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Transcript
MICR 304 Immunology & Serology Lecture 14 Hypersensitivities Chapter 9.24, 9.25;13.1 – 13.4, 13.6 – 13.12, 13.14, 13.16 –19 Overview of Today’s Lecture • • • • Definition Classification of hypersensitivities Key players in hypersensitivities Immunopathology of hypersensitivities Definition of Hypersensitivity • Hypersensitivity reactions are immune responses to innocuous, non-infectious, environmental antigen that lead to symptomatic reactions upon re-exposure • Harmful immune responses • Hypersensitivity diseases result from repetitively occurring reactions • Antigen is in this context “allergen” Key Players in Hypersensitivities • • • • • • • • IgE Eosinophils IgG Complement Mast cells Basophils Eosinophils Phagocytes, Dendritic cells, NK cells T-cells Properties of IgE and IgG IgE IgG 180 kD, no hinge 150 kD, hinge 0.00003 14 Mast Cell Sensitization +++ - Basophil sensitization + - Binding to eosinophils*, basophils, mast cells + (+) NK-Binding - ++ Neutralization, complement activation, opsonization - +++ Placenta transport - +++ Size, structure Blood levels [mg/ml] * activated Two Types of IgE Receptors • High affinity (FceRI) – IgE is captured without antigen binding – Present on resting mast cells, basophils – Present on activated eosinophils – Cross-linking with antigen granule release • Low affinity (FceRII) – Present on many cells – B-Lymphocytes – Activated Tlymphocytes – Phagocytes – Dendritic cells – Thymic epithelial cells Production of IgE • Under primary influence of IL4, also IL13 • Antigen-dependent dendritic cells promote development of TH0 to TH2 in the absence of inflammation • Exposure of TH0 to certain cytokines will promote TH2 development – IL4, IL5, IL9, and IL13 • Mast cells and TH2 secrete IL4 • TH2 secrete IL4, IL5, IL9, and IL13 • B-cell respond to IL4 , IL13, CD40 (B-ly): CD40L (TH) – JAK signal transduction pathway – phosphorylation of STAT (signal transducer and activator of transcription) – Ig- class switch to IgE Mast Cells • Mast cells derive from bone marrow, myeloid lineage • Prominent histamine rich granules • Line body surfaces – In vascularized connective tissues just beneath epithelial surfaces • • • • Primary function is to alert to local infection High affinity IgE receptor Release granules upon receptor cross-linking Role in defense against parasites, allergy Mast Cells are Activated Upon IgE Cross-Linking Mast Cell Products • Histamine, Heparin – Toxic – Endothelial permeability increase, edema – Smooth muscle contraction • Chymase, tryptase – Tissue remodeling • Cytokines – IL4, IL13: IgE, TH2 response – TNFa: Proinflammatory – Chemokines: Recruit eosinophils, basophils • Lipid mediators – PAF: recruit leukocytes, activates neutrophils, eosinophils, platelets – Leukotriene, prostaglandins: smooth muscle cell contraction, mucus secretion, increased vascular permeability Mast Cells Amplify IgE Production Mast Cell Effects Depend on Site of Activation Anaphylaxis • Disseminated mast cell activation • Widespread increase in vasopermeability leads to catastrophic drop in blood pressure (shock) • Airway constriction causes breathing problems • Swelling of epiglottis can cause suffocation Basophils • Myeloid cell lineage • Develop under the influence of IL3, IL5, GM-CSF, TGFb – IL3 + TGFb increase basophil production and decrease eosinophil production • Polymorphonuclear • Basophil granules – Histamin Differences Between Basophils and Mast Cells Basophils • In peripheral blood (but enter tissue during inflammation) • Lobular nucleus • Tryptase +/? • Life span hours Mast Cells • In tissue around blood vessels • (skin, epithelial mucosa, in particular gut, lung) • Round nucleus • Tryptase (a serine protease) +++ • Survive months to years Eosinophils • • • • • • • • Derive from bone marrow Myeloid lineage Granules contain major basic protein (arginine rich) Predominant in connective tissue, subepithelial in respiratory, intestinal and urogenital tract Express high affinity IgE receptor after activation Can present antigen to T cells Promote TH1 apotosis Two major effector functions – Direct killing via exocytosis – Orchestrating an inflammatory response Eosinophils Secrete a Range of Highly Toxic Molecules • Tissue remodeling – Peroxidase – Collagenase – Matrix metalloprotease • Direct Killing – Toxic proteins • Major basic protein • Cationic protein • Neurotoxin – Oxidative burst • Inflammation – Cytokines • IL3, IL5, GM-CSF • CXCL-8 – Lipid mediators Anti-parasitic, activate mast cells, proinflammatory Classification of Hypersensitivities by Mechanism in Four Types Antibody • Type I (“Allergy”) – Soluble antigen: IgE: Mastcells – Immediate-type – Atopy: Exaggerated tendency to mount an IgE response • Type II – Cell associated antigen: IgG: phagocytes, NK cells • Type III Cell – Soluble antigen Antigen-Antibody complexes • Type IV – T-cell mediated Immunological Mechanisms of Hypersensitivities Type I Hypersensitivities (Allergies) Pathogenesis of Type I Hypersensitivity • Antigen is soluble • Antibody is IgE • Mast cell degranulation IgE Mediated Reactions to Allergens •Always involve mast cell mast cell degranulation •Symptomatic depends on site of entry and mast cell activation and dose Examples for Inhaled Allergens Dust mite (Dermatophagoides sp.) dust mite fecal pellet dead skin / dander pollen mineral 92608A plant debris Allergens Promote TH2 Development Can easily spread in tissue and reach subepithelial APC (primarily DC) with subsequent Th2 priming Typical for inhaled allergens Enzymatic Activity of Some Allergens Enables Easy Penetration of Epithelial Cell Barriers The cysteine protease Der p 1 is from fecal pellets of house dust mite. Protease inhibitors may be a novel therapeutic approach for allergies. Genes and Environment in Allergies • Both environmental and inherited factors are important • Environment: – Exposure to infectious agents in early childhood drives a TH1 response – Too hygienic environment with too little infectious agents drive a TH2 response • Susceptibility genes for asthma – – – – IL4, IL4 receptor High affinity IgE receptor MHC II allele TCR a locus Allergies!! Less allergies!! Allergic Reactions Can be Divided into 2 Phases Immediate within minutes •Histamine mediated •Smooth muscle cell contraction •Vascular endothelium leakage Lung Skin Late after several hours •Chemokine mediated •Inflammatory cell influx PFER: Peak expiratory flow rate Immediate and Late Phase in Acute Allergy Food Allergies • About 1 – 4 % of European and US population suffers from true food allergies • 25% of true food allergies are against peanuts – 30,000 anaphylactic reactions and 200 deaths per year in US • Food allergens have high resistance against gastric pepsin • Allergens are resorbed and activate resident mast cells • Urticaria and asthma after systemic dissemination the allergen Approaches to Treat Allergies Pathogenesis of Type II Hypersensitivity • Antigen is cell-or matrix associated • Antibody is IgG Activation of complement – Hemolysis, platelet lysis Binding through Fcg receptors – Phagocytosis Antibody itself induces cell changes Pathogenesis of Type III Hypersensitivity • Soluble antigen • Antibody is IgG • Deposition of immune complexes • Activation of complement • Inflammation – Local (Arthus reaction) – Systemic (serum sickness) Arthus Reaction: Local Type III Hypersensitivity Serum sickness: Systemic Type III Hypersensitivity Pathogenesis of Type IV Hypersensitivity • Mediated by T-cells • Soluble antigen: TH mediated – TH1 – TH2 • Cell associated antigen: CTL mediated Type IV Hypersensitivity Responses are Mediated by Antigen-specific Effector T cells Antigen injected into skin Antigen absorbed through skin Antigen absorbed through gut Injected Allergen and TH1 Mediated Type IV Hypersensitivity Cell infiltrate!! Example: Tuberculin skin test Examples for Positive Tuberculin Tests TH1 Cytokines in Type IV Hypersensitivity Response Absorbed Allergen and TH1 Mediated Type IV Hypersensitivity Example: Contact dermatitis TH2 Mediated Type IV Hypersensitivity Immediate Late Example: Chronic asthma Eosinophils!! Chronic Asthma Can Lead to Complete Airway Occlusion Mucus plug in the airways Dense inflammatory infiltrate with eosinophils, neutrophils, and lymphocytes CTL Mediated Type IV Hypersensitivity • Example: Poison ivy contact dermatitis • Lipid soluble allergen is absorbed through skin and crosses cell membranes • Allergen modifies self peptides • Presentation of modified self peptide via MHC I to CTL • Destruction of modified cell Additional Resources Accessed 5/17/2008 http://medicalimages.allrefer.com/large/epiglottis.jpg http://www.denniskunkel.com/product_info.php?products_id=9797