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Unit 1 Part 6 Hypersensitivity Reactions. Terry Kotrla, MS, MT(ASCP)BB. Hypersensitivity Reactions. When the immune system "goes wrong" . Immune response should be protective. In this process damage to host occurs.
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Unit 1 Part 6Hypersensitivity Reactions Terry Kotrla, MS, MT(ASCP)BB
Hypersensitivity Reactions • When the immune system "goes wrong" . • Immune response should be protective. • In this process damage to host occurs. • Hypersensitivity denotes a state of increased reactivity of the host to an antigen and implies that the reaction is damaging to the host. • The individual must first have become sensitized by previous exposure to the antigen. • On second and subsequent exposures, symptoms and signs of a hypersensitivity state occur.
Hypersensitivity Reactions • Immediate hypersensitivity refers to antibody mediated reactions – symptoms develop within minutes to hours • Delayed hypersensitivityrefers to cell mediated immunity, symptoms not observed for 24 to 48 hours.
Four Classifications • Type I (Immediate) Hypersensitivity • Type II (cytotoxic) hypersensitivity • Type III (immune complex mediated) hypersensitivity • Type IV (delayed) hypersensitivity
Type I (Immediate) Hypersensitivity • Distinguishing feature short lag time. • Key reactant is IgE • Antigens which trigger response called atopic antigens or allergens. • Atopy – inherited tendency to immunologically respond to inhaled or ingested allergens with increased IgE production.
Type I (Immediate) Hypersensitivity • IgE primarily synthesized in lymphoid tissue of respiratory and GI tract. • Regulated by T helper cells. • Specific interleukins are involved in development of eosinophils and promote development of mast cells. • All act to stimulate overproduction of mucus. • Basophils and mast cells have highest number of receptors for Fc portion of IgE on surface.
Type I (Immediate) Hypersensitivity • Reactions range from mild manifestations associated with food allergies to life-threatening anaphylactic shock. • Atopic allergies include hay fever, asthma, food allergies and eczema. • Exposure to allergens can be through inhalation, absorption from the digestive tract or direct skin contact. • Extent of allergic response related to port of entry, i.e., bee sting introduces allergen directly into the circulation. • Caused by inappropriate IgE production • This antibody has an affinity for mast cells or basophils.
Type I (Immediate) Hypersensitivity • When IgE meets its specific allergen it causes the mast cell to discharge its contents of vasoactive substances into the circulation. • This release leads to symptoms of: • sneezing, • runny noses, • red watery eyes and • wheezing. • Symptoms subside when allergen is gone. • The most common immunological abnormality seen in medical practice, estimated that 30% of US population has allergies.
Type I (Immediate) Hypersensitivity • Anaphylactic shock is the most serious and fortunately the rarest form of this Type I hypersensitivity. • Symptoms are directly related to the massive release of vasoactive substances leading to fall in blood pressure, shock, difficulty in breathing and even death. • It can be due to the following: • Horse gamma globulin given to patients who are sensitized to horse protein. • Injection of a drug that is capable of acting as a hapten into a patient who is sensitive, ie, penicillin. • Following a wasp or bee sting in highly sensitive individuals. • Foods – peanuts, shellfish, etc.
Type I (Immediate) Hypersensitivity • Treatment • Avoidance of known allergens • Localized reactions use OTC antihistamines and decongestants. • Asthma uses combination – antihistamines, bronchodilators and corticosteroids. • Systemic use epinephrine • Hyposensitization – inject antigen to cause production of IgG which binds to antigen (allergen) before it reaches IgE coated cells. • Monocolonal anti-IgE – inject, binds to receptors on mast cells blocking them from the IgE.
Type I (Immediate) Hypersensitivity • Testing • In-Vivo Tests - Skin tests • Small amount of allergen injected into skin • Look for wheal formation of 3mm or greater in diameter • Simple, inexpensive, can screen for multiple allergens. • Stop anti-histamines 24-72 hours before test. • Danger of systemic reaction • Not for children under 3
Type I (Immediate) HypersensitivityDoctors sometimes use skin tests to diagnose allergies.
Type I (Immediate) HypersensitivityThe reactions shown here demonstrate allergic response.
Type I (Immediate) Hypersensitivity • In-Vitro Tests • Measure total IgE or antigen-specific IgE • Less sensitive than skin tests. • RIST, RAST, Allergen specific and Microarray will be covered later.
Type II (Cytotoxic) Hypersensitivity • Triggered by antigens found on cell surfaces • Altered self antigens • Heteroantigens • Manifested by the production of IgG or IgM antibodies which coat the antigens. • Mechanisms • Antibody coats cell surface promotes phagocytosis – macrophages, neutrophils and eosinophils have Fc receptors to bind to antibody on target cell. • Natural Kill cells have Fc receptors, bind, results in cytotoxicity • Complement • Coats cells which enhances phagocytosis • Complement cascade goes to completion results in cell lysis.
Type II (Cytotoxic) Hypersensitivity • Transfusion reactions • Hundreds of different antigens expressed on RBCs • Antibodies can be produced naturally or through exposure, transfusion or pregnancy most common • Most well known example due to ABO incompatibility. • Individuals form potent antibodies against ABO antigens not present on their red blood cells. • Group O individuals have anti-A and if transfused with group A blood will have an immediate, and possibly fatal, reaction • Other blood groups may cause delayed reaction or acute reactions.
