Hypersensitivity diseases Definition • Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. 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 50-69% 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 http://pathmicro.med.sc.edu/mayer/IgStruct2000.htm 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 Functions of Th1 and Th2 cells Mast cell Macrophage Inhibits production Th1 cell Th2 cell B cell Eosinophil 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.. 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 Downloaded from: StudentConsult (on 4 August 2013 10:32 AM) © 2005 Elsevier Physiological role of IgE-Mastocyte-Eosinophil system Immediate and late phase of allergic reaction Phases of type-I hypersensitivity reaction • Immediate phase – clinical symptons evolve in 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. Allergic reaction in bronchi 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), eosinophilderived neurotoxin (EDNT), eosinophil peroxidase (EPO) - these proteins are toxic for many cells, including epitelial cells. Eozinophil granulocyte 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 • Past history • Eosinophilia • 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). 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) Type-II hypersensitivity (cytotoxic) • Mediated by IgG or IgM. • Interaction between antigen and antibody leads to cell death, usually mediated by the complement system or phagocytosis. • The antigen may be autoantigen(so it includes antibody-mediated autoimmune diseases) or may be of external origin (components of microbes, drugs.. which attach to a cell membrane). • Includes also post-transfusion hemolytic reactions. • Also interactions between receptors and autoantibodies (leading to receptor activation or blocade are involved in this group of hypersensitivity reactions). Anti-GBP antibodies Type-III (immunocomplex) hypersenseitivity • Caused by inflammation caused by the activation of the immune system by immunocomplexes (usually deposited in inappropitate sites). • In the case of excess of antibodies, the symptoms appear after several hours anter after exposition to an antigen (approximately 6-8 hour), this type is also called late-type of hypersensitivity. Downloaded from: StudentConsult (on 18 July 2006 11:40 AM) © 2005 Elsevier Examples of antibody- mediated autoimmune diseases (type-II hypersensitivity) Diseased caused by immune complexes deposition • Caused by a disturbed transport or metabolism of immune complexes. • They usually deposit in the wall of vessels (causing vasculitis) or glomeruli (causing glomerulonephritis), less frequently in the place of their formation (extrinsic alveolitis). • The most important laboratory test is the direct immunofluorescence to detect the IgG part of the complexes. Immunocomplex diseases (type III immunopathological reaction • Caused by deposition of immune complexes in places different from their normal metabolism. • In case of circulating immune complexes (small, soluble complexes with excess of antigen), they deposit mainly in blood vessels walls and glomeruli leading to vasculitis and/or glomerulonephritis. • Less frequent is the situation when immune complexes deposit in the place of their formation (large complexes with excess of antibodies). They deposit in the place of their formation. • By activation of the complement system and phagocytioc cells they induce local inflammation. Type III hypersensitivity Serum sickness • Manifests 8-12 days after the uses of xenogenic serum. • Urticaria, fever, arthralgia, lymphadenopathy • Albuminuria • Deposits of immunocomplexes in vessels. • Self-limiting disease, in case of need steroids or antihistaminics can be used. Serum Sickness Extrinsic alveolitis • Caused by deposition if insoluble immune complexes in the lung tissue. The complexes are formed from exogenous antigen and excess of antibodies of IgG class. • 6-8 hours after exposition the patient suffers from dry cough, dyspnea, increased body temperature, lymphadenopathy. • Repeated expositions lead to lung fibrosis.. • Most frequently caused by bird antigens (pigeons – pigeon breeder´s disease, parrots), thermophil actinomycetes (farmers´s lungs disease). Patogenesis of extrinsic alveolitis Type-IV hypersensitivity • Mediated by T-lymphocytes, predominantly Th1 lymphocytes which consequently activate macrophages – also called cellular hypersensitivity • This reaction develops 1-2 days after exposure – delayed type of hypersensitivity. • Also autoimmunity caused by Tc lymphocytes is included into this group of immunopathological diseases. Downloaded from: StudentConsult (on 18 July 2006 11:40 AM) © 2005 Elsevier Mechanisms of T-cell mediated tissue injury (type-IV hypersensitivity) Function of Th1 cells Tuberculin reaction Examples of diseases where type-IV hypersensitivity plays a key role • Contact exzema • Cavitation in tuberculosis • Sarcoidosis • Several types of vasculitis • Autoimmune diseases where Tlymphocytes play a major role ( multiple sclerosis) Contact eczema (contact dermatitis) • Contact dermatitis is a red, itchy rash caused by direct contact with a substance as a type-IV allergic reaction to it. • The reaction develops several days after the exposure. • Many substances can cause such reactions, including soaps, cosmetics, perfumes, metals (incl. jewelry), plants. Contact dermatitis due to nickel hypersensitivity Allergy Capital: Contact dermatitis. Australian Allergy, Asthma and Immunology Information. http://www.allergycapital.com.au/allergycapital/Contact_dermatitis.html Contact dermatitis Skin pathch test • Is used for detection of type-IV hypersensitivity (usually in the case of contact eczema). • The antigen is included into an ointment. • The ointment with the antigen is placed on the skin and covered by an adhesive tape • After one day, the tape + the antigen are washed. • The results are read the next day. • A positive reaction is an eczema-like exanthema (red skin spots).