Genetic Predisposition to Allergies

Chapter 8 This chapter outlines the different types of immune system alterations, specifically hypersensitivity reactions and deficiencies in immunity. Hypersensitivity reactions can be categorized by the immunologic mechanism causing the disease and the source of the antigen being attacked by the immune system. There are four main types of hypersensitivity reactions: type I (IgE-mediated reactions), type II (tissue-specific reactions), type III (immune complex-mediated reactions), and type IV (cell-mediated reactions). Effects of allergens on the mucosa of the eyes, nose, and respiratory tract: Conjunctivitis (inflammation of eyelid membranes) Rhinitis (inflammation of nasal mucous membranes) Asthma (bronchial constriction) Symptoms caused by vasodilation, hypersecretion of mucus, edema, and swelling of the respiratory mucosa Genetic predisposition to allergies (atopy): Atopic individuals produce higher quantities of IgE and have more Fc receptors for IgE on their mast cells Airways and skin of atopic individuals have increased responsiveness to various stimuli Evaluation and treatment of IgE hypersensitivity: Life-threatening allergic reactions require identification of specific allergens and avoidance of contact with them Evaluation of allergies Tests include food challenges, skin tests with allergens, and laboratory tests for total IgE and allergen-specific IgE Treatment of allergies Treatment can include the use of antihistamines or other drugs that block the action of synthesized mediators involved in the type I reaction (e.g., corticosteroids, leukotriene receptor inhibitor, platelet activating receptor inhibitor) Type II hypersensitivity reactions Type II hypersensitivities involve immune reactions against a specific cell or tissue Cells express tissue-specific antigens on their surfaces Environmental antigens may bind to the plasma membranes of specific cells and trigger type II reactions There are five general mechanisms by which type II hypersensitivity reactions can affect cells Mechanisms of type II hypersensitivity reactions Complement-mediated lysis: Antibody and complement cause lysis of the target cell Clearance (phagocytosis) by macrophages: Macrophages in the tissue clear the target cells Neutrophil-mediated immune destruction: Neutrophils destroy the target cells Antibody-dependent cell-mediated cytotoxicity (ADCC): Natural killer cells induce apoptosis of target cells through the release of granzymes and perforin, or by interactions with Fas ligand and Fas receptors Modulation or blocking of receptor function: Antireceptor antibodies interfere with the normal function of receptors Example of a type II hypersensitivity reaction In myasthenia gravis, acetylcholine receptor antibodies block acetylcholine from attaching to its receptors on motor end plates, causing muscle weakness Type II hypersensitivity reactions Antibody binds to and destroys cells through complement-mediated lysis Antibodies can also cause destruction through phagocytosis by macrophages Toxic products produced by neutrophils may cause tissue damage Antibodies against specific cell surface receptors can change their function Examples include autoimmune hemolytic anemia, alloimmune reactions, and immune reactions against neoplasms Type III hypersensitivity reactions Immune complexes formed in the circulation are deposited in vessel walls or tissues Complement activation and attempted phagocytosis by neutrophils cause tissue damage Most commonly result in vasculitis in the skin, kidney, or lungs Mechanism of Type III, Immune Complex-Mediated Reactions: Immune complexes form in the blood from circulating antigen and antibody. Both small and large immune complexes are removed successfully from the circulation and do not cause tissue damage. Intermediate-sized complexes are deposited in certain target tissues where the circulation is slow or blood filtration occurs. The complexes activate the complement cascade through C1 and generate fragments like C5a and C3b. C5a chemotactically attracts neutrophils into the inflamed area, where they attach to the IgG and C3b in the immune complexes. Neutrophils unsuccessfully attempt to phagocytose the tissue, releasing degradative enzymes that destroy healthy tissues. Mechanisms of type III, immune-mediated hypersensitivity reactions: Serum sickness is a model of systemic type III hypersensitivities, caused by the formation of immune complexes in the blood and their subsequent generalized deposition in target tissues. The Arthus reaction is a model of localized or cutaneous reactions, caused by repeated local exposure to an antigen that reacts with preformed antibody and forms immune complexes in the walls of local blood vessels. Type IV: Cell-Mediated Hypersensitivity Reactions: Type IV hypersensitivity reactions are mediated by T lymphocytes and do not involve antibodies. Type IV mechanisms occur through cytotoxic T lymphocytes (Tc cells) or T-helper cells (Th cells) producing Th1 and Th17 cytokines. Tc cells directly attack and destroy cellular targets. Th1 and Th17 cytokines recruit and activate phagocytic cells, especially macrophages. Tissue destruction is caused by direct killing by Tc cells or the release of soluble factors from activated macrophages. The response is delayed, occurring 24 to 72 hours after antigen reexposure. Mechanism of Type IV, Cell-Mediated Reactions T cells differentiate into T-cytotoxic cells (Tc cells) and T-helper cells (Th1 cells) when stimulated by antigens from target cells Th1 cells produce lymphokines, especially interferon-y (IFN-y), that activate macrophages through specific receptors (e.g., IFN-y receptor [IFNyR]) Activated macrophages attach to target cells and release enzymes and reactive oxygen species, leading to tissue destruction Clinical Examples of Type IV Hypersensitivity Graft rejection Reaction on the skin test for tuberculosis Allergic reactions from skin contact with substances like poison ivy and metals Autoimmune diseases with a type IV component, such as rheumatoid arthritis and insulin-dependent diabetes mellitus