1. Define the terms: inflammation, hypersensitivity, allergy, and atopy.

Inflammation vascular and cellular reaction to a wide variety of injuries and dangerous stimuli. Many immunological disease manifest as chronic infection. Disease that are cased by abnormal response and involved more significant inflammation are called immune mediated inflammatory diseases - Highly regulated physiologic response to perceived injury (physical, chemical, biological) characterized by: -Cellular changes: vascular dilation and leakage, leukocyte infiltration local hypoxic environment, secondary tissue damage An inflammatory response begins when antibodies bound to cells or tissues activate complement. Complement activates macrophages and neutrophils. Once activated those cells relapse pro inflammatory mediators, lysosomes enzymes and reactive oxygen species, causing inflammation and leading to cell lysis. Hypersensitivity: describe abnormal or pathological immune reaction that is caused by repeated exposure to an antigen. They include autoimmune diseases in which immune response are directed against self-antigens and disease that result from uncontrolled or excessive response to foreign antigens. Antibodies bound to antigens directly bind Fc receptors of neutrophils and monocytes Autoimmunity: response of adaptive immune system to self-antigens that occurs when mechanism of self-tolerance fail. Autoimmunity is one cause of hypersensitivity Allergy: immune mediated hypersensitivity (IgE mediated) Atopy Hemolytic anemia: antibodies are directed against protein antigen on the surface of circulating RBC, Fc receptors on the surface of macrophage recognizing the bound antibody. This targets RBC for phagocytosis. As more and more RBC are destroyed the bodys supply of oxygen carrying cells becomes depleted 2. Describe the pathophysiologic mechanisms of Types II, III, IV hypersensitivity, and I. Type of hypersensitivity Pathological immune Mechanisms of tissue injury mechanisms and disease Type 1: immediate TH2, IgE, mast cells, eosinophils Mast cell derived mediators hypersensitivity (histamine, leukotrienes and prostaglandins) Cytokine mediated inflammation (eosinophils, neutrophils) Antibody mediated IgM, IgG antibodies against the Complement and Fc receptor diseases cell surface or ECM antigens. mediated recruitment and activation of neutrophils and macrophages which cause tissue damage Opsonization and phagocytosis of cells Type III: Immune Immune complexes of circulating Complement and Fc receptorcomplex mediated antigens and IgM and IgG are mediated recruitment and

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depositing in vascular basement membrane so that macrophages can phagocytose that macrophages can phagocytose

Type IV: Delayed Type Tcell mediated Diseases:

CD4 T cells (cytokine mediated inflammation) CD8 CTLs (T cell mediated cytolysis) In different T cellmediated diseases, tissue injury is caused by inflammation induced by cytokines that are produced mainly by CD4 + T cells or by killing of host cells by CD8 + CTL **IgG opsonization of antigens for phagocytosis by macrophages and neutrophils bind to neutrophil and macrophage Fc receptors and activate these leukocytes **IgE: mass cell degranulation can bind to Fc receptors on mast cells

activation of leukocytes Activated cells try to phagocytose immune complex leading to a release of pro inflammatory substances 1. Macrophage activation, cytokine mediated inflammation 2. Direct target cell lysis, cytokine mediated inflammation

2. Describe the cellular mechanisms of IgE-initiated hypersensitivity. . Immediate hypersensitivity - rapid IgE and mast cell mediated vascular and smooth muscle response that occurs in genetically susceptible people 1) First exposure: allergen enters body and is phagocytosed by APCs that display allergen antigens via MHC II molecules. Initial exposure to the allergen stimulates strong Th-2 response. Th-2 cells release cytokines that cause plasma cells that are producing antibodies specific for allergen (IgM) are induced to switch to IgE production. IgE antibodies are made against the allergen. 2) IgE is released and binds to Fce R1receptors on mast cells and basophils must wait for second exposure. 3) When antigen is exposed again, the antigen binds to IgE causing crosslinking of the Cv receptors. This cause cell to degranulate and release histamine and cytokines 4) allergic reaction: mediators released by mass cells include vasoactive amines, proteases, prostaglandins and cytokines to cause 2 distinct phases: a. early phase (driven by histamine, proteases, prostaglandins) occurs in minutes and causes small bC to dialer, increasing vascular permeability and stimulating contraction of SM. Proteases may cause direct damage to local tissues b. late phase (driven by cytokines) occurs 6-24 hrs after exposures where leukocyte and other inflammatory cells are recruiting to the site to promote inflammation at stie of allergen exposure . Mast cell derived TNF and IL-4 promote neutrophil and eosinophil rich inflammation. **if allergen inhaled vascular bed of lung, in stomach: vascular tissue of gut 4. Describe the differences between mast cells and basophils. Mass cells: mononuclear, tissue, metachormic granules, inflammatory mediators , FcRI Basophils: polnuclear, circulation, metachormic granules, inflammatory mediators, FcRI

5. Outline the mast cell-associated mediators of inflammation. a. Release of preformed mediators: histamine (vascular dilation, smooth muscle contraction) and proteinases (tissue damage) b. Enzymatic breakdown of arachidonic acid lipid mediators prostaglandins (vascular dilation) and leukotrienes (smooth muscle contraction) c. Generate variety of inflammatory cytokines such as TNF - through leukocyye recruitment 6. Describe eosinophil involvement in inflammatory injury. Eosinophils polymoryponuclear leukocytes with basic protein containing granule. - TH2 and IL5 directed production d activation - Granule proteins: major basic protein, eosinophil cationic protein, eosinophil divided neurotoxin - Cytokines : IL1, TNF alpha, TGF alpha and beta - Effector functions: fighting helminths infections via ADCC and fighting viral infections. Used in allergic responses and asthma pathogenesis and ca cause tissue damage 7. Define and use in the proper context the following terms: A. Immediate hypersensitivity: Type 1 response, Ag specific Igm and bCells are induced to switch to IgE production B. Late phase reaction c. Delayed hypersensitivity: activated Th1 cells secrete large amounts of interferon gamma , who recruits macrophages. D. Immediate hypersensitivity skin test: small amounts of potential allergens are introduced at specific skin sties by intradermal injection or by superficial scratching. FI person is allergic, local mast cells degranulate and the release of histamine and other mediators produces a wheal and flare within 30 min. Delayed hypersensitivity skin test: Radioallergosorbent test (RAST) measures IgE antibodies in serum by radioimmunoassay and identifies specific allergens that cause rashes, and another atopic complains. In vitro test. RAST maybe be more useful when reading skin test is difficult, when patient requires continual antihistamine therapy or when skin test are negative but clinical history suggests otherwise.

