Hypersensitivities

In Adaptive Specific Host Defenses, we discussed the mechanisms by which adaptive immune defenses, both humoral and cellular, protect us from infectious diseases. However, these same protective immune defenses can also be responsible for undesirable reactions called hypersensitivity reactions. Hypersensitivity reactions are classified by their immune mechanism.

• Type I hypersensitivity reactions involve immunoglobulin E (IgE) antibody against soluble antigen, triggering mast cell degranulation.
• Type II hypersensitivity reactions involve IgG and IgM antibodies directed against cellular antigens, leading to cell damage mediated by other immune system effectors.
• Type III hypersensitivity reactions involve the interactions of IgG, IgM, and, occasionally, IgA antibodies with antigen to form immune complexes (D.S. Strayer et al., eds., Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7th ed. (Philadelphia, PA: Lippincott, Williams & Wilkins, 2014)). Accumulation of immune complexes in tissue leads to tissue damage mediated by other immune system effectors.
• Type IV hypersensitivity reactions are T-cell–mediated reactions that can involve tissue damage mediated by activated macrophages and cytotoxic T cells.

Type I Hypersensitivities

When a presensitized individual is exposed to an allergen, it can lead to a rapid immune response that occurs almost immediately. Such a response is called an allergy and is classified as a type I hypersensitivity. Allergens may be seemingly harmless substances such as animal dander, molds, or pollen. Allergens may also be substances considered innately more hazardous, such as insect venom or therapeutic drugs. Food intolerances can also yield allergic reactions as individuals become sensitized to foods such as peanuts or shellfish (shown below). Regardless of the allergen, the first exposure activates a primary IgE antibody response that sensitizes an individual to type I hypersensitivity reaction upon subsequent exposure.

For susceptible individuals, a first exposure to an allergen activates a strong T_H2 cell response (illustrated below). Cytokines interleukin (IL)-4 and IL-13 from the T_H2 cells activate B cells specific to the same allergen, resulting in clonal proliferation, differentiation into plasma cells, and antibody-class switch from production of IgM to production of IgE. The fragment crystallizable (Fc) regions of the IgE antibodies bind to specific receptors on the surface of mast cells throughout the body. It is estimated that each mast cell can bind up to 500,000 IgE molecules, with each IgE molecule having two allergen-specific fragment antigen-binding (Fab) sites available for binding allergen on subsequent exposures. By the time this occurs, the allergen is often no longer present and there is no allergic reaction, but the mast cells are primed for a subsequent exposure and the individual is sensitized to the allergen.

On subsequent exposure, allergens bind to multiple IgE molecules on mast cells, cross-linking the IgE molecules. Within minutes, this cross-linking of IgE activates the mast cells and triggers degranulation, a reaction in which the contents of the granules in the mast cell are released into the extracellular environment. Preformed components that are released from granules include histamine, serotonin, and bradykinin (see the table below). The activated mast cells also release newly formed lipid mediators (leukotrienes and prostaglandins from membrane arachidonic acid metabolism) and cytokines such as tumor necrosis factor (see the table below).

Selected Preformed Components of Mast Cell Granules

Selected Newly Formed Chemical Mediators of Inflammation and Allergic Response

Extended description

1. On first exposure to an allergen, an antigen-presenting cell engulfs the antigen, processes it, and displays a fragment on a class II MHC molecule at its surface, where a TH2 cell’s receptor binds it. 2. The TH2 cell releases IL-4 and IL-13, which activate a B cell displaying the same antigen on its own MHC II and antibodies. 3. The activated B cell proliferates and differentiates into plasma cells that synthesize and secrete IgE antibody. 4. The secreted IgE binds to mast cells by its Fc region, sensitizing the mast cells. 5. On a later exposure to the allergen, the antigen binds the IgE on the sensitized mast cell, and the mast cell releases inflammatory molecules, producing allergy symptoms.

Type I hypersensitivity reactions can be either localized or systemic. Localized type I hypersensitivity reactions include hay fever rhinitis, hives, and asthma (see the table below). Systemic type I hypersensitivity reactions are referred to as anaphylaxis or anaphylactic shock. Although anaphylaxis shares many symptoms common with the localized type I hypersensitivity reactions, the swelling of the tongue and trachea, blockage of airways, dangerous drop in blood pressure, and development of shock can make anaphylaxis especially severe and life-threatening. In fact, death can occur within minutes of onset of signs and symptoms.

Late-phase reactions in type I hypersensitivities may develop 4–12 hours after the early phase and are mediated by eosinophils, neutrophils, and lymphocytes that have been recruited by chemotactic factors released from mast cells. Activation of these recruited cells leads to the release of more chemical mediators that cause tissue damage and late-phase symptoms of swelling and redness of the skin, coughing, wheezing, and nasal discharge.

Individuals who possess genes for maladaptive traits, such as intense type I hypersensitivity reactions to otherwise harmless components of the environment, would be expected to suffer reduced reproductive success. With this kind of evolutionary selective pressure, such traits would not be expected to persist in a population. This suggests that type I hypersensitivities may have an adaptive function. There is evidence that the IgE produced during type I hypersensitivity reactions is actually meant to counter helminth infections (C.M. Fitzsimmons et al., “Helminth Allergens, Parasite-Specific IgE, and Its Protective Role in Human Immunity,” Frontier in Immunology 5 (2015): 47). Helminths are one of few organisms that possess proteins that are targeted by IgE. In addition, there is evidence that helminth infections at a young age reduce the likelihood of type I hypersensitivities to innocuous substances later in life. Thus it may be that allergies are an unfortunate consequence of strong selection in the mammalian lineage or earlier for a defense against parasitic worms.

