Type I: IgE-Mediated Hypersensitivity Reactions

Type I reactions are mediated by antigen-specific IgE and the products of tissue mast cells⁴ (Figure 9-1). Most common allergies (e.g., pollen allergies) are type I reactions. In addition, most type I reactions occur against environmental antigens and are therefore allergic. Because of this strong association, many healthcare professionals use the term allergy to indicate only IgE-mediated reactions. However, IgE can contribute to a few autoimmune and alloimmune diseases, and many common allergies (e.g., poison ivy) are not mediated by IgE.

In some individuals, exposure to an environmental antigen causes primarily IgE production. Repeated exposure to the antigen usually is required to elicit enough IgE so that the person becomes “sensitized.” IgE has a relatively short life span in the blood because it rapidly binds to very-high-affinity Fc receptors on the plasma membranes of mast cells (see Figure 9-1). The subclass IgG4 also has specific receptors on the mast cell and may contribute to the type I mechanism. Antibody that binds to mast cells is termed cytotropic antibody (able to bind to cell surfaces) or reagin (skin-sensitizing antibody). Unlike Fc receptors on phagocytes, which bind IgG that has reacted with antigen, the Fc receptors on mast cells bind with IgE that has not previously interacted with antigen.

If further exposure of a sensitized individual to the antigen occurs, one molecule of antigen may bind simultaneously to two molecules of IgE-Fc receptor complexes on the mast cell’s surface (cross-link) resulting in activation of intracellular signaling pathways and mast cell degranulation (see Figure 9-1, B, and Chapter 7). The antigen that triggers cross-linking must have at least two antigenic determinants on the same molecule. Sometimes an IgE-mediated response is beneficial to the host, as is the case of some immune reactions against parasites. (This mechanism is described in Chapter 8 and illustrated in Figure 8-26.)

The products of mast cell degranulation can modulate almost all aspects of an acute inflammatory response. (The effects of biochemical mediators released by mast cells are illustrated in Figure 7-11). The most potent mediator is histamine, which affects several key target cells. Acting through the H1 receptors, histamine contracts bronchial smooth muscles, causing bronchial constriction; increases vascular permeability, causing edema; and causes vasodilation, increasing blood flow into the affected area (see Figures 7-3 and 7-12). The interaction of histamine with H2 receptors results in increased gastric acid secretion and a decrease of histamine released from mast cells and basophils. The action of histamine through H2 receptors suggests an important negative-feedback mechanism that stops degranulation. That is, the released histamine inhibits release of additional histamine by interacting with H2 receptors on the mast cells. Histamine also may affect control of the immune response through H2 receptors on most cells of the immune system. Another important activity of histamine is enhancement of the chemotactic activity of other factors, such as eosinophil chemotactic factor of anaphylaxis (ECF-A), which attracts eosinophils into sites of allergic inflammatory reactions and prevents them from migrating out of the inflammatory site. (The role of the eosinophil in inflammation is discussed in Chapter 7.)

Type II: Tissue-Specific Hypersensitivity Reactions

Type II hypersensitivity reactions are generally characterized by a specific cell or tissue being the target of an immune response. In addition to major histocompatibility locus antigens (HLAs; discussed in Chapter 8), most cells have other antigens on their surfaces. Some of these other antigens are called tissue-specific antigens because they are expressed on the plasma membranes of only certain cells in specific tissues. Platelets, for example, have groups of antigens that are found on no other cells of the body. The symptoms of many type II diseases are determined by which tissue or organ expresses the particular antigen. Environmental antigens (e.g., drugs or their metabolites) may bind to the plasma membranes of specific cells (especially erythrocytes and platelets) and function as targets of type II reactions.

The five general mechanisms by which type II hypersensitivity reactions can affect cells are shown in Figure 9-2. All of these mechanisms begin with antibody binding to tissue-specific antigens or antigens that have attached to particular tissues. First, the cell can be destroyed by antibody (IgG or IgM) and activation of the complement cascade through the classical pathway. Formation of the membrane attack complex (C5-9) damages the membrane and may result in lysis of the cell (see Figure 9-2, A). For example, erythrocytes are destroyed by complement-mediated lysis in individuals with autoimmune hemolytic anemia (see Chapter 28) or as a result of an alloimmune reaction to ABO-mismatched transfused blood cells.

