Hypersensitivity Reactions (PDF)

Hypersensitivity Teaching objectives: 1. Understand the classification of hypersensitivity reactions 2. Know the diseases associated with hypersensitivity reactions 3. Understand the mechanisms of damage in hypersensitivity reactions 4. Know the methods for diagnosing conditions due to hypersensiti...

Hypersensitivity Teaching objectives: 1. Understand the classification of hypersensitivity reactions 2. Know the diseases associated with hypersensitivity reactions 3. Understand the mechanisms of damage in hypersensitivity reactions 4. Know the methods for diagnosing conditions due to hypersensitivity Hypersensitivity Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune system and these reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. The excessive or inappropriate immune responses sometimes lead to host tissue damage resulting from prolonged or repeated antigen exposure. These reactions, called hypersensitivity reactions, cause tissue injury by the release of chemical substances that attract and activate cells and molecules resulting in inflammation. These reactions are classified into four hypersensitivity types , type I, type II, type III and type IV, depending on the mechanisms that underlie the tissue damage and time taken for the reaction.The first three types involve antigen antibody reactions (humoral), whereas the fourth is antibody-independent, involving cell-mediated immune responses only (cellular). Hypersensitivity reactions – originally divided into 2 categories: immediate and delayed belonging into 4 types of reactions-: Type I : Classical immediate hypersensitivity Type II : Cytotoxic hypersensitivity Type III : Immune-complex mediated hypersensitivity Type IV :Cell mediated or delayed hypersensitivity 1 TYPE I HYPERSENSITIVITY Commonly called allergic or immediate hypersensitivity reactions, type I responses occur within minutes to hours of antigen exposure. Some individuals develop IgE antibodies in response to relatively harmless environmental antigens or allergens. IgE molecules readily bind to (IgE receptor) on the surfaces of mast cells and basophils. Unlike other FcRs, FcɛRS bind antigen-free immunoglobulin (IgE), and the IgE-CD23 complexes function as antigen-specific cell-surface receptors. Cross linking of surface-bound IgE molecules generates intracellular signals via IgE receptor, leading to mast cell or basophil degranulation and the release of vasoactive amines (e.g., histamine) and other inflammatory mediators. Histamine and other inflammatory mediators cause (vasodilation) and increase vascular permeability, resulting in fluid accumulation in the tissues (edema). Histamine also induces bronchoconstriction. The reaction usually takes 15 – 30 minutes from the time of exposure to the antigen. Immediate hypersensitivity is mediated by IgE and the primary cellular component in this hypersensitivity is the mast cells or basophils. Figure (1)- Type I hypersensitivity reactions. These reactions result from the interaction of surface-bound IgE with antigen 2 Methods of diagnosis: 1) History taking for determining the allergen involved 2) Skin tests: Intradermal injection of battery of different allergens A wheal and flare (erythema) develop at the site of allergen to which the person is allergic 3) Determination of total serum IgE level- Radioimmunosorbent test (RIST) 4) Determination of specific IgE levels to the different allergens- Radioallergosorbent test (RAST). 3  Figure(2)-Skin test TYPE II HYPERSENSITIVITY Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement. Phagocytes and NK cells may also play a role. The lesion contains antibody, complement and neutrophils. Diagnostic tests Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence. A. Interaction of antibody with cells Cell-surface or extracellular matrix epitope binding by antibodies (usually lgM or IgG) results in a conformational change in the Fc portion of the antibody molecule.The conformational change in the Fc portion of the antibody molecule is recognized by cellular FcRs and by complement; and several immune-mediated destructive mechanisms may then come into play, targeted on the sites of antibody binding. 4 1. Antibody-dependent cell-mediated cytotoxicity (ADCC) : This is complement independent but requires the cooperation of leukocytes (Fig. 3). FcR-bearing cells (e.g., monocytes, neutrophils, eosinophils, and natural killer [NK] cells) bind to cells that have IgG or lgM antibodies bound to surface epitopes on a cell. Figure -3 Antibody dependent cell mediated cytotoxicity 2. Complement: Complement activated by IgM and IgG antibodies generates active components of the classical pathway, namely, C3b and C4b. These components are then deposited on the surfaces of antibody-coated cells or extracellular matrix to function as opsonin. Phagocytes recognize bound antibody through their FcRs and bound complement components through their complement receptors. In this manner, both complement and antibody function as opsonin to increase phagocytosis and the destruction of microorganisms (Fig. -4). 