Type I Hypersensitivities

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Type II (Cytotoxic) Hypersensitivities

Immune reactions categorized as type II hypersensitivities, or cytotoxic hypersensitivities, are mediated by IgG and IgM antibodies binding to cell-surface antigens or matrix-associated antigens on basement membranes. These antibodies can either activate complement, resulting in an inflammatory response and lysis of the targeted cells, or they can be involved in antibody-dependent cell-mediated cytotoxicity (ADCC) with cytotoxic T cells.

In some cases, the antigen may be a self-antigen, in which case the reaction would also be described as an autoimmune disease. (Autoimmune diseases are described in Autoimmune Disorders.) In other cases, antibodies may bind to naturally occurring, but exogenous, cell-surface molecules such as antigens associated with blood typing found on red blood cells (RBCs). This leads to the coating of the RBCs by antibodies, activation of the complement cascade, and complement-mediated lysis of RBCs, as well as opsonization of RBCs for phagocytosis. Two examples of type II hypersensitivity reactions involving RBCs are hemolytic transfusion reaction (HTR) and hemolytic disease of the newborn (HDN). These type II hypersensitivity reactions, which will be discussed in greater detail, are summarized in the table below.

Immunohematology is the study of blood and blood-forming tissue in relation to the immune response. Antibody-initiated responses against blood cells are type II hypersensitivities, thus falling into the field of immunohematology. For students first learning about immunohematology, understanding the immunological mechanisms involved is made even more challenging by the complex nomenclature system used to identify different blood-group antigens, often called blood types. The first blood-group antigens either used alphabetical names or were named for the first person known to produce antibodies to the red blood cell antigen (e.g., Kell, Duffy, or Diego). However, in 1980, the International Society of Blood Transfusion (ISBT) Working Party on Terminology created a standard for blood-group terminology in an attempt to more consistently identify newly discovered blood group antigens. New antigens are now given a number and assigned to a blood-group system, collection, or series. However, even with this effort, blood-group nomenclature is still inconsistent.

Common Type II Hypersensitivities

ABO Blood Group Incompatibility

The recognition that individuals have different blood types was first described by Karl Landsteiner (1868–1943) in the early 1900s, based on his observation that serum from one person could cause a clumping of RBCs from another. These studies led Landsteiner to the identification of four distinct blood types. Subsequent research by other scientists determined that the four blood types were based on the presence or absence of surface carbohydrates “A” and “B,” and this provided the foundation for the ABO blood group system that is still in use today (shown below). The functions of these antigens are unknown, but some have been associated with normal biochemical functions of the cell. Furthermore, ABO blood types are inherited as alleles (one from each parent), and they display patterns of dominant and codominant inheritance. The alleles for A and B blood types are codominant to each other, and both are dominant over blood type O. Therefore, individuals with genotypes of AA or AO have type A blood and express the A carbohydrate antigen on the surface of their RBCs. People with genotypes of BB or BO have type B blood and express the B carbohydrate antigen on the surface of their RBCs. Those with a genotype of AB have type AB blood and express both A and B carbohydrate antigens on the surface of their RBCs. Finally, individuals with a genotype of OO have type O blood and lack A and B carbohydrate on the surface of their RBCs.

It is important to note that the RBCs of all four ABO blood types share a common protein receptor molecule, and it is the addition of specific carbohydrates to the protein receptors that determines A, B, and AB blood types. The genes that are inherited for the A, B, and AB blood types encode enzymes that add the carbohydrate component to the protein receptor. Individuals with O blood type still have the protein receptor but lack the enzymes that would add carbohydrates that would make their red blood cell type A, B, or AB.

IgM antibodies in plasma that cross-react with blood group antigens not present on an individual’s own RBCs are called isohemagglutinins (shown above). Isohemagglutinins are produced within the first few weeks after birth and persist throughout life. These antibodies are produced in response to exposure to environmental antigens from food and microorganisms. A person with type A blood has A antigens on the surface of their RBCs and will produce anti-B antibodies to environmental antigens that resemble the carbohydrate component of B antigens. A person with type B blood has B antigens on the surface of their RBCs and will produce anti-A antibodies to environmental antigens that are similar to the carbohydrate component of A antigens. People with blood type O lack both A and B antigens on their RBCs and, therefore, produce both anti-A and anti-B antibodies. Conversely, people with AB blood type have both A and B antigens on their RBCs and, therefore, lack anti-A and anti-B antibodies.

Extended description

Type A blood: red blood cells carry the A antigen; the plasma carries anti-B isohemagglutinins. Type B blood: red blood cells carry the B antigen; the plasma carries anti-A isohemagglutinins. Type AB blood: red blood cells carry both A and B antigens; the plasma carries neither isohemagglutinin. Type O blood: red blood cells carry neither antigen; the plasma carries both anti-A and anti-B isohemagglutinins.