Second, antibody may cause cell destruction through phagocytosis by macrophages. IgG and also C3b of the complement system are opsonins that bind to receptors on the macrophage (see Figure 9-2, B). Phagocytosis of the target cell follows. (Phagocytosis is illustrated in Figures 7-15 and 7-16.) For example, antibodies against platelet-specific antigens or against red blood cell antigens of the Rh system coat those cells at low density, resulting in their preferential removal by phagocytosis in the spleen, rather than by complement-mediated lysis.

Third, antibody and complement may attract neutrophils. Either antigen expressed normally on the vessel walls or soluble antigen in the circulation (e.g., released from cells within the body or from infectious agents or by way of drugs or medications) that has been deposited on the surface of endothelial cells may bind antibody (see Figure 9-2, C). The antibody initiates the complement cascade, resulting in the release of C3a and C5a, which are chemotactic for neutrophils, and deposition of complement component C3b. Neutrophils bind to the tissues through receptors for the Fc portion of antibody (Fc receptor) or for C3b and attempt to phagocytose the tissue. Because the tissue is large, phagocytosis cannot be completed; even so, neutrophils release their granules onto the healthy tissue. The components of neutrophil granules, as well as the several toxic oxygen products produced by these cells, will damage the tissue.

The fourth mechanism is antibody-dependent cell-mediated cytotoxicity (ADCC) (see Figure 9-2, D). This mechanism involves a subpopulation of cytotoxic cells that are not antigen specific (natural killer [NK] cells). Antibody on the target cell is recognized by Fc receptors on the NK cells, which release toxic substances that destroy the target cell.

The fifth mechanism does not destroy the target cell, but rather causes it to malfunction. In this mechanism of type II injury, the antibody is usually directed against antigenic determinants associated with specific cell surface receptors, and the symptoms of the disease are a result of a direct effect of antibody binding alone (see Figure 9-2, E). The antibody reacts with the receptors on the target cell surface and modulates the function of the receptor by preventing interactions with their normal ligands, replacing the ligand and inappropriately stimulating the receptor, or destroying the receptor. For example, in the hyperthyroidism (excessive thyroid activity) of Graves disease, autoantibody binds to and activates receptors for thyroid-stimulating hormone (TSH) (a pituitary hormone that controls the production of the hormone thyroxine by the thyroid). In this way the antibody stimulates the thyroid cells to produce thyroxine.⁵ Under normal conditions, the increasing levels of thyroxine in the blood would signal the pituitary to decrease TSH production, which would result in less stimulation of the TSH receptor in the thyroid and a concomitant decrease in thyroxine production. Because the level of anti-TSH receptor antibody is not controlled by the pituitary, increasing amounts of thyroxine in the blood have no effect on antibody levels, and thyroxine production continues to increase despite decreasing amounts of TSH (see Chapter 22).

Type III: Immune Complex–Mediated Hypersensitivity Reactions

Mechanisms of Type III Hypersensitivity

Most type III hypersensitivity diseases are caused by antigen-antibody (immune) complexes that are formed in the circulation and deposited later in vessel walls or extravascular tissues (Figure 9-3). The primary difference between type II and type III mechanisms is that in type II hypersensitivity antibody binds to the antigen on the cell surface, whereas in type III the antibody binds to soluble antigen that was released into the blood or body fluids, and the complex is then deposited in the tissues. Type III reactions are not organ specific, and symptoms have little to do with the particular antigenic target of the antibody. The harmful effects of immune complex deposition are caused by complement activation, particularly through the generation of chemotactic factors for neutrophils. The neutrophils bind to antibody and C3b contained in the complexes and attempt to ingest the immune complexes.

They are often unsuccessful because the complexes are bound to large areas of tissue. During the attempted phagocytosis, large quantities of lysosomal enzymes are released into the inflammatory site instead of into phagolysosomes. The attraction of neutrophils and the subsequent release of lysosomal enzymes cause most of the resulting tissue damage.

Immune complexes can be of various sizes, depending on the relative amounts of antigen and antibody. Fairly large immune complexes are cleared rapidly from the circulation by tissue macrophages, whereas very small complexes eventually are filtered from blood through the kidneys, without any pathologic consequences. Intermediate-sized immune complexes (formed at a ratio of antigen to antibody that has a slight excess of antigen) are likely to be deposited in certain target tissues, where they have severe pathologic consequences, such as inflammation in the kidneys (glomerulonephritis), the vessels (vasculitis), or the joints (arthritis or degenerative joint disease).

