Done by : Ala’a Abdullah Supervised by : Dr. Hassan Abu-al Ragheb

Hypersensitivity

Hypersensitivity

• Typically, it is an excessive response to a harmless antigen that results in injury to the tissue, disease, or even death.

• Over reaction of immune system to a harmless antigen that results in tissue injury. It occurs when an already sensitized individual is re-exposed to the same foreign substance.

Hypersensitivity reactions

Type I: cell-bound antibody reacts with antigen to release physiologically active substances.

Type II: are those in which free antibody reacts with antigen associated with cell surfaces.

Type III: antibody reacts with soluble antigen to form complexes that precipitate in the tissues.

Type IV: sensitized T cells rather than antibody are responsible for the symptoms that develop.

I-III are Ig mediated and they are referred to as immediate hypersensitivity. IV use cell mediators and it is referred to as delayed hypersensitivity.

Type I Hypersensitivity

• The distinguishing feature of type I hypersensitivity is the short time lag, usually seconds to minutes, between exposure to antigen and the onset of clinical symptoms.

• The key reactant present in type I, or immediate sensitivity reactions, is IgE. Antigens that trigger formation of IgE are called atopic antigens, or allergens.

• Atopy refers to an inherited tendency to respond to naturally occurring inhaled and ingested allergens with continued production of IgE.

• Carl Wilhelm Prausnitz and Heinz Küstner were the first researchers to show that a serum factor was responsible for type I reactions. Serum from Küstner, who was allergic to fish, was injected into Prausnitz. A later exposure to fish antigen at the same site resulted in an allergic skin reaction.

passive cutaneous anaphylaxis

It occurs when serum is transferred from an allergic individual to a nonallergic individual, and then the second individual is challenged with specific antigen.

• The regulation of IgE production is a function of a subset of T cells called type 2 helper cells (Th2).

• Th2 cells respond instead and produce interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-9 (IL-9), and interleukin-13 (IL-13).

• IL-4 and IL-13 are responsible for the final differentiation that occurs in B cells.

• IL-5 and IL-9 are involved in the development of eosinophils.

• IL-4 and IL-9 promote development of mast cells.

• IL-4, IL-9, and IL-13 all act to stimulate overproduction of mucus, a characteristic of most allergic reactions.

Triggering of Type I Reactions by IgE

• Tendency to respond to specific allergens appears to be linked to inheritance of certain major histocompatibility complex (MHC) genes.

• Various human leukocyte antigen (HLA) class II molecules, especially HLA-DR2, DR4, and DR7, seem to be associated with a high response to individual allergens.

• Individuals who are prone to allergies exhibit certain variations in the gene found on chromosome 11q that codes for receptors for IgE found on several types of cells.

Triggering of Type I Reactions by IgE

Role of Mast Cells and Basophils

• Mast cells are the principle effector cells of immediate hypersensitivity.

• These cells contain numerous cytoplasmic granules that are enclosed by a bilayered membrane.

• Histamine, which comprises approximately 10 percent of the total weight of granular constituents, is found in 10 times greater supply per cell than in basophils.

• Mast cells release a variety of cytokines and other mediators that enhance the allergic response.

• Basophils represent approximately 1 percent of the white blood cells in peripheral blood. They have a half-life of about 3 days. They contain histamine-rich granules and high-affinity receptors for IgE, just as in mast cells.

Mediators Released from Granules

Preformed mediators Newly synthesized mediators

Preformed Mediators

• These preformed or primary mediators include histamine, heparin, eosinophil chemotactic factor of anaphylaxis (ECF-A), neutrophil chemotactic factor, and proteases.

• Release of these substances is responsible for the early phase symptoms seen in allergic reactions, which occur within 30 to 60 minutes after exposure to the allergen.

Histamine

• It is major component of mast cell granules, is appear within 30 to 60 seconds after release, are dependent on activation of four different types of receptors found on cells in various types of tissue.