A patient may require a blood transfusion because they lack sufficient RBCs (anemia) or because they have experienced significant loss of blood volume through trauma or disease. Although the blood transfusion is given to help the patient, it is essential that the patient receive a transfusion with matching ABO blood type. A transfusion with an incompatible ABO blood type may lead to a strong, potentially lethal type II hypersensitivity cytotoxic response called hemolytic transfusion reaction (HTR) (shown below).

For instance, if a person with type B blood receives a transfusion of type A blood, their anti-A antibodies will bind to and agglutinate the transfused RBCs. In addition, activation of the classical complement cascade will lead to a strong inflammatory response, and the complement membrane attack complex (MAC) will mediate massive hemolysis of the transfused RBCs. The debris from damaged and destroyed RBCs can occlude blood vessels in the alveoli of the lungs and the glomeruli of the kidneys. Within 1 to 24 hours of an incompatible transfusion, the patient experiences fever, chills, pruritus (itching), urticaria (hives), dyspnea, hemoglobinuria (hemoglobin in the urine), and hypotension (low blood pressure). In the most serious reactions, dangerously low blood pressure can lead to shock, multi-organ failure, and death of the patient.

Hospitals, medical centers, and associated clinical laboratories typically use hemovigilance systems to minimize the risk of HTRs due to clerical error. Hemovigilance systems are procedures that track transfusion information from the donor source and blood products obtained to the follow-up of recipient patients. Hemovigilance systems used in many countries identify HTRs and their outcomes through mandatory reporting (e.g., to the Food and Drug Administration in the United States), and this information is valuable to help prevent such occurrences in the future. For example, if an HTR is found to be the result of laboratory or clerical error, additional blood products collected from the donor at that time can be located and labeled correctly to avoid additional HTRs. As a result of these measures, HTR-associated deaths in the United States occur in about one per 2 million transfused units (E.C. Vamvakas and M.A. Blajchman, “Transfusion-Related Mortality: The Ongoing Risks of Allogeneic Blood Transfusion and the Available Strategies for Their Prevention,” Blood 113, no. 15 (2009): 3406–3417).

Extended description

1. Donated type A blood carrying type A antigens enters the bloodstream of a type B recipient, whose plasma carries anti-A antibodies. 2. The recipient’s anti-A antibodies in plasma bind to the donated type A red blood cells. 3. The bound anti-A antibodies activate the complement cascade, releasing hemoglobin and destroying the donor red blood cells.

Rh Factors

Many different types of erythrocyte antigens have been discovered since the description of the ABO red cell antigens. The second most frequently described RBC antigens are Rh factors, named after the rhesus macaque (Macaca mulatta) factors identified by Karl Landsteiner and Alexander Weiner in 1940. The Rh system of RBC antigens is the most complex and immunogenic blood group system, with more than 50 specificities identified to date. Of all the Rh antigens, the one designated Rho (Weiner) or D (Fisher-Race) is the most immunogenic. Cells are classified as Rh positive (Rh+) if the Rho/D antigen is present or as Rh negative (Rh−) if the Rho/D antigen is absent. In contrast to the carbohydrate molecules that distinguish the ABO blood groups and are the targets of IgM isohemagglutinins in HTRs, the Rh factor antigens are proteins. As discussed in B Lymphocytes and Humoral Immunity, protein antigens activate B cells and antibody production through a T-cell–dependent mechanism, and the T_H2 cells stimulate class switching from IgM to other antibody classes. In the case of Rh factor antigens, T_H2 cells stimulate class switching to IgG, and this has important implications for the mechanism of HDN.

Like ABO incompatibilities, blood transfusions from a donor with the wrong Rh factor antigens can cause a type II hypersensitivity HTR. However, in contrast to the IgM isohemagglutinins produced early in life through exposure to environmental antigens, production of anti-Rh factor antibodies requires the exposure of an individual with Rh− blood to Rh+ positive RBCs and activation of a primary antibody response. Although this primary antibody response can cause an HTR in the transfusion patient, the hemolytic reaction would be delayed up to 2 weeks during the extended lag period of a primary antibody response (see B Lymphocytes and Humoral Immunity). However, if the patient receives a subsequent transfusion with Rh+ RBCs, a more rapid HTR would occur with anti-Rh factor antibody already present in the blood. Furthermore, the rapid secondary antibody response would provide even more anti-Rh factor antibodies for the HTR.

Rh factor incompatibility between a pregnant person and fetus can also cause a type II hypersensitivity hemolytic reaction, referred to as hemolytic disease of the newborn (HDN) (illustrated below). If an Rh− female carries an Rh+ baby to term, pregnant person’s immune system can be exposed to Rh+ fetal red blood cells. This exposure will usually occur during the last trimester of pregnancy and during the delivery process. If this exposure occurs, the Rh+ fetal RBCs will activate a primary adaptive immune response in the pregnant person, and anti-Rh factor IgG antibodies will be produced. IgG antibodies are the only class of antibody that can cross the placenta to impact the fetus; however, in most cases, the first Rh+ baby is unaffected by these antibodies because the first exposure typically occurs late enough in the pregnancy that the pregnant person does not have time to mount a sufficient primary antibody response before the baby is born.