Type IV: Cell-Mediated Hypersensitivity Reactions

Whereas types I, II, and III hypersensitivity reactions are mediated by antibody, type IV reactions are mediated by T lymphocytes and do not involve antibody (Figure 9-4). Type IV mechanisms occur through either cytotoxic T lymphocytes (Tc cells) or lymphokine-producing Th1 and Th17 cells. Tc cells attack and destroy cellular targets directly. Th1 and Th17 cells produce cytokines that recruit and activate phagocytic cells, especially macrophages. Destruction of the tissue is usually caused by direct killing by toxins from Tc cells or by the release of soluble factors, such as lysosomal enzymes and toxic reactive oxygen species (ROS), from activated macrophages.

Clinical examples of type IV hypersensitivity reactions include graft rejection and allergic reactions resulting from contact with such substances as poison ivy and metals. A type IV component also may be present in many autoimmune diseases. For example, T cells against type II collagen (a protein present in joint tissues) contribute to the destruction of joints in rheumatoid arthritis; T cells against a thyroid cell surface antigen contribute to the destruction of the thyroid in autoimmune thyroiditis (Hashimoto disease); and T cells against an antigen on the surface of pancreatic beta cells (the cell that normally produces insulin) are responsible for beta-cell destruction in insulin-dependent (type 1) diabetes mellitus.⁸

A type IV hypersensitivity reaction in the skin was thoroughly described first by Ehrlich in 1891 and led to the development of a diagnostic skin test for tuberculosis.⁹ The reaction follows an intradermal injection of tuberculin antigen into a suitably sensitized individual and is called a delayed hypersensitivity skin test because of its slow onset—24 to 72 hours to reach maximum intensity. The reaction site is infiltrated with T lymphocytes and macrophages, resulting in a clear hard center (induration) and a reddish surrounding area (erythema).

Genetic Predisposition

Certain individuals are genetically predisposed to develop allergies, particularly type I allergies, and are called atopic.¹¹ In families in which one parent has an allergy, allergies develop in about 40% of the offspring. If both parents have allergies, the incidence in the offspring may be as high as 80%. (Principles of genetic inheritance are discussed in Chapter 4.)

Atopic individuals tend to produce higher quantities of IgE and to have more Fc receptors for IgE on their mast cells. The airways and the skin of atopic individuals are also more responsive to a wide variety of both specific and nonspecific stimuli than are the airways and skin of individuals who are not atopic. Multiple genes have been associated with the atopic state, including polymorphisms in a large variety of cytokines that regulate IgE synthesis (e.g., interleukin [IL]-4, IL-5, IL-12, IL-13) and cellular receptors.

Clinical Symptoms of Type I Allergies

The clinical manifestations of type I reactions are attributable mostly to the biologic effects of histamine. Tissues most commonly affected contain large numbers of mast cells and are sensitive to the effects of histamine released from them. These tissues are found in the gastrointestinal tract, the skin, and the respiratory tract (Figure 9-5 and Table 9-4). The particular symptoms frequently reflect the main portal of entry for the allergen. For instance, pollens and other airborne allergens usually cause respiratory symptoms.

Effects of allergens on the mucosa of the eyes, nose, and respiratory tract include conjunctivitis (inflammation of the membranes lining the eyelids), rhinitis (inflammation of the mucous membranes of the nose), and asthma (constriction of the bronchi).¹² Symptoms are caused by vasodilation, hypersecretion of mucus, edema, and swelling of the respiratory mucosa. Because the mucous membranes lining the respiratory tract (accessory sinuses, nasopharynx, and upper and lower respiratory tracts) are continuous, they are all adversely affected. The degree to which each is affected determines the symptoms of the disease.

Gastrointestinal allergies are caused primarily by allergens that enter through the mouth—usually foods or medicines. Symptoms include vomiting, diarrhea, or abdominal pain and may be severe enough to result in malabsorption or protein-losing enteropathy, if the reactions are prolonged or recurrent. Foods most often implicated in gastrointestinal allergies are milk, chocolate, citrus fruits, eggs, wheat, nuts, peanut butter, and fish.¹³ When food is the allergen, the active immunogen may be a product of food breakdown by digestive enzymes.

Urticaria, or hives, is a dermal (skin) manifestation of type I allergic reactions (see Figure 9-5). The underlying mechanism is the localized release of histamine and increased vascular permeability, resulting in limited areas of edema. Urticaria is characterized by white fluid-filled blisters (wheals) surrounded by areas of redness (flares). The wheal and flare reaction is usually accompanied by itching. Not all urticarial symptoms are caused by allergic (immunologic) reactions. Some, termed nonimmunologic urticaria, result from exposure to cold temperatures, emotional stress, medications, systemic diseases, hyperthyroidism, or malignancies (e.g., lymphomas).