1 Immediate hypersensitivity (type I hypersensitivity) is caused by the release of mediators from mast cells triggered by antigen cross-linking of immunoglobulin E bound to IgE receptors. Antibodies specific for cell or tissue antigens can cause damage by activating complement and engaging phagocytes (type II hypersensitivity). Antibody-antigen complexes (immune complexes) deposit in blood vessels, causing

inflammation and tissue injury (type III hypersensitivity). Reactions of T lymphocytes, often against self-antigens in tissues, can cause tissue damage (type IV hypersensitivity). 2 All types of antigens may induce responses that cause hypersensitivity reactions. Environmental noninfectious antigens can induce IgE antibody responses, leading to immediate hypersensitivity. Microbial antigens and self-antigens can lead to antibody responses that form immune complexes, leading to vasculitis. Self-antigens expressed on cell surfaces can induce antibody responses that lead to complement- and phagocyte-mediated damage to the cells. Microbial antigens can also induce helper T cell responses that lead to delayed-type hypersensitivity reactions. 3 Exposure to an environmental antigen induces a T H2 response, which in turn induces IgE antibody responses to the same antigen. The IgE binds to high-affinity IgE receptors on mast cells in tissues throughout the body. On subsequent exposure to the same antigen, the mast cellbound IgE molecules bind the antigen and become crosslinked, generating signals from the associated Fc receptors that lead to mast cell granule release, enzymatic generation of leukotrienes and prostaglandins, and synthesis of cytokines. Biogenic amines such as histamine, released from the granules, and the secreted prostaglandins, cause acute vascular changes leading to increased blood vessel permeability and edema, usually within minutes of exposure to the antigen. The late-phase reaction is an inflammatory response in which blood leukocytes are recruited to the site of mast cell degranulation, caused by TNF and other cytokines secreted by the mast cells. 4 Allergic rhinitis and sinusitis are immediate hypersensitivity reactions to inhaled allergens, such as pollen proteins, leading to upper airway mucosal mast cell secretion of histamine, IL-13 production by T H2 cells, and long-lasting inflammation due to various cytokines. Food allergies are caused by ingested allergens leading to intestinal mucosal mast cell histamine release, causing increased peristalsis. Allergic bronchial asthma is caused by inhaled allergens inducing bronchial mast cell release of mediators, including leukotrienes, which cause bronchial constriction and airway obstruction. Chronic asthma involves eosinophils in the bronchial mucosa and excessive secretion of mucus in the airways, as well as bronchial smooth muscle hypertrophy and hyperactivity. Anaphylaxis is a severe systemic immediate hypersensitivity reaction characterized by shock and airway obstruction resulting from mast cell degranulation in many tissue sites, usually after exposure to an antigen that is injected or ingested. Allergic rhinitis is treated with antihistamines, bronchial asthma with corticosteroids and bronchial smooth muscle relaxants, and anaphylaxis is most effectively treated with epinephrine. Many allergic patients are treated with repeated administration of small doses of allergens, called desensitization. 5 Antibodies cause tissue injury and disease by activating cytotoxic and inflammatory effector functions, mainly complement activation and phagocyte activation via Fc receptors. Some antibodies may cause disease by binding to and interfering with the normal function of a particular protein. 6

Examples include thrombocytopenia or anemia caused by antibodies specific for platelet or red cell membrane proteins and blistering diseases such as pemphigus vulgaris, caused by antibodies against cell adhesion proteins on skin keratinocytes. In myasthenia gravis, loss of muscle function results from antibodies specific for the acetylcholine receptor. In rheumatic fever, an antibody specific for a streptococcal bacterial antigen that cross-reacts with a myocardial antigen causes cardiac inflammation. 7 Immune complexes deposit in the walls of blood vessels and cause inflammation of the vessel (vasculitis), which leads to blood clotting in the vessel lumen (thrombosis) and loss of blood supply to tissues supplied by the vessels. The site of immune complex deposition is not related to the specificity of the antibodies. Therefore, immune complex disease may simultaneously affect many different tissue sites, as occurs in systemic lupus erythematosus, arteritis syndromes associated with chronic infections, and serum sickness after therapeutic injection of antibodies from another species. Diseases caused by antibodies against cell surface or extracellular matrix proteins are usually characterized by injury and loss of function restricted to the particular organ or tissue that expresses the protein. 8 Type 1 diabetes is caused by CD4 + and CD8 + T cells that are specific for pancreatic islet cell proteins and that destroy insulin-producing cells, leading to impaired glucose metabolism and cardiovascular disease. Multiple sclerosis is caused by CD4 + T cells that are specific for central nervous system (CNS) myelin sheath proteins, leading to demyelination and CNS motor and sensory symptoms. Contact hypersensitivity (e.g., poison ivy, nickel hypersensitivity) is caused by T cells specific for skin proteins that are modified by plant toxins, metals, and other chemicals, leading to inflammation and blistering.