If a subsequent pregnancy with an Rh+ fetus occurs, however, the female’s second exposure to the Rh factor antigens causes a strong secondary antibody response that produces larger quantities of anti-Rh factor IgG. These antibodies can cross the placenta to the fetus and cause HDN, a potentially lethal condition for the baby (shown below).

Prior to the development of techniques for diagnosis and prevention, Rh factor incompatibility was the most common cause of HDN, resulting in thousands of infant deaths each year worldwide (G. Reali, “Forty Years of Anti-D Immunoprophylaxis,” Blood Transfusion 5, no. 1 (2007): 3–6). For this reason, the Rh factors of prospective parents are regularly screened, and treatments have been developed to prevent HDN caused by Rh incompatibility. To prevent Rh factor-mediated HDN, human Rho(D) immune globulin (e.g., RhoGAM) is injected intravenously or intramuscularly into pregnant people during the 28th week of pregnancy and within 72 hours after delivery. Additional doses may be administered after events that may result in transplacental hemorrhage (e.g., umbilical blood sampling, chorionic villus sampling, abdominal trauma, amniocentesis). This treatment is initiated during the first pregnancy with an Rh+ fetus. The anti-Rh antibodies in Rho(D) immune globulin will bind to the Rh factor of any fetal RBCs that gain access to the pregnant person’s bloodstream, preventing these Rh+ cells from activating the primary antibody response. Without a primary anti-Rh factor antibody response, the next pregnancy with an Rh+ fetus will have minimal risk of HDN. However, the person will need to be retreated with Rho(D) immune globulin during that pregnancy to prevent a primary anti-Rh antibody response that could threaten subsequent pregnancies.

Extended description

(a) 1. Rh-positive fetal red blood cells cross the placenta into the Rh-negative pregnant person’s circulation during a first pregnancy with an Rh-positive fetus. 2. Anti-Rh antibodies are produced in the pregnant person upon exposure to the fetal Rh antigens. 3. During a second pregnancy with an Rh-positive fetus, the anti-Rh antibodies remain in the pregnant person’s circulation and cross the placenta. 4. The maternal anti-Rh antibodies attack and destroy the fetal Rh-positive red blood cells, and the fetus becomes hemolytic. (b) 1. The pregnant person is injected with Rho(D) immune globulin during the first pregnancy with an Rh-positive fetus. 2. Rh-positive fetal red blood cells enter the pregnant person’s bloodstream. 3. The injected anti-Rh antibodies bind and inactivate the fetal Rh antigens before they can stimulate an immune response in the pregnant person.

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Type III Hypersensitivities

Type III hypersensitivities are immune-complex reactions that were first characterized by Nicolas Maurice Arthus (1862–1945) in 1903. To produce antibodies for experimental procedures, Arthus immunized rabbits by injecting them with serum from horses. However, while immunizing rabbits repeatedly with horse serum, Arthus noticed a previously unreported and unexpected localized subcutaneous hemorrhage with edema at the site of injection. This reaction developed within 3 to 10 hours after injection. This localized reaction to non-self serum proteins was called an Arthus reaction. An Arthus reaction occurs when soluble antigens bind with IgG in a ratio that results in the accumulation of antigen-antibody aggregates called immune complexes.

A unique characteristic of type III hypersensitivity is antibody excess (primarily IgG), coupled with a relatively low concentration of antigen, resulting in the formation of small immune complexes that deposit on the surface of the epithelial cells lining the inner lumen of small blood vessels or on the surfaces of tissues (shown below). This immune complex accumulation leads to a cascade of inflammatory events that include the following:

1. IgG binding to antibody receptors on localized mast cells, resulting in mast-cell degranulation
2. Complement activation with production of pro-inflammatory C3a and C5a (see Chemical Defenses)
3. Increased blood-vessel permeability with chemotactic recruitment of neutrophils and macrophages

Because these immune complexes are not an optimal size and are deposited on cell surfaces, they cannot be phagocytosed in the usual way by neutrophils and macrophages, which, in turn, are often described as “frustrated.” Although phagocytosis does not occur, neutrophil degranulation results in the release of lysosomal enzymes that cause extracellular destruction of the immune complex, damaging localized cells in the process. Activation of coagulation pathways also occurs, resulting in thrombi (blood clots) that occlude blood vessels and cause ischemia that can lead to vascular necrosis and localized hemorrhage.

Systemic type III hypersensitivity (serum sickness) occurs when immune complexes deposit in various body sites, resulting in a more generalized systemic inflammatory response. These immune complexes involve non-self proteins such as antibodies produced in animals for artificial passive immunity (see Vaccines), certain drugs, or microbial antigens that are continuously released over time during chronic infections (e.g., subacute bacterial endocarditis, chronic viral hepatitis). The mechanisms of serum sickness are similar to those described in localized type III hypersensitivity but involve widespread activation of mast cells, complement, neutrophils, and macrophages, which causes tissue destruction in areas such as the kidneys, joints, and blood vessels. As a result of tissue destruction, symptoms of serum sickness include chills, fever, rash, vasculitis, and arthritis. Development of glomerulonephritis or hepatitis is also possible.

Autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis can also involve damaging type III hypersensitivity reactions when auto-antibodies form immune complexes with self antigens. These conditions are discussed in Autoimmune Disorders.