5  Figure -4- Type II hypersensitivity reactions. These reactions involve complement mediated lysis 3. Blood group antibodies: These exemplify type II hypersensitivity reactions. Hemolytic anemia may result from the binding of IgM antibodies to carbohydrate structures on erythrocytes (notably anti-A or anti-B antibodies) resulting in their phagocytosis and in the presence of complement, their rapid lysis (hemolysis) (Fig. 5). Antibodies (IgG) to certain protein molecules on erythrocytes (e.g. Rh factors) do not activate complement, erythrocytes are destroyed by phagocytosis. 6  Figure- 5- Natural" antibodies against blood group AB antigens B. Interaction of antibody with the extracellular matrix Antibodies that bind to extracellular matrix proteins (e.g. basement membrane) may activate the classical pathway of complement, generating anaphylatoxins (e.g., C5a, C4a, C3a, that recruit neutrophils and monocytes. FcR engagement with the bound antibody results in the release of reactive oxygen intermediates, resulting in inflammation and tissue injury (Fig. 6) 7  Figure-6-Antibodies against matrix proteins. C. Antibody-mediated disruption of cellular functions Sometimes antibodies bind to cell surface receptors without activating complement or binding to FcRs. This binding blocks the receptor's ability to interact with its natural ligand (Fig. 7). The antibody-receptor interaction may be stimulatory (e.g. , G raves disease) or inhibitory (e.g. , myasthenia gravis) to the receptor's signaling pathways. Figure -7-Disruption of cellular function by antibody. Autoantibodies 8 Clinical Conditions: 1) Transfusion reaction due to ABO incompatibility. 2) Rh-incompatibility (Haemolytic disease of the newborn ( 3) Autoimmune diseases e.g. SLE, autoimmune haemolytic anaemia , idiopathic thrombocytopenic purpura , myasthenia gravis, nephrotoxic nephritis, Hashimoto’s thyroiditis. Graves’s disease. Graft rejection cytotoxic reactions and drug reaction. TYPE III HYPERSENSITIVITY: Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganisms. The reaction may take 3 - 10 hours after exposure to the antigen. It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is caused by platelets and neutrophils. The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process. The affinity of antibody and size of immune complexes are important in production of disease and determining the tissue involved. Diagnostic tests Diagnosis involves examination of tissue biopsies for deposits of immunoglobulin and complement by immunofluorescence microscopy. The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. 9  Figure (8) TYPE IV HYPERSENSITIVITY Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The classical example of this hypersensitivity is tuberculin (Mantoux) reaction which peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by induration and erythema. Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, etc.) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy, chemicals, heavy metals, etc.) in which the lesions are more popular. Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T cells (CTLs) cause direct damage whereas helper T (TH1) cells secrete cytokines which activate cytotoxic T cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage. The delayed hypersensitivity lesions mainly contain monocytes and a few T cells. Major lymphokines involved in delayed 10 hypersensitivity reaction include monocyte chemotactic factor, IL-2, IFN- ɤ, TNFα, etc. Diagnostic tests Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lympho-cytotoxicity and IL- 2 production. Type IV hypersensitivity mediated by cytotoxic CD8+ T lymphocytes. DNP that penetrates the epidermis may covalently bond to self-proteins present on cell surfaces. CD8+ T cells enter the site, where they recognize and kill the hapten-modified cell and release substances that invoke an inflammatory response. 11 12 Tab-1 Comparison between types of hypersensitivity 13 Hypersensitivity Diagnosis 1. In Vitro Tests: Total IgE Testing Principles In vitro tests involve measurement of either total IgE or antigen- specific IgE. These are less sensitive than skin testing but usually are less traumatic to the patient. Total IgE testing has become more important as a screening test before a patient is referred to an allergy specialist. Total serum IgE testing is used clinically to aid in diagnosis of allergic rhinitis, asthma, or other allergic conditions that may be indicated by patient symptoms 2. Antigen-Specific IgE Testing The original commercial testing method for determining specific IgE was known as the radioallergosorbent test (RAST), introduced in 1966. Principles of the test remain the same, but newer testing methods involve the use of enzyme or fluorescent labels rather than radioactivity. Allergen-specific IgE testing is safer to perform than skin testing and is easier on some patients, especially children or apprehensive adults, and the sensitivity now approaches that of skin testing. It is especially useful in detecting allergies to common triggers such as ragweed, trees, grasses, molds, animal dander, milk, and egg albumin. 