Allergic disorders Downloaded from: StudentConsult (on 18 July 2006 11:40 AM) © 2005 Elsevier Type-I Hypersensitivity Basic terms • Type-I = Early= IgE-mediated = Atopic = Anaphylactic type of hypersensitivity • Atopy = genetic predisposition to type-I hypersensitivity diseases. It is a genetic predisposition to react by IgE production to various stimuli. Frequency of atopic diseases • 20-30% of general population is estimated to be atopic. • Prevalence of bronchial asthma: – General population 5-6% – Children: 10% • Every year 100 people die in Europe of anapylactic shock due to wasp/bee sting. Genetic aspects of atopy • Probability of atopy in a child : – Both parents atopics: 80%, – One parent atopic: 50%, – No parent is atopic: 15%. • Concordance of asthma in monozygotic twins: only 50-70% Candidate genes of atopic diseases • 5q31-33 : cytokines and their receptors: IL-4, IL-5, IL-9, IL-13 • 11q13: high affinity receptor for IgE • 6p: HLA genes. TNF-a • 1q, 4q,7q31, 12q14.3-q24.31, 14q11.2-g13, 16p21, 17q, 19q Common allergens • Pollens (grass, trees) • House dust mites (Dermatophagoides pteronyssimus and farinae) • Foods: nuts, chocolate, shellfish, milk, egg, fruits • Pets (cat, dog) • Moulds Type-I hypersensitivity two phases of the disease Sensitisation - formation of specific IgE, it binds to mast cells Clinical manifestaton of allergy http://pathmicro.med.sc.edu/mayer/IgStruct2000.htm Very low leves in serum (mg/l, normally expressed in IU/ml), short half life in serum (2 days). But long half life if bound to FceR of mast cells. Serum IgE levels in atopic dirseses Regulation of IgE production • Positive regulation: IL-4 a IL-13 – products of Th2 cells • Negative regulation: IFNg - product of Th1 cells Mast cells Ways of Activation of Mast Cells Antigen (alergen) Degranulation Neuropeptides (ie, substance P) Stem cell faktor Complement fragments (C3a, C5a) Cytokines (eg, IL4, IL6) Chemokines (RANTES) MIP 1α Bacterial peptides Various histaminoliberators in food, drugs.. FceR Biological effects of histamin • H1: Smooth muscle contraction, increased permeability of capillaries, vasodilatation, increased production of nasal and bronchial secretions, chemotaxis of leukocytes • H2: increase of gastric juice production, increased production of secretions in respiratory tract • H3: receptors present in CNS Consequences of Mast Cell Activation Release of granules Activated phospholipase A2 Release of histamine, proteolytic enzymes, heparin, chemotactic factors Preformed mediators Arachidonic acid Cyclo-oxygenase pathway Lypoxygenase pathway Prostaglandis Leukotrienes Newly-synthesized mediators Antigen (alergen) Phospholipase A2 Downloaded from: StudentConsult (on 18 July 2006 11:40 AM) © 2005 Elsevier Consequences of activation of mast cells Immediate and late phase of allergic reaction Phases of type-I hypersensitivity reaction • Immediate phase – clinical symptons evolve in a few minutes. Mediated mainly by histamin. • Late phase – symptoms evolve after hours (6-8). Mediated mainly by leukotriens. Presence of eosinophils plays an important role in allergic inflammation. Eosinophil granulocytes • Type-I hypersensitivity is usually accompanied by the eosinophilic inflammation. • Eosinophils produce several highly toxic mediators: incl. major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDNT), eosinophil peroxidase (EPO). • These proteins are toxic for many cells, including epitelial cells. Eozinophil granulocyte Downloaded from: StudentConsult (on 4 August 2013 10:32 AM) © 2005 Elsevier Physiological role of IgE-Mastocyte-Eosinophil system Clinical diseases caused by atopic hypersensitivity • Allergic conjunctivitis • Allergic rhinitis • Bronchial asthma • Allgergy of gastrointestinal tract • Urticaria and angioedema • Atopic eczema • Anaphylactic shock Allergic conjunctivitis Allergic rhinitis Bronchial asthma currently defined as chronic eosinophilic inflammation of bronchi Urticaria Angioedema Atopic eczema Atopic eczema Atopic eczema Treatment of allergic diseases • Allergen avoidance • Antihistaminics • Topical or systemic corticosteroids • Antilekotriens • Cromons (cromolyn sodium, nedocromil) stabilise membrane of the mast cells • In asthma: b-2 agonists, xantins • Allergen immunotherapy (desensitisation) Diagnostic approaches in type-I hypersensitivity • Done by any doctor: • Past history • Eosinophilia • Done by specialists, usully by allergists • Skin tests • Laboratory tests for specific IgE • Provocation and elimination tests Intradermal allergy test Skin prick tests Skin prick test • Water solution of the antigen is dropped on the skin ( usually forearm). • Using a lancet, a prick (in the place of the drop) into the epidermis is made – it transfers the allergen into the epidermis. • The allergen triggers local IgE mediated allergic reaction. • The results are read after 15 minutes. • Positive reaction is a red weal ( usually more than 4 mm in diameter). Anaphyctic shock • A severe and sometimes life-threatening immune system reaction to an allergen (or other stimuli). • Systemic effect of released histamin plays a crucial pathogenic role. • Gemeralized vasodilation and increased capillary permeability leads to hypotension and compensatory tachycardia. • Other organ (skin, respiratory, GIT tract..) symptoms are frequently present. If these symptoms are present without circulation collapse we speak about anaphylactic reaction. Causes of anaphylactic shock • Drugs - penicillins, cephalosporins, proteolytic enzymes, local anestetics • Food - nuts, seafood, chocolate • Allergen desensitisation, allergen skin tests • Bee or wasp sting • X-ray contrast media Clinical symptoms of anaphylactic shock • Hypotension (systolic pressure 90 mm Hg or less) • Tachykardia • Dyspnea • Abdominal pain, nausea • Anxiety • Urticaria on the skin, sweating, itching • Contractions of the uterus Treatment of anaphylactic shock • Adrenalin intramusculary or intravenously (in monitored patients) • Antihistaminics intravenously • Syntophyllin or inhalation of b-2-mimetics • Corticosteroids intravenously • Oxygen • Vasopressor agents (dopamin or noradrenalin)