Extended description

(a) An immune complex made of IgG antibodies bound to antigen deposits in the blood vessel wall lining. Fc receptors, C5a, C3b, and C1 mark the deposit site, and neutrophils bind the IgG. The vessel wall lists the body sites this deposition can damage, from top to bottom: blood vessels, heart, joints, skin, and kidneys. (b) A patient sits connected by tubing to a dialysis machine, which treats the kidney damage a type III hypersensitivity reaction can cause.

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Type IV Hypersensitivities

Type IV hypersensitivities are not mediated by antibodies like the other three types of hypersensitivities. Rather, type IV hypersensitivities are regulated by T cells and involve the action of effector cells. These types of hypersensitivities can be organized into three subcategories based on T-cell subtype, type of antigen, and the resulting effector mechanism (see the table below).

In the first type IV subcategory, CD4 T_H1-mediated reactions are described as delayed-type hypersensitivities (DTH). The sensitization step involves the introduction of antigen into the skin and phagocytosis by local antigen presenting cells (APCs). The APCs activate helper T cells, stimulating clonal proliferation and differentiation into memory T_H1 cells. Upon subsequent exposure to the antigen, these sensitized memory T_H1 cells release cytokines that activate macrophages, and activated macrophages are responsible for much of the tissue damage. Examples of this T_H1-mediated hypersensitivity are observed in tuberculin the Mantoux skin test and contact dermatitis, such as occurs in latex allergy reactions.

In the second type IV subcategory, CD4 T_H2-mediated reactions result in chronic asthma or chronic allergic rhinitis. In these cases, the soluble antigen is first inhaled, resulting in eosinophil recruitment and activation with the release of cytokines and inflammatory mediators.

In the third type IV subcategory, CD8 cytotoxic T lymphocyte (CTL)-mediated reactions are associated with tissue transplant rejection and contact dermatitis (shown below). For this form of cell-mediated hypersensitivity, APCs process and present the antigen with MHC I to naïve CD8 T cells. When these naïve CD8 T cells are activated, they proliferate and differentiate into CTLs. Activated T_H1 cells can also enhance the activation of the CTLs. The activated CTLs then target and induce granzyme-mediated apoptosis in cells presenting the same antigen with MHC I. These target cells could be “self” cells that have absorbed the foreign antigen (such as with contact dermatitis due to poison ivy), or they could be transplanted tissue cells displaying foreign antigen from the donor.

Extended description

(a) A photo of poison ivy leaves sits above a cross-section of skin. Antigen from the plant enters the skin and is taken up by a dendritic cell, whose branching processes reach through the tissue. The dendritic cell activates a T cell, which becomes a memory helper T cell. (b) A photo of a raised, reddened lesion on a forearm sits above a second cross-section of skin. A macrophage, a memory helper T cell, and a cytotoxic T cell release cytokines that build the lesion shown in the photo above.

Type IV Hypersensitivities

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Micro Connection. Using Delayed Hypersensitivity to Test for TB

Austrian pediatrician Clemens von Pirquet (1874–1929) first described allergy mechanisms, including type III serum sickness (B. Huber, “100 Jahre Allergie: Clemens von Pirquet–sein Allergiebegriff und das ihm zugrunde liegende Krankheitsverständnis,” Wiener Klinische Wochenschrift 118, no. 19–20 (2006): 573–579). His interest led to the development of a test for tuberculosis (TB), using the tuberculin antigen, based on earlier work identifying the TB pathogen performed by Robert Koch. Pirquet’s method involved scarification, which results in simultaneous multiple punctures, using a device with an array of needles to break the skin numerous times in a small area. The device Pirquet used was similar to the tine test device with four needles shown below.

The tips of all the needles in the array are coated with tuberculin, a protein extract of TB bacteria, effectively introducing the tuberculin into the skin. One to 3 days later, the area can be examined for a delayed hypersensitivity reaction, signs of which include swelling and redness.

As you can imagine, scarification was not a pleasant experience (C.A. Stewart, “The Pirquet Test: Comparison of the Scarification and the Puncture Methods of Application,” Archives of Pediatrics & Adolescent Medicine 35, no. 3 (1928): 388–391), and the numerous skin punctures put the patient at risk of developing bacterial infection of the skin. Mantoux modified Pirquet’s test to use a single subcutaneous injection of purified tuberculin material. A positive test, which is indicated by a delayed localized swelling at the injection site, does not necessarily mean that the patient is currently infected with active TB. Because type IV (delayed-type) hypersensitivity is mediated by reactivation of memory T cells, such cells may have been created recently (due to an active current infection) or years prior (if a patient had TB and had spontaneously cleared it, or if it had gone into latency). However, the test can be used to confirm infection in cases in which symptoms in the patient or findings on a radiograph suggest its presence.

Hypersensitivity Pneumonitis

Some disease caused by hypersensitivities are not caused exclusively by one type. For example, hypersensitivity pneumonitis (HP), which is often an occupational or environmental disease, occurs when the lungs become inflamed due to an allergic reaction to inhaled dust, endospores, bird feathers, bird droppings, molds, or chemicals. HP goes by many different names associated with various forms of exposure (shown below). HP associated with bird droppings is sometimes called pigeon fancier’s lung or poultry worker’s lung—both common in bird breeders and handlers. Cheese handler’s disease, farmer’s lung, sauna takers’ disease, and hot-tub lung are other names for HP associated with exposure to molds in various environments.