3. 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 the next 48 hours. Redness with papules or tiny blisters is considered a positive test. 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. 4. Skin testing can be performed by a skin puncture test (SPT) to assist in the identification of foods that may provoke IgE-mediated, food induced allergic reactions 5. MELISA (Memory Lymphocyte Immunostimulation Assay) is a blood test that detects type IV hypersensitivity to metals, chemicals, environmental toxins and molds. Type IV hypersensitivity reactions, particularly to nickel, are well established and may affect 20% of the population 6. The oral food challenge (OFC) remains the gold standard for the diagnosis of food allergy. During the OFC, a standard serving size of the allergen is divided into 4-7 servings and administered over 60 90 minutes, with each dose being given 15 20 minutes apart. The initial amount fed to the patient is typically a very small proportion 14 of the total serving, and each successive dose administers a larger amount of protein. At the first sign of an objective reaction, the OFC is stopped and appropriate treatment administered. 15  Clinical Cases Allergy Type of hypersensitivity reactions of the immune system. Allergy may involve more the one type of reaction.An allergy is an immune reaction to something that does not affect most other people. Substances that often cause reactions are: Pollen ,Dust mites ,Mold spores ,Pet dander ,Food ,Insect stings,, Medicines Penicillin allergy Is an abnormal reaction of your immune system to the antibiotic drug penicillin. Signs and symptoms penicillin allergy includes hives, rash and itching, Fever, Swelling, Shortness of breath, Wheezing, Runny nose, watery eyes. Severe reactions include anaphylaxis, a life-threatening condition that affects multiple body systems. 16 Causes :- Penicillin allergy occurs when your immune system becomes hypersensitive to the drug -mistakenly reacting to the drug as a harmful substance. Before the immune system can become sensitive to penicillin, you have to be exposed to the medication at least once. If and when your immune system misidentifies penicillin as a harmful substance, it develops an antibody to the drug. The next time you take the drug, these specific antibodies flag it and direct immune system attacks on the substance. Penicillins include: Amoxicillin, Ampicillin, Dicloxacillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Ticarcillin. Mechanism: - There are two mechanisms for a drug allergy to occur: IgE or non-IgE mediated. In IgE-mediated reactions, also known as Immunoglobulin E mediated reactions, drug allergens bind to IgE antibodies, which are attached to mast cells and basophils, resulting in IgE cross-linking, cell activation and release of preformed and newly formed mediators. 17  Insect bites and stings Occur when an insect is agitated and seeks to defend itself through its natural defense mechanisms, or when an insect seeks to feed off the bitten person. Some insects inject formic acid, which can cause an immediate skin reaction often resulting in redness and swelling in the injured area. Stings from fire ants, bees, wasps and hornets are usually painful, and may stimulate a dangerous allergic reaction called anaphylaxis for at-risk patients, and some wasps can also have a powerful bite along with a sting. Bites from mosquitoes and fleas are more likely to cause itching than pain. Signs and symptoms The reaction to a sting is of three types. 1-The normal reaction involves the area around the bite with redness, itchiness, and pain. 2-A large local reaction occurs when the area of swelling is greater than 5 cm. 3-Systemic reactions are when symptoms occur in areas besides that of the bites. 18  CONTACT DERMATITIS: Contact-dermatitis reactions to formaldehyde, trinitrophenol , nickel, turpentine, and active agents in various cosmetics and hair dyes, poison oak, and poison ivy are mediated by TH1 cells. Most of these substance are haptens that can complex with skin proteins. Approximately 48–72 h after the second exposure, the secreted cytokines cause macrophages to accumulate at the site. Activation of these macrophages and release of lytic enzymes result in the redness and pustule Contact dermatitis reaction Granuloma in a leprosy patient 19