Activation of H1 receptors Activation of H2 receptors Activation of H3 receptors Activation of H4 receptors

In the skin, histamine is responsible for local erythema or redness and wheal and flare formation. Contraction of the smooth muscle in the bronchioles may result in airflow obstruction. Increased vascular permeability may cause hypotension or shock.

Eosinophil chemotactic factor of anaphylaxis (ECF-A)

• is another preformed factor released from granules. This attracts eosinophils to the area and induces expression of eosinophil receptors for C3b.

• Eosinophils have granules that contain major basic protein, eosinophil cationic protein, eosinophil peroxidase, eosinophil derived neurotoxins, histaminases, and phospholipase D. All of these products are toxic to bronchial epithelial cells and to helminth parasites. Killing of parasites is thought to be the reason that IgE production evolved.

• One of the proteolytic enzymes released is tryptase, Which induces prolonged smooth muscle contraction and increases vascular permeability and secretory activity. Complement split products are also released when C3 is converted to C3a and C3b.

Newly Synthesized Mediators

• mast cells and basophils are triggered to synthesize certain other reactants from the breakdown of phospholipids in the cell membrane. These products are responsible for a late phase allergic reaction seen within 6 to 8 hours after exposure to antigen.

• Newly formed mediators include platelet activating factor (PAF); prostaglandin (PG) D2; leukotrienes (LT) B4, C4, D4, and E4; and cytokines.

Prostaglandins & leukotrienes

• PGD2 is the major product of mast cell. it mimics the effects of histamine, causing bronchial constriction and vasodilation It is much more potent than histamine, but it is released in smaller quantities.

• Leukotrienes, are also responsible for late-phase symptoms of immediate sensitivity.

• Leukotrienes C4, D4, and E4 were originally collectively named the slow reacting substances of anaphylaxis (SRS-A).

• LTC4 and LTD4 are 1000 times more potent than histamine in causing increased vascular permeability, bronchoconstriction, and increased mucous secretion in small airways.

PAF & Cytokines

• Platelet activating factor (PAF) is a phospholipid released by monocytes, macrophages, neutrophils, eosinophils, mast cells, and basophils.

• The effects of PAF include platelet aggregation, chemotaxis of eosinophils and neutrophils, increased vascular permeability, and contraction of smooth muscle in the lungs and intestines.

• Cytokines released from mast cells include IL-1, IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, IL-14, IL-16, GM-CSF, and TNF alpha.

• These cytokines alter the local microenvironment, leading to an increase in inflammatory cells such as neutrophils, eosinophils, and macrophages.

Clinical Manifestations of ImmediateHypersensitivity

• The clinical manifestations caused by release of both preformed and newly synthesized mediators from mast cells and basophils vary from a localized skin reaction to a systemic response known as anaphylaxis.

• Anaphylaxis is the most severe type of allergic response, because it is an acute reaction that simultaneously involves multiple organs.

• Anaphylactic reactions are typically triggered by glycoproteins or large polypeptides. Smaller molecules, such as penicillin, are haptens that may become immunogenic by combining with host cells or proteins.

Typical agents that induce anaphylaxis include: • venom from bees.• Wasps.• Hornets.• drugs such as penicillin.• foods such as shellfish, peanuts, or dairy products.• Latex sensitivity is now a significant cause of anaphylaxis among health-

care workers and in patients who have had multiple surgery procedures.

Clinical Manifestations of ImmediateHypersensitivity

Clinical signs of anaphylaxis

• It is begin within minutes after antigenic challenge and may include edema, vascular congestion, skin manifestations such as urticaria (hives) and angioedema, diarrhea or vomiting, and intractable shock because of the effect on blood vessels and smooth muscle of the circulatory system.

• The severity of the reaction depends on the number of previous exposures to the antigen with consequent buildup of IgE on mast cells and basophils.

• Massive release of reactants, especially histamine, from the granules is responsible for the symptoms. Death may result from suffocation due to upper-airway edema and congestion, irreversible shock, or a combination of these symptoms.