Pathology associated with HP can be due to both type III (mediated by immune complexes) and type IV (mediated by T_H1 cells and macrophages) hypersensitivities. Repeated exposure to allergens can cause alveolitis due to the formation of immune complexes in the alveolar wall of the lung accompanied by fluid accumulation, and the formation of granulomas and other lesions in the lung as a result of T_H1-mediated macrophage activation. Alveolitis with fluid and granuloma formation results in poor oxygen perfusion in the alveoli, which, in turn, can cause symptoms such as coughing, dyspnea, chills, fever, sweating, myalgias, headache, and nausea. Symptoms may occur as quickly as 2 hours after exposure and can persist for weeks if left untreated.

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The table below summarizes the mechanisms and effects of each type of hypersensitivity discussed in this section.

Hypersensitivity Types and Their Mechanisms

Diagnosis of Hypersensitivities

Diagnosis of type I hypersensitivities is a complex process requiring several diagnostic tests in addition to a well-documented patient history. Serum IgE levels can be measured, but elevated IgE alone does not confirm allergic disease. As part of the process to identify the antigens responsible for a type I reaction allergy, testing through a prick puncture skin test (PPST) or an intradermal test can be performed. PPST is carried out with the introduction of allergens in a series of superficial skin pricks on the patient’s back or arms (shown below). PPSTs are considered to be the most convenient and least expensive way to diagnose allergies, according to the US Joint Council of Allergy and the European Academy of Allergy and Immunology. The second type of testing, the intradermal test, requires injection into the dermis with a small needle. This needle, also known as a tuberculin needle, is attached to a syringe containing a small amount of allergen. Both the PPST and the intradermal tests are observed for 15–20 minutes for a wheal-flare reaction to the allergens. Measurement of any wheal (a raised, itchy bump) and flare (redness) within minutes indicates a type I hypersensitivity, and the larger the wheal-flare reaction, the greater the patient’s sensitivity to the allergen.

Type III hypersensitivities can often be misdiagnosed because of their nonspecific inflammatory nature. The symptoms are easily visible, but they may be associated with any of a number of other diseases. A strong, comprehensive patient history is crucial to proper and accurate diagnosis. Tests used to establish the diagnosis of hypersensitivity pneumonitis (resulting from type III hypersensitivity) include bronchoalveolar lavage (BAL), pulmonary function tests, and high-resolution computed tomography (HRCT).

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Treatments of Hypersensitivities

Allergic reactions can be treated in various ways. Prevention of allergic reactions can be achieved by desensitization (hyposensitization) therapy, which can be used to reduce the hypersensitivity reaction through repeated injections of allergens. Extremely dilute concentrations of known allergens (determined from the allergen tests) are injected into the patient at prescribed intervals (e.g., weekly). The quantity of allergen delivered by the shots is slowly increased over a buildup period until an effective dose is determined and that dose is maintained for the duration of treatment, which can last years. Patients are usually encouraged to remain in the doctor’s office for 30 minutes after receiving the injection in case the allergens administered cause a severe systemic reaction. Doctors’ offices that administer desensitization therapy must be prepared to provide resuscitation and drug treatment in the case of such an event.

Desensitization therapy is used for insect sting allergies and environmental allergies. The allergy shots elicit the production of different interleukins and IgG antibody responses instead of IgE. When excess allergen-specific IgG antibodies are produced and bind to the allergen, they can act as blocking antibodies to neutralize the allergen before it can bind IgE on mast cells. There are early studies using oral therapy for desensitization of food allergies that are promising (C.L. Schneider et al., “A Pilot Study of Omalizumab to Facilitate Rapid Oral Desensitization in High-Risk Peanut-Allergic Patients,” Journal of Allergy and Clinical Immunology 132, no. 6 (2013): 1368–1374; P. Varshney et al., “A Randomized Controlled Study of Peanut Oral Immunotherapy: Clinical Desensitization and Modulation of the Allergic Response,” Journal of Allergy and Clinical Immunology 127, no. 3 (2011): 654–660). These studies involve feeding children who have allergies tiny amounts of the allergen (e.g., peanut flour) or related proteins over time. Many of the subjects show reduced severity of reaction to the food allergen after the therapy.

There are also therapies designed to treat severe allergic reactions. Emergency systemic anaphylaxis is treated initially with an epinephrine injection, which can counteract the drop in blood pressure. Individuals with known severe allergies often carry a self-administering auto-injector that can be used in case of exposure to the allergen (e.g., an insect sting or accidental ingestion of a food that causes a severe reaction). By self-administering an epinephrine shot (or sometimes two), the patient can stem the reaction long enough to seek medical attention. Follow-up treatment generally involves giving the patient antihistamines and slow-acting corticosteroids for several days after the reaction to prevent potential late-phase reactions. However, the effects of antihistamine and corticosteroid treatment are not well studied and are used based on theoretical considerations.

Treatment of milder allergic reactions typically involves antihistamines and other anti-inflammatory drugs. A variety of antihistamine drugs are available, in both prescription and over-the-counter strengths. There are also antileukotriene and antiprostaglandin drugs that can be used in tandem with antihistamine drugs in a combined (and more effective) therapy regime.

