Informations on exams

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1 Informations on exams II year BMC: English or Italian (free choice) I year MBC: Mandatory English EXAM vote: 1.Journal Club presentation 2. Open written exam 1.1 argument free ( ) 2.1 argument chosen at the exam

2 ALLERGY: AN OVERVIEW

3 Contents Allergy Hypersensitivity Allergy: IgE Mediated: Type I Immunopathogenesis Performed Mediators Food Hypersensitivity Laboratory Tests Prevention Treatment

4 Allergy Type of hypersensitivity reactions of the immune system. Allergy may involve more than one type of reaction. An allergy is a 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. Mechanisms of tissue injury are the same as the effector mechanisms of defense against infectious pathogens The problem is that these reactions are poorly controlled

5 Allergy Risk factor Host factors; heredity, gender, race, and age HLA and non-hla genes Environmental factor; infectious diseases during early childhood, environmental pollution, allergen levels and dietary changes.

6 Hypersensitivity Hypersensitivity (hypersensitivity reaction) refers to undesirable immune reactions produced by the normal immune system. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. Hypersensitivity reactions: four types; based on the mechanisms involved and time taken for the reaction, a particular clinical condition (disease) may involve more than one type of reaction.

7 Classification of Immunologic Reactions (Gell and Coombs)

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9 Hypersensitivity Reactions

10 Allergy Allergy Ig E mediated (Type I hypersensitivity) Non Ig E mediated

11 IgE Mediated: Type I Overreaction to an allergen that is contacted through skin, inhaled through lung, swallowed or injected. Individuals must be previously sensitized Triggered by harmless substances such as; pollen, dust, animal danders, food, can also occur as a result of drug or bee stings or stings from other insects (an allergen). An allergen; an antigen that causes allergy. Either inhaled, ingested,.. Can be complete protein antigens (Pollen and animal dander) or low molecular weight proteins.

12 Atopy Atopy is the genetic predisposition to make IgE antibodies in response to allergen exposure. Etiology is unknown but there is strong evidence for a complex of genes with a variable degree of expression encoding protein factors. Allergic rhinitis, allergic athma, atopic dermatitis are the most common manifestation of atopy. Allergic gastroenteropathy is rara. These manifestation may coexist in the same patients at different times. Atopy can be asymptomatic.

13 Genes Identified to date in Atopy

14 Common allergens associated with type I hypersenstivity Proteins Foreign serum Vaccines Plant pollens Rye grass Ragweed Timothy grass Birch trees Drugs Penicillin Sulfonamides Local anethetics Salicylates Foods Nuts Seafood Eggs Peas, beans Milk Insect products Bee venom Wasp venom Ant venom Cockroach calyx Dust mites Mold spores Animal hair and dander

15 Mechanism While first-time exposure may only produce a mild reaction, repeated exposures may lead to more serious reactions. Once a person is sensitized (has had a previous sensitivity reaction), even a very limited exposure to a very small amount of allergen can trigger a severe reaction. Most occur within seconds or minutes after exposure to the allergen, but some can occur after several hours, particularly if the allergen causes a reaction after it is partially digested. In very rare cases, reactions develop after 24 hours.

16 Immunopathogenesis Both mast cells and basophils are involved in immunopathogenesis of IgE mediated diseases. Mast cells and basophils have a high affinity IgE cell membrane receptors for IgE. Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these antibodies

17 Phases of immediate hypersensitivity reactions Phases of immediate hypersensitivity reactions. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later. The immediate reaction (B) is characterized by vasodilation, congestion, and edema, and the late-phase reaction (C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells.

18 Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production in genetically susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity

19 Mast Cell Mast cell are abundant in the mucosa of the respiratory, gastrointestinal tracts and in the skin, where atopic reaction localize. Mast cell release mediator cause the pathophysiology of the immediate and late phases of atopic diseases.

20 Mast Cell Activation

21 Mast cell Minutes Classic Allergic Reaction Flushing Hypotension Increased mucus production Pruritus Smooth muscle contraction Vascular leakage Hours Late phase Reaction Eosinophil infiltration Neutrophil infiltration Fibrin deposition Mononuclear infiltration Tissue destruction

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23 Fc Receptor structure

24 Signal transduction pathway mediated by Antigen binding to IgE

25 Performed Mediators/ Primary Mediators Histamine: is one well-known mediator. This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vascular permeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Serotonin: increased vascular permeability and contraction of smooth Muscles. Tryptase: is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: include heparin and chondroitin sulfate. Chemotactic factors.