If possible, avoidance of the allergen is the best method to limit allergic responses. Approximately 30% of laboratory animal handlers have allergies to animal dander and must use face masks or other devices to avoid contact.

Although some type I allergic responses can be controlled by blocking histamine receptors with antihistamines, the primary mechanism of control is the autonomic nervous system. The autonomic nervous system includes biochemical mediators (e.g., epinephrine, acetylcholine) that, like the mediators of the inflammatory response, have profound effects on cells. These mediators bind to appropriate receptors on mast cells and the target cells of inflammation (e.g., smooth muscle), thereby controlling (1) the release of inflammatory mediators from mast cells and (2) the degree to which target cells respond to inflammatory mediators (see Chapter 7).

Allergic Disease: Bee Sting Allergy

An example of a life-threatening allergy is an anaphylactic reaction to a bee sting. Bee venoms contain a mixture of enzymes and other proteins that may serve as allergens. About 1% of children may have an anaphylactic reaction to bee venom. Within minutes they may develop excessive swelling (edema) at the bee sting site, followed by generalized hives, itching, and swelling in areas distal from the sting (e.g., eyes, lips), and other systemic symptoms including flushing, sweating, dizziness, and headache. The most severe symptoms may include gastrointestinal (e.g., stomach cramps, vomiting), respiratory (e.g., tightness in the throat, wheezing, difficulties breathing), and vascular (e.g., low blood pressure, shock) reactions. Severe respiratory and vascular reactions may lead to death.

If a child has had a previous anaphylactic reaction to bee stings, the chance of having another is about 60%. During the reaction the administration of antihistamines has little effect because histamine has already bound H1 receptors and initiated severe bronchial smooth muscle contraction. Most individuals carry self-injectable epinephrine. Autonomic nervous system mediators, such as epinephrine, bind to specific receptors on smooth muscle and reverse the effects of histamine and result in muscle relaxation. Similar anaphylactic reactions have been described against peanuts and other nuts, shellfish, fish, milk, eggs, and some medications.

Tests of IgE-Mediated Allergy

Allergic reactions can be life threatening; therefore, it is essential that severely allergic individuals be made aware of the specific allergen against which they are sensitized and instructed to avoid contact with that material.¹⁴ Several tests are available, including food challenges, skin tests with allergens, and laboratory tests for measurements of total IgE and allergen-specific IgE in the blood.¹⁵

Reactivity to a particular food allergen may be tested by controlled administration of small doses of the suspected allergen in order to evoke a mild allergic response. This approach can be dangerous if the individual has a history of anaphylactic responses. A safer approach is injection of an allergen into (intradermal) or onto (epicutaneous or prick test) the skin. If the individual is allergic to a particular allergen, a local wheal and flare reaction may occur within a few minutes at the site of injection. The diameter of the flare reaction is usually indicative of the individual’s degree of sensitivity to that allergen. In the most severely allergic individuals, even the extremely small amounts of allergen used for the skin test may evoke a systemic anaphylaxis. Skin test is also contraindicated if the individual is using medications that may affect the test or has diffuse dermatitis, which would make the reaction difficult to interpret.

A variety of laboratory tests can detect IgE antibodies in serum. These assays have various commercial acronyms, depending on whether they are radioimmunoassays (RIAs; reactivity detected by measuring a radioactive reagent) or enzyme immunoassays (EIAs or ELISA [enzyme-linked immunosorbent assay]; reactivity detected by measuring a color change caused by an enzyme-labeled reagent). One set of assays measures circulating levels of total IgE, with atopic individuals usually having elevated levels. Other assays are capable of measuring circulating levels of specific IgE antibodies against selected allergens. The amount of IgE against a specific allergen correlates well with the degree of skin test reactivity and the severity of clinical symptoms related to the same allergen, although the laboratory text is less sensitive.

Type IV Allergic Hypersensitivities

The allergens that induce a type IV allergic reaction are mostly haptens that react with normal self-proteins in the skin. When presented in this fashion, these antigens are recognized by pattern recognition receptors (PRRs) on antigen-presenting cells in the skin and induce a cell-mediated response.¹⁸ (Pattern recognition receptors are discussed in Chapter 7.) The primary result is an allergic contact dermatitis that is confined to the area of contact with the allergen. The best-known example is poison ivy (Figure 9-6). The antigen in that instance is a plant catechol, urushiol, that reacts with normal skin proteins and evokes a cell-mediated immune response.