Treatments of type III hypersensitivities include preventing further exposure to the antigen and the use of anti-inflammatory drugs. Some conditions can be resolved when exposure to the antigen is prevented. Anti-inflammatory corticosteroid inhalers can also be used to diminish inflammation to allow lung lesions to heal. Systemic corticosteroid treatment, oral or intravenous, is also common for type III hypersensitivities affecting body systems. Treatment of hypersensitivity pneumonitis includes avoiding the allergen, along with the possible addition of prescription steroids such as prednisone to reduce inflammation.

Treatment of type IV hypersensitivities includes antihistamines, anti-inflammatory drugs, analgesics, and, if possible, eliminating further exposure to the antigen.

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Summary

• An allergy is an adaptive immune response, sometimes life-threatening, to an allergen.
• Type I hypersensitivity requires sensitization of mast cells with IgE, involving an initial IgE antibody response and IgE attachment to mast cells. On second exposure to an allergen, cross-linking of IgE molecules on mast cells triggers degranulation and release of preformed and newly formed chemical mediators of inflammation. Type I hypersensitivity may be localized and relatively minor (hives and hay fever) or system-wide and dangerous (systemic anaphylaxis).
• Type II hypersensitivities result from antibodies binding to antigens on cells and initiating cytotoxic responses. Examples include hemolytic transfusion reaction and hemolytic disease of the newborn.
• Type III hypersensitivities result from formation and accumulation of immune complexes in tissues, stimulating damaging inflammatory responses.
• Type IV hypersensitivities are not mediated by antibodies, but by helper T-cell activation of macrophages, eosinophils, and cytotoxic T cells.

Key terms

• hypersensitivity — potentially damaging immune response against an antigen.
• allergen — antigen capable of inducing type I hypersensitivity reaction.
• allergy — hypersensitivity response to an allergen.
• type I hypersensitivity — rapid-onset allergic reaction due to cross-linking of antigen-specific IgE on the outside of mast cells, resulting in release of inflammatory mediators.
• degranulation — release of the contents of mast cell granules in response to the cross-linking of IgE molecules on the cell surface with allergen molecules.
• anaphylaxis — systemic and potentially life-threatening type I hypersensitivity reaction.
• anaphylactic shock — another term for anaphylaxis.
• type II hypersensitivities — cytotoxic reaction triggered by IgG and IgM antibodies binding to antigens on cell surfaces.
• ABO blood group system — set of glycoprotein antigens found on the surface of red blood cells; the presence or absence of specific carbohydrates determining blood type.
• isohemagglutinin — IgM class antibodies produced against A or B red blood cell antigens.
• hemolytic transfusion reaction (HTR) — condition resulting after an incompatible blood transfusion; caused by type II hypersensitivity reaction and destruction of red blood cells.
• Rh factor — red blood cell surface antigen that can trigger type II hypersensitivity reactions.
• hemolytic disease of the newborn (HDN) — type II hypersensitivity reaction that occurs when maternal anti-Rh antibodies cross the placenta and target fetal Rh+ red blood cells for lysis.
• Arthus reaction — localized type III hypersensitivity.
• immune complex — large group of antigens bound by antibodies; large enough to settle out of fluid suspension.
• type III hypersensitivity — inflammatory reaction induced by formation of immune complexes and their deposition in tissues and blood vessels.
• serum sickness — systemic type III hypersensitivity reaction.
• type IV hypersensitivities — delayed T-cell-mediated inflammatory reaction that takes longer to manifest than the first three hypersensitivity types, due to the need for activation of antigen-presenting cell and T-cell subsets.
• contact dermatitis — inflammation of the skin resulting from a type IV hypersensitivity to an allergen or irritant.
• hypersensitivity pneumonitis (HP) — type III and IV hypersensitivities in the lungs that are caused by environmental or occupational exposure to allergens such as mold and dust.
• wheal-flare reaction — localized type I hypersensitivity reaction, involving a raised, itchy bump (wheal) and redness (flare), to injected allergen.
• desensitization — injections of antigen that lead to production of antigen-specific IgG molecules, effectively outcompeting IgE molecules on the surface of sensitized mast cells for antigen.
• blocking antibodies — antigen-specific antibodies (usually of the IgG type) produced via desensitization therapy.

Practice

Identify and compare the distinguishing characteristics, mechanisms, and major examples of type I, II, III, and IV hypersensitivities