• Rhinitis is the most common form of atopy, or allergy. It affects about 15 to 20 percent of children in developed Immune Disorders countries. Symptoms include paroxysmal sneezing; runny nose; nasal congestion; and itching of the nose and eyes.

Asthma

• is derived from the Greek word for “panting” or “breathlessness.” It can be defined clinically as recurrent airflow obstruction that leads to intermittent sneezing, breathlessness, and occasionally, a cough with sputum production.

• Particles no larger than 2 to 4 micro meter in diameter such as pollen, dust, or fumes, may reach the lower respiratory tract to cause asthma.

Food allergies

• are another example of type I immediate hypersensitivity reactions.

• Some of the most common food allergies involve cow’s milk, peanuts, and eggs. Symptoms limited to the gastrointestinal tract include cramping, vomiting, and diarrhea, while spread of antigen through the bloodstream may cause hives and angioedema on the skin, as well as asthma or rhinitis.

• Eczema, an itchy red skin rash, may be caused by food allergens or exposure to house dust mites.

Treatment of Immediate Hypersensitivity

• Avoidance of known allergens is the first line of defense.

• Drugs used to treat immediate hypersensitivity vary with the severity of the reaction.

• Immunotherapy or hyposensitization. Very small quantities of sensitizing antigen are injected into the patient with the idea of building up IgG antibodies. Individuals with moderate to severe symptoms are given weekly doses of antigen that gradually increases in strength. The blocking antibodies formed circulate in the blood and combine with antigen before it can reach IgE-coated cells.

• A new approach involves use of an anti-IgE monoclonal antibody.

Testing for Immediate Hypersensitivity

1. In Vivo Skin Tests: Cutaneous & intradermal tests

2. In Vitro Tests: Total IgE Antigen & Specific IgE Testing

3. Microarray test

In Vivo Skin Tests

• Cutaneous and intradermal tests are the two skin tests most often used.

• Skin testing is relatively simple and inexpensive, and it lends itself to screening for a number of allergens.

• antihistamines must be stopped 24 to 72 hours before testing, and there is the danger that a systemic reaction can be triggered.

• In addition, skin testing is not recommended for children under 3 years of age.

prick tests

• A small drop of material is injected into the skin at a single point Controls should always be included:

Negative control: saline Positive control: histamine

• After 15 minutes, the spot is examined a positive reaction is formation of a wheal that is 3 mm greater in diameter than the negative control.

prick tests

Intradermal tests

• Intradermal tests use a greater amount of antigen and are more sensitive than cutaneous testing.

• It is performed only if prick tests are negative and allergy is still suspected.

• Tourniquet can be applied on an extremity to stop an unexpected systemic reaction.

• A 1 mL tuberculin syringe is used to administer 0.01 to 0.05 mL of test solution between layers of the skin.

• The test allergen is diluted 100 to 1000 times more than the solution used for cutaneous testing.

• After 15 to 20 minutes, the site is inspected for erythema and wheal formation.• A wheal 3 mm greater than the negative control is considered a positive test.

Intradermal tests

In Vitro Tests

• Involves measurement of:1. Total IgE2. Antigen-specific IgE

• These are less sensitive than skin testing put usually are less traumatic to the patient.

Total IgE

• The first test developed for the measurement of total IgE was the competitive radioimmunosorbent test (RIST).

• The RIST used radio labeled IgE to compete with patient IgE for binding sites on a solid phase coated with anti-IgE.

• It has been replaced by noncompetitive solid-phase immunoassays due to the expense and difficulty of working with radioactivity.

• It serves as a screening test to determine if more specific allergy testing is indicated.

• It is also important in diagnosis of parasitic infections; bronchopulmonary aspergillosis; and hyper-IgE syndrome, a condition in which excessive amounts of IgE are produced.

• Total IgE values are reported in kilo international units (IU) per liter.

• IgE concentration varies with the individual’s age, sex, smoking history and his or her family history of allergy.

• In infants, normal serum levels of IgE are less than 2 k IU/L; increases up to 10 kIU/L are indicative of allergic disease.