As noted, type I hypersensitivity reactions may result in a skin reaction (e.g., hives formed during an allergic reaction to a particular food). The distribution of the lesions may suggest whether the reaction is caused by immediate (type I) or delayed (type IV) hypersensitivity mechanisms.¹⁹ Immediate hypersensitivity reactions, termed atopic dermatitis, are usually characterized by widely distributed lesions, whereas contact dermatitis (delayed hypersensitivity) consists of lesions only at the site of contact with the allergen, such as a metal allergy to jewelry (see Figure 9-6).

Autoimmunity

Original Insult

Although many theories exist, the initial cause of most autoimmune diseases is unknown (see What’s New? Maternal Microchimerism and Autoimmune Disease).

WHAT’S NEW?

Maternal/Fetal Microchimerism and Autoimmune Disease

A rapidly growing body of evidence suggests that we are in a state of microchimerism (Mc); possessing a small number of cells originating from another individual.¹ The placenta, which was once considered a cellular “barrier,” is more porous than suspected and routinely allows bidirectional passage of both maternal and fetal cells. Passage results during normal pregnancy, as well as spontaneous miscarriages and elective terminations,² and includes a broad spectrum of cells, ranging from erythrocytes and mature white blood cells, to stem cells at various stages of differentiation. Most gravid women (having been pregnant) have detectable fetal cells (fetal Mc) in their blood and many organs (e.g., white blood cells, hepatocytes, kidney tubular epithelium, neurons and glia, cardiomyocytes, endothelial cells, thyrocytes, intestinal epithelium, and islet β cells), which apparently originated as fetal stem cells that differentiated in the maternal tissues. As early as 6 weeks gestation, maternal Mc is apparent in fetal blood and tissues (e.g., thymus, lung, heart, pancreas, liver, spleen, kidney, adrenal gland, ovary, testis, and brain).³ Maternal Mc originates predominately from maternal cells, but may also include cells from one’s grandmother, a non-identical twin, or older siblings, all of which were harbored in the mother’s blood and tissues. Both maternal and fetal Mc persists for decades after pregnancy.

The long-term implications of Mc may include both detrimental and beneficial effects. Fetal cells express both maternal and paternal HLA antigens and are recognized as partially foreign by maternal immune cells. Most studies of maternal Mc use assays for the presence of the Y chromosome in maternal blood or organs. Many autoimmune diseases are associated with increased numbers of male cells in the diseased organs (e.g., scleroderma, dermatomyositis, Sjögren syndrome, thyroiditis, primary biliary cirrhosis, hyper- and hypothyroidism, and systemic lupus erythematosus) suggesting that Mc may contribute to the etiology of these diseases.¹ Maternal Mc in the offspring also may affect their risk for autoimmune disease. Increased levels of maternal cells in the child’s blood have been reported in cases of juvenile inflammatory myopathy, neonatal lupus syndrome, type 1 diabetes, and biliary atresia. Maternal cells were found as myocytes in the myocardium of infants with fatal neonatal lupus-associated heart block and as insulin-producing cells in the pancreas of diabetics.¹ It cannot yet be determined whether the foreign cells are initiators of autoimmune damage or whether injury to the tissue results in increased proliferation. Thus these observations remain intriguing but of unknown significance.

Beneficial effects of Mc are also observed. Treg cells may control immunologic tolerance to maternal cells. A significantly greater success rate of liver transplantation was observed with maternal or sibling donors than paternal donors.⁴ Thus Mc may modulate the immune response and minimize rejection of organs from selected donors. Fetal Mc occurs in several regions of the brain, but at a significantly lower incidence and concentration in women with Alzheimer’s disease than those without neurologic disease.⁵ Whether Mc is protective or not remains unknown.

References

1. Nelson, J. L. Trends Immunol. 2012; 33(8):421–427.

2. Peterson, S. E., et al. Human Reprod. 2012; 27(9):2607–2612.

3. Boyon, C., et al. Eur J Obset Gynecol Reprod Biol. 2011; 158(2):148–152.

4. Nijagal, A., Fleck, S., Mackenzie, T. C. Chimerism. 2012; 3(2):37–39.

5. Chan, W. F.N., et al. Plos ONE. 2012:e45592, doi; 7(9): 10.1371/journal.pone.0045592.

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