This section is adapted from Microbiology, Section 19.1: Hypersensitivities by Nina Parker, Mark Schneegurt, Anh-Hue Thi Tu, Philip Lister, Brian M. Forster, and OpenStax, © OpenStax, licensed under CC BY-NC-SA 4.0. Access the original for free at openstax.org. Changes: all eleven source figures re-encoded as WebP and rendered as mediafigures after image and PDF inspection; kind="photo" set on the Allergen, tine-test, occupational-exposure, and skin-test figures (four photographic panels or photo-only compositions) and kind="diagram" on the mast-cell-sensitization, ABO, HTR, HDN, Type III, Type IV, and hypersensitivity-types-recap figures (each has at least one drawn or rendered-table panel, and the drawn half is what the caption or the page teaches), overriding the media manifest’s JPEG-based photo guess for the diagrams; the Allergen figure carries eager="true" as the page’s first figure; a longdesc walk-through was added to the mast-cell-sensitization (5 steps), ABO (4-cell table), hemolytic-transfusion-reaction (3 steps), hemolytic-disease-of-the-newborn (two panels, 4 and 3 steps), type III (two-panel mechanism-and-consequence), and type IV (two-panel sensitization-and-response) figures, because their multi-part content is not fully carried by the caption or alt; the ABO figure prints no caption in the source and is rendered with none; the hypersensitivity-types-recap figure (OSC_Microbio_19_01_Types), a rendered table image, is transcribed as a Markdown table from the image (checked against the PDF page) rather than from the source alt, which carries three defects this page’s transcription does not reproduce: a typo (“secreete”), a doubled period, and a “Local and systemic” phrase copied onto the Type III examples cell from the Type I cell — the rendered image itself shows no such phrase on the Type III row — and the vendored figure is kept after it with an alt describing the table’s layout rather than repeating the values already transcribed; four one-word or one-character source defects are corrected in place with no inline note — “arachadonic acid” to “arachidonic acid” in the degranulation-mediators paragraph, the Strayer et al. citation’s stray “2” before “Philadelphia,” the doubled “with a with a” in the HDN figure caption, and the missing noun in “the next pregnancy with an Rh+ will have minimal risk,” corrected to “the next pregnancy with an Rh+ fetus will have minimal risk”; the HDN figure’s source alt uses an ASCII hyphen for “Rh-” where the prose uses the minus sign “Rh−,” so this page’s rewritten alt and longdesc spell out “Rh-positive”/“Rh-negative” throughout, which resolves the inconsistency without a separate disclosure; all twelve of the module’s footnotes are rendered as inline parenthetical citations placed after the sentence they support, with the one bare access URL (the CDC’s Diphtheria Antitoxin page) dropped and every other citation’s authors, title, journal, and year kept verbatim; the Fill in the Blank items are rendered as textin, keeping the source’s exact wording; the five tables with a summary are all transcribed as Markdown, and three become a sortbins in the Practice block or body — the two mast-cell-mediator tables (preformed and newly formed components) as one combined Preformed/Newly formed sortbins, and the Type I Hypersensitivities conditions table as one four-bin sortbins, both placed in Practice under the section’s single objective; the Common Type II Hypersensitivities table (two rows) is left as Markdown only, too thin for a sortbins without inventing items; the Type IV Hypersensitivities table becomes a Subcategory 1/2/3 sortbins built with the row’s effector mechanism and examples (and, for subcategory 3 only, its antigen form, since subcategories 1 and 2 share the same “soluble antigen” antigen form and an item built from it would not identify a single bin) — this sortbins is placed at the position of, and replaces, the body Check Your Understanding bullet “Describe the three subtypes of type IV hypersensitivity,” per the rule that a body item already asking a table’s own contrast is the one that becomes the sortbins, so it is not duplicated in Practice; of the module’s fourteen body Check Your Understanding bullets across seven boxes, seven are graded from a single module sentence, a table, or a compare-and-contrast pair of module passages — “What are the cells that cause a type I hypersensitivity reaction?” (textin, keyed from “The chemical mediators released by mast cells collectively cause the inflammation and signs and symptoms associated with type I hypersensitivity reactions”), “What happens to cells that possess incompatible antigens in a type II hypersensitivity reaction?” (multiplechoice), “Why is antibody excess important in type III hypersensitivity?” (multiplechoice), “Describe the differences between the Arthus reaction and serum sickness” (sortbins, two bins), “Describe the three subtypes of type IV hypersensitivity” (sortbins, described above), “Describe the prick puncture skin test” (multiplechoice), and “Explain the role of epinephrine in treatment of hypersensitivity reactions” (multiplechoice, keyed from “Emergency systemic anaphylaxis is treated initially with an epinephrine injection, which can counteract the drop in blood pressure”) — and the remaining seven stay body self-checks, with model answers assembled from this section’s own text; the module’s two unkeyed Short Answer questions and two unkeyed Critical Thinking questions are rendered as selfchecks in Practice, since no single module sentence fixes any of the four — the two Critical Thinking model answers say what the section states about skin testing and the tuberculin test and stop, since the section does not state the reasoning the questions ask for; the module’s eight Multiple Choice and four Fill in the Blank items are rendered exactly as keyed, in source order and source option order; four author-written multiplechoice items built from the body Check Your Understanding bullets above vary their key position (A, B, C, D across the four) rather than clustering; no source exercise, table, or Check Your Understanding bullet is omitted; key terms are compiled from the module’s 23 <term> elements and the book’s Glossary appendix, giving 23 distinct bullets, all with a Glossary entry (none sentence-derived); the source’s cross-references to Adaptive Specific Host Defenses, B Lymphocytes and Humoral Immunity (twice), Chemical Defenses, Vaccines, and Autoimmune Disorders (twice) are rendered as live links to their authored pages; the Clinical Focus case (patient Kerry) runs Parts 1–3 within this section — each of Part 1 and Part 2’s closing “jump to the next box” sentence is replaced with a same-page “The case continues in Part N below,” and the source’s “go back to the previous box” pointers are dropped as redundant on a single page — and Part 3’s closing sentence is replaced with a link to where the case resolves, Organ Transplantation and Rejection; the closing questions inside each Clinical Focus part stay as unanswered bulleted prose, as printed.