Type II (Cytotoxic) Hypersensitivity • Hemolytic disease of the fetus and newborn • Mother exposed to blood group antigens due to previous pregnancy with antigen positive child or transfusion. • Antibody must be IgG • Crosses placenta and coats fetal RBCs, destruction of RBCs causes increased bilirubin and anemia. • If first pregnancy is first exposure infant usually not affected. • Subsequent pregnancies have increased risk and the disease ranges from mild to fatal. • All pregnant women are screened for blood group antibodies.
Type II (Cytotoxic) Hypersensitivity • Autoimmune hemolytic anemia • Patients form antibodies to antigens on their on RBCs. • Warm antibodies react at 37C • Cold antibodies react best in-vitro at 4C and will dissociate at 37C • This will be discussed in detail during Immunohematology. • Drug induced hemolysis • Some drugs may act as haptens, attach to the RBC membrane causing antibodies to be formed. • Antibody reacts with drug on RBC causing hemolysis.
Type II (Cytotoxic) Hypersensitivity • Tests • Coomb’s or anti-human globulin test. • Direct Coomb’s • Add anti-IgG to washed drop of RBCs • If cells are coated with IgG then agglutination will occur. • Indirect Coomb’s • Incubate patient serum with RBCs of known antigenic make up. • Wash and add anti-IgG • If patient has antibody against antigen on RBC agglutination will occur.
Type II (Cytotoxic) Hypersensitivity • Some individuals make antibody which cross reacts with self antigens found in both the lung and kidney. • Goodpasturesyndrome most well known example • Antibody produced against basement membrane protein. • This protein present in lungs and kidneys. • Antibody binding results in inflammation • Symptoms are hemoptysisand hematuria. • Others will be discussed later • Hashimoto’s disease • Myasthenia Gravis • Diabetes mellitus
Type III (immune complex mediated) Hypersensitivity • Similar to Type II, IgG or IgM involved and destruction is complement mediated. • Difference is that antigen is SOLUBLE. • Soluble antigen and antibody combine to form complexes. • Usually complexes cause no symptoms, quickly disappear from the circulation. • Size of complexes produced seems important in determining whether they will be eliminated quickly from the body or retained long enough to cause damage. • In some individuals the immune complexes persist in circulation causing clinical symptoms, some of them serious.
Type III (immune complex mediated) Hypersensitivity • Mechanism • Soluble immune complexes which contain a greater proportion of antigen than antibody penetrate blood vessels and lodge on the basement membrane • At the basement membrane site, these complexes activate the complement cascade. • During complement activation, certain products of the cascade are produced,`attract neutrophils to the area. Such substances are known as chemotactic substances. • Once the polymorphs reach the basement membrane they release their granules, which contain lysosomal enzymes which are damaging to the blood vessel. • This total process leads to the condition recognized histologically as vasculitis.
Type III (immune complex mediated) Hypersensitivity • Tissues most frequently affected are: • Glomerular basement • Vascular endothelium • Joint linings • Pulmonary alveolar membranes • Classical clinical symptoms of immune complex disease are due to blood vessel involvement, i.e., vasculitis. • Blood vessels of joints and the kidney are most frequently affected, giving rise to symptoms of arthritis and glomerulonephritis.
Type III (immune complex mediated) Hypersensitivity • Arthus Reaction • Immunized rabbits to antigen • Rabbits then injected intradermally with antigen • Localized inflammatory reaction occurred followed by hemorrhagic necrotic lesion. • Occurred due to immune complexes depositing in dermal blood vessels. • Complement, neutrophils and platelets caused toxic affects. • Rare in humans. • Serum Sickness • Due to passive immunization with animal serum, bovine or horse. • Vaccines and bee stings may also trigger. • Symptoms appear 7 – 21 days after exposure to animal serum. • Headache, fever, nausea, vomiting, joint pain, rashes and lymphadenopathy. • Symptoms due to antibody being formed at same time antigen is present = immune complexes form. • Benign, self limiting, 7-30 days for recovery.
Type III (immune complex mediated) Hypersensitivity • Chronic immune complex diseases are naturally occurring diseases caused by deposits of immune complex and complement in the tissues. • Systemic Lupus Erythematosus (SLE) • Acute glomerulonephritis • Rheumatic fever • Rheumatoid arthritis
Type IV (delayed) Hypersensitivity • Used to describe the signs and symptoms associated with a cell mediated immune response. • Results from reactions involving T lymphocytes. • Characteristics of this phenomenon are: • Delayed, taking 12 hours to develop. • Causes accumulation of lymphs and macrophages. • Reaction is not mediated by histamine. • Antibodies are not involved in the reaction.
Type IV (delayed) Hypersensitivity • Most well known is the Koch Phenomenon • Inject tuberculoprotein (PPD test) intradermally • Reaction results in an area of induration of 5 mm or more in diameter and surrounded by erythema • Reaction which occurs within 48 hours is a positive.
Type IV (delayed) Hypersensitivity • Contact dermatitis due to contact with chemicals • Poison ivy, oak and sumac give off urushiol. • Nickel, rubber, formaldehyde, hair dyes, comsetics • Latex allergies • Function as haptens • Causes erythema, swelling and formation of papules • Hypersensitivity Pneumonitis • Response of sensitized T cells to inhaled allergens. • Caused by chronic inhalation of microorganisms. • Occupationally related – pigeons, farmers
References • http://www.thebody.com/nih/immune_system.html • http://pathmicro.med.sc.edu/ghaffar/hyper00.htm • http://home.kku.ac.th/acamed/kanchana/bsi.html