• A cutoff point of 100 IU, for adults.

Total IgE

Antigen-specific IgE

• The method that used to be done was radioallergosorbent test (RAST). • Newer testing methods involve the use of enzyme or fluorescent labels

rather than radioactivity.• The sensitivity of the new test approaches that of skin testing and it is safer

to perform.

• Because of this test IgE can now be measured quantitatively, and concentrations as low as 0.35 KIU/L can be detected.

• A negative test may be used to confirm the absence of a specific atopic disease, and this has a higher negative predictive value than total IgE testing.

• However, in a positive test, the quantity of antibody measured does not necessarily correlate with the severity of disease.

• It is very useful to determine common food allergies and sensitivity to the venom of stinging insects, it is more difficult to determine inhalant allergies.

Antigen-specific IgE

Comparison of RIST and RAST. RIST measures total IgE by capturing the antibody with solidphase anti-IgE. A second anti-IgE immunoglobulin with an enzyme label is used to produce a visible reaction. RAST measures antigen-specific IgE by using solid-phase antigen to capture patient antibody. Then a second antibody, enzyme-labeled anti-IgE immunoglobulin, is added. This combines with any bound IgE to produce a visible reaction in the presence of substrate.

Microarray testing

• It allows for multiallergen diagnosis with a low sample volume and a high throughput capacity.

• Microarrays can be attached to a standard microscope slide, using only a few picograms of each allergen to be tested.

• At least 5000 allergens can be tested for at once, using a minimal amount of serum.

• Patient serum with possible IgE is allowed to react with the microarray of allergens, and then an anti-IgE with a fluorescent tag is added, The presence of color indicates a positive test for that allergen.

• The reactants responsible for type II hypersensitivity, or cytotoxic hypersensitivity, are IgG and IgM.

• They are triggered by antigens found on cell surfaces. These antigens may be altered self-antigens or heteroantigens.

• Antibody coats cellular surfaces and promotes phagocytosis by both opsonization and activation of the complement cascade.

• Macrophages, neutrophils, and eosinophils have FC receptors that bind to the FC region of antibody on target cells, thus enhancing phagocytosis.

• Natural killer (NK) cells also have FC receptors, and if these link to cellular antigens, cytotoxicity results.

Type II Hypersensitivity

Transfusion Reactions

• Transfusion reactions are examples of cellular destruction that result from antibody combining with heteroantigens.

• Major groups involved in transfusion reactions include the ABO, Rh, Kell, Duffy, and Kidd systems.

• Certain antibodies are produced naturally with no prior exposure to red blood cells, while other antibodies are produced only after contact with cells carrying that antigen.

• Acute hemolytic transfusion reactions may occur within minutes or hours after receipt of incompatible blood.

• Reactions that begin immediately are most often associated with ABO blood group incompatibilities, and antibodies are of the IgM class.

• If a patient is given blood for which antibodies are already present, a transfusion reaction occurs. This can range from acute massive intravascular hemolysis to an undetected decrease in red blood cell survival.

• Delayed hemolytic reactions occur within the first 2 weeks following a transfusion and are caused by a secondary response to the antigen to which the patient has previously been exposed.

• The type of antibody responsible is IgG, which was initially present in such low titer that it was not detectable with an antibody screen.

• Antigens most involved in delayed reactions include those in the Rh, Kell, Duffy, and Kidd blood groups.

• Rh, Kell, and Duffy antigens may also be involved in immediate transfusion reactions.

Transfusion Reactions

Hemolytic Disease of the Newborn

• Hemolytic disease of the newborn (HDN) appears in infants whose mothers have been exposed to blood-group antigens on the baby’s cells that differ from their own. The mother makes IgG antibodies in response, and these cross the placenta to destroy fetal red cells.

• Severe HDN is called erythroblastosis fetalis.

• The most common antigen involved in severe reactions is the D antigen, a member of the Rh blood group.

• HDN due to ABO incompatibility is actually more common, but the disease is milder because the majority of antibodies formed are IgM, which cannot cross the placenta.

