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HYPERSENSITIVITY HYPERSENSITIVITY undesirable (damaging, discomfort producing and sometimes fatal) reaction produced by the normal immune system • hypersensitivity reactions require a pre-sensitized (immune) state of the host HYPERSENSITIVITY Hypersensitivity reactions can be divided into four types according to Gell and Coombs: • type I, • type II, • type III • type IV, based on: • time taken for the reaction • type of antygen • the mechanisms involved • clinical symptoms Frequently, a particular clinical condition (disease) may involve more than one type of reaction. TYPE I HYPERSENSITIVITY TYPE I HYPERSENSITIVITY known also as immediate or anaphylactic hypersensitivity 15-30 minutes from the time of exposure, although sometimes may have a delayed onset (10 - 12 h) symptoms depends on the place of antigen entrance and reaction appearance - weal & flare histology - basophils and eosinophils TYPE I HYPERSENSITIVITY ANTIGEN: is soluble exogenous e.g: Drugs (antibiotics) Foods (nuts, shellfish) Insect venoms pollens Antigens enter body by: Injection Ingestion Inhalation Absorption Induces antibody formation Anaphylaxis Pathophysiology IMMUNOGLOBULIN – IgE very high affinity for its receptor on mast cells and basophils = is homocytotropic IMMUNE CELLs Mast cells In all subcutaneous/submucosal tissues, Including conjunctiva, upper/lower respiratory tracts, and gut Basophils Circulate in blood mechanisms: Subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances degranulation is preceded by increased Ca++ influx. The reaction is amplified and/or modified by: platelets, neutrophils -which release various hydrolytic enzymes that cause necrosis eosinophils -may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E TYPE I HYPERSENSITIVITY IMMUNE ANTIGEN MECHANISM antigen reenters body soluble attach to IgE on the surface of mast or basophil cells cross links the cell- EFFECT bound IgE IMMUNO vasodilation mast cell GLOBULINE degranulation - increased capillary permeability IgE releases: Histamine, smooth muscle homocytotropic binded with Leukotrienes, spasm basophiles, SRS-A, ECF, mast cells and others skin- reaction- weal & flare TYPE I HYPERSENSITIVITY Induction and effector mechanisms Antigen enters body Antibodies produced Attach to surface of mast or basophil cells Mast cells become sensitized Second or subsequent contact with the allergen Anaphylaxis Attaches to antibodies on mast or basophil cells Mast cell degranulates, releases Histamine Leukotrienes Slow reacting substance of anaphylaxis (SRS-A) Eosinophil chemotactic factor (ECF) clinical effects TYPE I HYPERSENSITIVITY Pharmacologic Mediators Preformed mediators in Newly formed mediators granules • leukotriene B4 • Histamine • basophil attractant • vasodilatation, • bronchoconstriction, • leukotriene C4, D4 • vascular permeability, mucus • same as histamine but 1000x secretion, more potent • Tryptase • prostaglandins D2 • proteolysis • edema • pain • Kininogenase • PAF • kinins • platelet aggregation • vasodilatation, • heparin release • vascular permeability, edema • microthrombi • ECF-A(tetrapeptides) • attract eosinophil and neutrophils TYPE I HYPERSENSITIVITY biological effects Vasodilation Increased Capillary Permeability Smooth Muscle Spasm TYPE I HYPERSENSITIVITY biological effects VASODILATION Decreased peripheral vascular resistance Hypotension Tachycardia Peripheral hypoperfusion TYPE I HYPERSENSITIVITY biological effects Increased Capillary Permeability Tissue edema, urticaria (hives), itching Laryngeal edema Airway obstruction Respiratory distress Stridor (Awhistling sound when breathing) Fluid leakage from vascular space Hypovolemic shock (shock caused by severe blood or fluid loss) TYPE I HYPERSENSITIVITY biological effects Smooth Muscle Spasm GI Tract Spasm Nausea, vomiting Cramping, diarrhea Bronchospasm Respiratory distress “Tight Chest” Wheezing Bladder Spasm Urinary urgency Urinary incontinence TYPE I HYPERSENSITIVITY CLINICAL MANIFESTATIONS: depends on place of antigen entrance and reaction skin -urticaria and eczema eyes -conjunctivitis,Hay fever nasopharynx -allergic rhinorrhea (persistent watery mucus discharge from the nose), gastrointestinal tract -gastroenteritis blood -anaphylactic shock bronchopulmonary -asthma may cause a range of symptoms from minor inconvenience to death Urticaria Anaphylaxis Systemic reaction of multiple organ systems to antigen-induced IgE-mediated immunulogic mediator release in previously sensitized individual limited or global Results in an acute allergic reaction with shortness of breath, rash, wheezing, hypotension. Atopy anaphlilatcic reactions of organisms with