Hypersensitivity Diseases PDF

Hypersensitivity diseases They are conditions in which the tissue damage is caused by immune responses. They may result from exaggerated responses against foreign antigens or from a failure of self-tolerance, in which case they are called autoimmune diseases. Classification of hypersensitivity rea...

Hypersensitivity diseases They are conditions in which the tissue damage is caused by immune responses. They may result from exaggerated responses against foreign antigens or from a failure of self-tolerance, in which case they are called autoimmune diseases. Classification of hypersensitivity reactions: Gel and Coombs consider four types of hypersensitivity reactions. Type I, II and III reactions are basically mediated by antibodies while type IV reactions are cell mediated. All types of hypersensitivity reactions have two phases: Sensitization phase: Priming of the immune system by the antigen. No symptoms in this stage Effector phase: Re-exposure to the same antigen causes a person to develop symptoms. Type I hypersensitivity reactions (IgE-mediated hypersensitivity, immediate hypersensitivity, atopic reactions): It is an immediate exaggerated immune response against harmless environmental antigens causing tissue injury. Environmental antigens that induce type I hypersensitivity reactions are called allergens. Common environmental allergens are plant pollens, drugs, dust, dust mites, animal dander and a variety of food. Most of the allergic diseases are classified as type I hypersensitivity reactions. Type I is the only type of hypersensitivity mediated by IgE antibodies, mast cells, basophils and eosinophils. Pathogenesis a- Sensitization phase APCs engulf the allergen, process and present allergen in association with MHC class II molecules to naive T helper cells. In allergic individuals, naïve T helper cells differentiate into Th2 and Tfh cells. Th2 and Tfh cells secrete IL-4, IL-5 and IL-13. The cytokine responses of these cells are often collectively called type 2 immune responses. IL-4 induces B cell growth and switching from IgM to IgE isotype. These IgE antibodies bind to the high affinity IgE receptors on the mast cells and basophils. b- Allergic phase Upon re-exposure to the same allergen, the allergen will cross-link sufficient IgE molecules to trigger mast cell to release their chemical mediators. Mast cells chemical mediators can be divided into: Preformed chemical mediators, newly synthesized lipid mediators and synthesis of cytokines, II- Newly synthesized lipid mediators Synthesis of lipid mediators is controlled by activation of the cytosolic enzyme phospholipase A2 (PLA2). This enzyme is activated by elevated cytoplasmic calcium. PLA2 hydrolyzes membrane phospholipids to generate arachidonic acid (the major substrate). Arachidonic acid is then metabolized by either the cyclooxygenase or lipoxygenase pathways, figure 3. The major mediator produced by the cyclooxygenase pathway is prostaglandins. The major derivatives by lipoxygenase are leukotrienes. Prostaglandins and leukotrienes are the most powerful known vasodilators and bronchoconstrictors. In addition, they act as chemotactic factors for eosinophils, basophils and Th2. They also stimulate mucus secretion. III- Synthesis and secretion of cytokines: such as IL-1, IL-3, IL-4, IL-5, IL-13 and TNF, figure 3. IL-4 and IL- 13 stimulate and amplify Th2 response while IL-3 and IL-5 promote eosinophils’ production and activation. Cytokines are responsible for late phase reactions (2-8 hours). Type I hypersensitivities are characterized by early and late responses Type I hypersensitivity responses are divided into an immediate early response and one or more late phase responses. The early response occurs within minutes of allergen exposure and results from sensitized mast cells degranulation with the release of histamine and other preformed mediators as well as lipid mediators, figure 4. Cytokines released from mast cells, particularly TNF- α and IL-1, increase the expression of cell adhesion molecules on endothelial cells, thus facilitating the influx of eosinophils, neutrophils, and Th2 cells. Eosinophils and neutrophils play a principal role in the late-phase reaction Methods used to diagnose type I hypersensitivity reactions 1- Skin prick test: Small amounts of potential allergens are introduced at specific skin sites. If a person is allergic to the injected allergen, local sensitized mast cells degranulate. The released histamine and other mediators produce a wheal and flare within 30 min. Disadvantage of skin test Sensitizes the allergic individual to new allergens Rarely may induce systemic anaphylactic shock. Few individuals may manifest a late-phase reaction Gives false negative reaction if patient treating with anti-histamine. 2- IgE test: To measure IgE level in patient’s serum Immunotherapy for allergy 1- Humanized monoclonal anti-IgE antibody binds to Fc portion of IgE antibody and block its binding to IgE receptor on mast cells. 2- Desensitization: Small quantities of antigen are repeatedly administered subcutaneously which induces IgG titer rising and IgE titer decline. Type II (antibody-mediated) hypersensitivity reactions Pathogenesis IgM or IgG antibodies directed against cellular or extracellular matrix antigens causing injury. IgM or IgG antibodies are specific to the tissues where those antigens are present; they are not usually systemic. Unlike type I HSRs, type 2 HSRs need not “await” re-exposure to antigen because the antigen is not eliminated during first exposure to the immune system. Type II hypersensitivity reactions are further subdivided into: cytotoxic and non-cytotoxic reactions. A- In cytotoxic reactions, antibody can activate the complement system or it can mediate cell destruction by ADCC or by opsonization, figure 9. Examples of type II hypersensitivity cytotoxic reactions without inflammation are blood transfusion reactions, drug-induced hemolytic anemia, and hemolytic anemia of newborns. Clinical case of type II HSRs without inflammation Drug-induced hemolytic anemia: Patients with drug-induced hemolytic anemia synthesize antibodies directed to drug or its metabolites bound to proteins on their own red cells. These antibodies cause RBCs hemolysis. Example of type II hypersensitivity cytotoxic reactions with inflammation is rheumatic heart disease (Abs attack proteins heart valves). B- In non-cytotoxic type II hypersensitivity reactions, binding of antibody to the antigen influences the cell function. The binding may stimulate or inhibit cell function. Examples for non-cytotoxic type II hypersensitivity reactions are Graves’ disease and myasthenia gravis