• Other antibodies associated with HDN include anti-c, anti-C, anti-E, anti-e, and less commonly those associated with the Kell, Duffy, and Kidd blood groups.

• Exposure usually occurs during the birth process, where fetal cells leak into the mother’s circulation. Typically the first child is unaffected, but the second and later children have an increased risk of the disease.

• Depending on the degree of antibody production in the mother, the fetus may be aborted, stillborn, or born with evidence of hemolytic disease as indicated by jaundice.

• Bilirubin levels above 20 mg/dL are associated with deposition in tissue such as the brain and result in a condition known as kernicterus. Treatment for severe HDN involves an exchange transfusion to replace antibody-coated red cells.

• To prevent the consequences of HDN, all women should be screened at the onset of pregnancy.

• In current practice, anti-D immune globulin, called Rhogam, is administered prophylactically at 28 weeks of gestation and within 72 hours following delivery.

Hemolytic Disease of the Newborn

Autoimmune Hemolytic Anemia

• Autoimmune hemolytic anemia is an example of a type II hypersensitivity reaction directed against self-antigens, because individuals with this disease form antibodies to their own red blood cells.

• Such antibodies can be categorized into two groups: warm reactive antibodies, which react at 37°C, and cold reactive antibodies, which react only below 30°C.

• Warm autoimmune hemolytic anemia, accounting for more than 70 percent of autoimmune anemias, is characterized by formation of IgG antibody, which reacts most strongly at 37°C. Some of these antibodies may be primary with no other disease association, or they may be secondary to another disease process.

• Associated diseases may include some of the following: viral or respiratory infections, such as infectious mononucleosis, cytomegalovirus, or chronic active hepatitis, or immunoproliferative diseases such as chronic lymphocytic leukemia and lymphomas.

• In addition, certain drugs can be adsorbed onto red blood cells and are capable of stimulating antibody production. examples include penicillins, cephalosporins, rifampin, sulfonamides, and methyldopa.

• Often, however, the underlying cause of antibody production is unknown, so this is referred to as idiopathic autoimmune hemolytic anemia.

• Hemolysis is primarily extravascular, because IgG is not as efficient as IgM in activating complement, but intravascular hemolysis can also occur if complement does become activated.

• Patients with warm autoimmune hemolytic anemia are usually treated with corticosteroids or splenectomy in more serious cases.

Autoimmune Hemolytic Anemia

• Cold autoagglutinins, a less frequent cause of immune hemolytic anemias.

• These are thought to be triggered by antigens on microorganisms, because antibodies have been known to occur following Mycoplasma pneumonia and infectious mononucleosis.

• Cold autoagglutinins have also been seen in such diseases as chronic lymphocytic leukemia, non- Hodgkin’s lymphoma, myelodysplastic syndrome, or systemic lupus erythematosus.

• These cold-reacting antibodies belong to the IgM class, and most are specific for the Ii blood groups on red cells. Reactions are seen only if the individual is exposed to the cold and the temperature in the peripheral circulation falls below 30°C.

• Although complement activation begins in the cold, it can proceed at body temperature. If the entire complement sequence is activated, intravascular hemolysis may occur.

• A simple treatment is to keep the patient warm, especially the hands and feet, to prevent complement activation.

Autoimmune Hemolytic Anemia

Type II Reactions Involving Tissue Antigens

• Some type II reactions involve destruction of tissues because of combination with antibody. Organ-specific autoimmune diseases in which antibody is directed against a particular tissue are in this category. Goodpasture’s syndrome is an example of such a disease.

• The antibody produced during the course of this disease reacts with basement membrane protein. Usually the glomeruli in the kidney and pulmonary alveolar membranes are affected. Antibody binds to glomerular and alveolar capillaries, Triggering the complement cascade, which provokes inflammation.

• An evenly bound linear deposition of IgG in glomerular basement membrane, as detected by fluorescent-labeled anti-IgG, is indicative of Goodpasture’s syndrome.