26 Performed Mediators/ Secondary Mediators Platelet activating factor Leukotriens Prostaglandinin Bardykainin Cytokines IL1,TNF IL2,IL3,IL4,IL5,L6

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28 Important Clinical Aspects of Immediate Hypersensitivity Main organ Disease Main symptoms Lung Asthma Wheezing, dyspnea, tachypnea Nose and Eyes Skin Intestinal tract Rhinitis, conjunctivitis Hay fever Eczema (atopic dermatitis) Urticaria Allergic gastroenteropathy Runny nose, redness and itching of eyes Pruritic, vesicular lesions Pruritic, bullous lesions Vomiting diarrhea Systemic Anaphylaxis Shock, hypotension, wheezing Typical allergens Pollens, house dust, animal danders Pollens Uncertain Various foods Drugs Various food Insect venom;bee Drugs; penicillin Foods; Peanuts Route of entery Inhalation Contact with mucous membrane Uncertain Ingestion Various Ingestion Sting Various Ingestion

29 Type II Hypersensitivity

30 Type II Hypersensitivity

31 Type II Hypersensitivity

32 Food Hypersensitivity Source:

33 Food Hypersensitivity Source:

34 Immunopathologic Response Classification System Proposed by Sell et al., 1996 Immunopathologic responses into the following 7 categories: Inactivation/activation antibody reactions Cytotoxic or cytolytic antibody reactions Immune-complex reactions Allergic reactions T-cell cytotoxic reactions Delayed hypersensitivity reactions Granulomatous reactions This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity reactions. For example, T cells play an important role in the pathophysiology of allergic reactions. In addition, the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the chronic allergic inflammation that often occurs with these types of reaction. References & more: References: Sell S, Rich RR, Fleisher TA, et al, eds. Clinical Immunology: Principles and Practice. ed. St. Louis, Mo: Mosby-Year Book; 1996:449-77

35 Allergic Hypersensitivity: Non IgE Mediated Hypersensitivity pneumonitis involves inhalation of an antigen. This leads to an exaggerated immune response (hypersensitivity). Type III hypersensitivity and type IV hypersensitivity occur in hypersensitivity pneumonitis. Allergic contact dermatitis.

36 Comparison of Allergy with other Responses Result Antigen source Mechanism Disease Disease Foreign Immunologic Allergy Prophylaxis Foreign Immunologic Immunity Disease Self Immunologic Autoimmunity Disease Foreign Toxic Toxicity

37 Type IV Hypersensitivity Mechanisms of T cell mediated (type IV) hypersensitivity reactions. A, CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ TH17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). B, In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells. APC, Antigenpresenting cell.

38 Laboratory Diagnosis IgE-Mediated Allergies Skin Tests Blood Tests

39 Skin Tests The cutaneous test (prick test, puncture test epicutaneous test) Routine diagnosis in diseases (atopic or anaphylactic). A single drop of concentrated aqueous allergen extract placed on the skin which is then pricked lightly with a needle point at the center of the drop. After 20 minutes the reaction is graded and recorded

40 Laboratory Tests IgE levels may be elevated in patients who are atopic, but the level does not necessarily correlate with clinical symptoms. The tryptase level can be elevated, which is indicative of mast cell degranulation. False-negative results can occur. An elevated eosinophil count may be observed in patients with atopic disease. RAST/CAP RAST/CAP FEIA (fluorenzymeimmunoassay): measures antigen-specific IgE.

41 Nasal smear/ Spirometry Nasal smear Elevated eosinophil levels can be consistent with allergic rhinitis. Spirometry or pulmonary function tests offer an objective means of assessingasthma. Peakflow meters can also be used for this and can be used by patients at home to monitor their status

42 Standardized diagnostic allergens are not available for drugs Penicillin is the only drug for which a standardized diagnostic allergen exists. While nonstandardized skin tests can be performed for the minor determinants in penicillin or for other drugs (ie, by pricking the skin where drug solution has been placed), these tests are only useful if findings are positive.

43 Prevention Avoid triggers such as foods and medications, that have caused an allergic reaction, even a mild one. This includes detailed questioning about ingredients when eating away from home. Ingredient labels should also be carefully examined. A medical ID tag should be worn by people who know that they have serious allergic reaction. If any history of a serious allergic reactions, carry emergency medications (such as diphenihydramine and injectable epinephrine. Do not use your injectable epinephrine on anyone else. They may have a condition (such as a heart problem) that could be affected by this drug.

44 Treatment Anaphylaxis: epinephrine (vasoconstriction, bronchospasm resolution), oxygen (intubation sometimes required), anti-histamine, glucocorticoids Urticaria: anti-histamine, adrenergic agonists Allergic rhinitis: anti-histamine, adrenergic agonists, glucocorticoids, Immunotherapy Asthma: Quick relief: ß-adrenergic agonists to release bronchospams Long-term control: glucocorticoids

45 Treatment

46 References &Further Reading Allergic diseases: in Medical Immunology.eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), 814 pages tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) (March 23, ISBN-13: ISBN-10: Anaphylaxis and Urticaria: in Medical Immunology.eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), 814 pages tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) (March 23, ISBN-13: ISBN-10: Adkinson NF Jr. Middleton s Allergy: Principles and Practice. 6th ed. Philadelphia, Pa: Mosby; Rakel RE. Textbook of Family Medicine. 7th ed. Philadelphia, Pa: WB Saunders; Miriam K Anand, Michael A Kaliner, et al., Advances in Immunology. N Engl. J.Med,. vol. 344, No.1. January4, Available from. Sell S, Rich RR, Fleisher TA, et al, eds. Clinical Immunology: Principles and Practice. ed. St. Louis, Mo: Mosby-Year Book; 1996:449-77

47 Image Citation SariSabban. Allergy Pathway. 1September 2011The Wolfgang Ihloff. Allergy skin testing. Mast cell. Wenliang Zhang. Universty of Geogorgia. Immunology. The immune system.. sitivitydiseases.html Dr. M. Yadav. Food Hypersensitivity.