hypersensitivity (Cell-Mediated) In type IV hypersensitivity, CD8 cytotoxic T cells and CD4 helper T cells recognize either intracellular or extracellular synthesized antigen when it is complexed, respectively, with either class I or class II MHC molecules (see Normal Immune System). Macrophages function as antigen-presenting cells and

Table. 27.1 Immunological Mechanisms of Tissue Injury and Inflammation

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Recent proposal for classification of the hypersensitivity reactions Some authors believe that this classification system may be too general and are now in favor of a more recent classification system proposed by Sell. This system divides immunopathologic responses into the following 7 categories:

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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. In addition, the term immediate hypersensitivity is something 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.

Questions
1. Describe the mechanism for Type I (IgE-mediated) hypersensitivity and give several examples and state how they are treated symptomatically. 2. When a person has hay fever, common symptoms include runny eyes, runny nose, swollen sinuses, and difficulty in breathing. In terms of humoral immunity, discuss the mechanism behind these symptoms. Also state the reason for giving antihistamines and describe how allergy shots may lessen the severity of this type of hypersensitivity. 3. Researchers are hoping that the injection of monoclonal antibodies against IgE may someday be used to prevent virtually any Type I hypersensitivity. Explain. 4. Describe how immune system has two faces. 5. Differentiate between the types of hypersensitivity reactions with respect to the immune system component involved.

Notes

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