• Treatment usually involves the use of corticosteroids or other drugs to suppress the immune response.

• Other examples of reactions to tissue antigens include some of the organ-specific autoimmune diseases such as Hashimoto’s disease, myasthenia gravis, and insulin-dependent diabetes mellitus.

Testing for Type II Hypersensitivity

• Direct antiglobulin testing (DAT) is performed to detect transfusion reactions, hemolytic disease of the newborn, and autoimmune hemolytic anemia.

• The indirect Coombs’ test is used in the crossmatching of blood to prevent a transfusion reaction. It is used either to determine the presence of a particular antibody in a patient or to type patient red blood cells for specific blood group antigens.

• Type III hypersensitivity reactions are similar to type II reactions in that IgG or IgM is involved and destruction is complement mediated.

• Soluble antigen combines with antibody, complexes are formed that precipitate out of the serum.

• Normally such complexes are cleared by phagocytic cells, but if the immune system is overwhelmed, these complexes deposit in the tissues.

• Deposition of antigen–antibody complexes is influenced by the relative concentration of both components.

• If a large excess of antigen is present, sites on antibody molecules become filled before cross-links can be formed.

• In antibody excess, a lattice cannot be formed because of the relative scarcity of antigenic determinant sites.

Type III Hypersensitivity

• The small complexes that result in either of the preceding cases remain suspended or may pass directly into the urine.

• Precipitating complexes, on the other hand, occur in mild antigen excess, and these are the ones most likely to deposit in the tissues. Sites in which this typically occurs include the glomerular basement membrane, vascular endothelium, joint linings, and pulmonary alveolar membranes.

• Complement binds to these complexes in the tissues, causing the release of mediators.

Type III Hypersensitivity

Arthus Reaction

• Antigen is injected into the skin of an individual who has circulating antibody of that specificity.

• Immune complexes are formed and deposit on the walls of blood vessels, activating complement.

• Complement fragments cause dilation and increased

permeability of blood vessels, edema, and accumulation of neutrophils.

Arthus Reaction

Serum Sickness

• Serum sickness is a generalized type III reaction that is seen in humans, although not as frequently as it used to be.

• Serum sickness results from passive immunization with animal serum, usually horse or bovine, used to treat such infections as diphtheria, tetanus, and gangrene. Vaccines and bee stings may also trigger this type of reaction.

• In this disease, the sensitizing and the shocking dose of antigen are one and the same, because antibodies develop while antigen is still present.

• Usually this is a benign and self-limiting disease, but previous exposure to animal serum can cause cardiovascular collapse on reexposure.

• These symptoms have occurred with monoclonal antibody treatment.

Autoimmune Diseases

• Type III hypersensitivity reactions can be triggered by either autologous or heterologous antigens.

• Systemic lupus erythematosus (SLE) and rheumatoid arthritis are two such examples.

• In SLE, antibodies are directed against DNA and nucleohistones, which are found in most cells of the body. Immune complex deposition involves multiple organs, but the main damage occurs to the glomerular basement membrane in the kidney.

• In rheumatoid arthritis, an antibody called rheumatoid factor is directed against IgG. Immune complex deposition occurs in the membranes of inflamed joints.

• Complement enhances tissue destruction in both diseases.

Testing for Type III Hypersensitivity

• In specific diseases such as SLE an rheumatoid arthritis, the presence of antibody can be detected by agglutination reactions using antigen-coated carrier particles, including red blood cells or latex particles, or enzym immunoassays.

• Fluorescent staining of tissue sections has also been used to determine deposition of immune complexes in the tissues. The staining pattern seen, and the particular tissue affected, helps to identify th disease and determine its severity.

• A more general method of determining immune complex diseases is by measuring complement levels. Decreased levels of individual components or decreased functioning of the pathway may be indicative of antigen–antibody combination.

Type IV Hypersensitivity

• Type IV hypersensitivity differs from the other three types of hypersensitivity in that sensitized T cells, usually a subpopulation of Th1 cells, play the major role in it manifestations.