genetic predidpositions There appears to be a genetic predisposition for atopic diseases: high levels of IgE are produced there is evidence for HLA (A2) association Anaphylactoid reaction Mast cells may be triggered by other stimuli such as: exercise, emotional stress, chemicals (e.g., photographic developing medium, calcium ionophores, codeine, etc.), anaphylotoxins (e.g., C4a, C3a, C5a, etc.) these reactions, mediated by agents without IgE- allergen interaction, are not hypersensitivity reactions although they produce the same symptoms TYPE I HYPERSENSITIVITY DIAGNOSTIC tests: skin tests prick and intradermal BUT also in dermographism, (common types of urticaria in which the skin becomes raised and inflamed when stroked, scratched, rubbed, and sometimes even slapped), is NOT anaphylactoid reaction IgE level total IgE : - RIST, PRIST specific IgE antibodies against the suspected allergens –RAST, FAST, BUT increased IgE levels may be elevated in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.). eosinophiles in blood smear in nasal smear, BAL BUT increased eosinophiles amount may be elevated in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.). histamin, tryptase, leucotrienes level - only in researches - ELISA Macrophages Eosinophils BAL SMEAR BAL SMEAR OF ASTHMA PERSON OF HEALTHY PERSON Eosinophils BLOOD SMEAR BLOOD SMEAR OF HEALTHY PERSON OF ASTHMA PERSON EOSINOPHILIA Prick test In the prick test, a few drops of the purified allergen are gently pricked on to the skin surface, usually the forearm. This test is usually done in order to identify allergies to pet dander, dust, pollen, foods or dust mites. Intradermal injections are done by injecting a small amount of allergen just beneath the skin surface. The test is done to assess allergies to drugs like penicillin or bee venom. To ensure that the skin is reacting in the way it is supposed to, all skin allergy tests are also performed with proven allergens like histamine or glycerin. The majority of people do react to histamine and do not react to glycerin. If the skin does not react appropriately to these allergens then it most likely will not react to the other allergens. These results are interpreted as falsely negative. Skin „Prick test” Interpretation of results The injection site is measured to look for the growth of wheal, a small swelling of the skin after 10 minutes. • + – wheal diameter 2 mm - 5 mm • ++ – wheal diameter 5 mm - 1 cm with flare reaction • +++ – wheal with a severe flare reaction and characteristic „pseudopodia” RAST - Radioallergosorbent Test is a blood test, which detect specific IgE antibodies to suspected or known allergens. If the serum contains antibodies to the allergen, those antibodies will bind to the allergen. Radiolabeled anti-human IgE antibody is added where it binds to those IgE antibodies already bound to the insoluble material. The unbound anti-human IgE antibodies are washed away. The amount of radioactivity is proportional to the serum IgE for the allergen. The RAST is scored on a scale from 0 to 6: RAST rating IgE level (IU/ml) comment ABSENT OR UNDETECTABLE 0 < 0.35 ALLERGEN SPECIFIC IgE LOW LEVEL OF ALLERGEN 1 0.35 – 0.69 SPECIFIC IgE MODERATE LEVEL OF ALLERGEN 2 0.70 – 3.49 SPECIFIC IgE HIGH LEVEL OF ALLERGEN 3 3.50 – 17.49 SPECIFIC IgE VERY HIGH LEVEL OF ALLERGEN 4 17.50 – 49.99 SPECIFIC IgE VERY HIGH LEVEL OF ALLERGEN 5 50.00 – 100.00 SPECIFIC IgE EXTREMELY HIGH LEVEL OF 6 > 100.00 ALLERGEN SPECIFIC IgE RIST - Radioimmunosorbent Test a radioimmunoassay technique for measuring total level of IgE immunoglobulins in serum, using radiolabeled IgE and anti-IgE bound to an insoluble matrix. Provocation tests: Nasal provocation test Bronchial provocation test Oral provocation test Bronchial provocation test used to detect asymptomatic allergic asthma. Testing involves exposing the patient to an allergen e.g., histamine by inhalation and then using a spirometer to measure corresponding lung function changes. Nasal provocation test Nasal provocation test is a diagnostic method involving the application of the alergen solution on the nasal cavity mucose to observe the changes in upper respiratory track. A positive nasal reaction is defined as the appearance of clinical symptoms such as rhinorrhoea, sneezing and nasal congestion combined with significant decreases in some parameters of rhinomanometry, acoustic rhinometry and/or peak inspiratory flows. Oral provocation test for oral food or drug allergy test, you ingest a food or drug in a capsule or in its natural form, and a physician observes you for the development of typical allergic symptoms. Food allergies can usually
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