• Antibody and complement are not directly involved.

• There is an initial sensitization phase of 1 to 2 weeks that takes place after the first contact with antigen.

• symptoms typically take several hours to develop and reach a peak 48 to 72 hours after exposure to antigen.

• Langerhans cells in the skin and macrophages in the tissue capture and present antigen to T helper cells of the Th1 subclass.

• Th1 cells are activated and release cytokines, including IL-3, interferon gamma (IFN), tumor necrosis factor-beta (TNF-), and tumor necrosis factor alpha (TNF), that recruit macrophages and neutrophils, produce edema, promote fibrin deposition, and generally enhance an inflammatory response.

• Cytotoxic T cells are also recruited, and they bind with antigen-coated target cells to cause tissue destruction.

• Allergic skin reactions to bacteria, viruses, fungi, and environmental antigens such as poison ivy typify this type of hypersensitivity.

Type IV Hypersensitivity

Contact Dermatitis

• Contact dermatitis is a form of delayed hypersensitivity.

• Reactions are usually due to low-molecular-weight compounds that touch the skin.

• The most common causes include poison ivy, poison oak, and poison sumac.

• Other common compounds that produce allergic skin manifestations include nickel; rubber; formaldehyde; hair dyes and fabric finishes; cosmetics; and medications applied to the skin, such as antiseptics, and antibiotics.

• A skin eruption characterized by erythema, swelling, and the formation of papules appears anywhere from 6 hours to several days after the exposure.

Hypersensitivity Pneumonitis

• hypersensitivity pneumonitis is mediated predominantly by sensitized T lymphocytes that respond to inhaled allergens.

• IgG and IgM antibodies are formed, but these are thought to play only a minor part.

• This is an allergic disease of the lung parenchyma, characterized by inflammation of the alveoli and interstitial spaces.

• The reaction is most likely due to microorganisms, especially bacterial and fungal spores, that ndividuals are exposed to from working with moldy hay, compost, moldy tobacco, infested flour, and moldy cheese.

• Symptoms include a dry cough, shortness of breath, fever, chills, weight loss, and general malaise.

• Systemic corticosteroid therapy is used for treatment.

Tuberculin-Type Hypersensitivity

• Testing for exposure to tuberculosis is a classic example of a delayed hypersensitivity reaction. This is based on the principle that soluble antigens from Mycobacterium tuberculosis induce a reaction in people who have or have had tuberculosis.

• When challenged with antigen intradermally, previously sensitized individuals develop an area of erythema and induration at the injection site.

• The blood vessels become lined with mononuclear cells, and the reaction reaches a peak by 72 hours after exposure.

• The tuberculin skin test uses a Mycobacterium tuberculosis antigen prepared by making a purified filtrate from the cell wall of the organism. This purified protein derivative (PPD) is injected under the skin, and the reaction is read at 48 to 72 hours.

• A positive test indicates that the individual has previously been exposed to Mycobacterium tuberculosis or a related organism, but it does not necessarily mean there is a presently active case.

Testing for Delayed Hypersensitivity (The patch test)

• The patch test is considered the gold standard in testing for contact dermatitis.

• This must be done when the patient is free of symptoms or when he or she at least has a clear test site.

• A nonabsorbent adhesive patch containing the suspected allergen is applied on the patient’s back, and the skin is checked for a reaction over the next 48 hours.

• Final evaluation is conducted at 96 to 120 hours. All readings should be done by a skilled evaluator.

• False negatives can result from inadequate contact with the skin.

The patch test

Testing for Delayed Hypersensitivity (Mantoux method)

• Mantoux method, is performed in much the same manner as testing for the presence of IgE.

• Typically, 0.1 mL of the antigen is injected intradermally, using a syringe and a fine needle.

• The test site is read at 48 and 72 hours for the presence of induration.

• An induration of 5 mm or more is considered a positive test.

• Antigens typically used for testing are Candida albicans, tetanus toxoid, tuberculin, and fungal antigens such as trichophyton and histoplasmin.

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