Allergy, Hypersensitivity, and the Lung PDF

Allergy, hypersensitivity and the lung Sympathetic regulation What type of response does the sympathetic nervous system regulate? The fight-and-flight response Which hormone is released by sympathetic nerve fibres?...

Allergy, hypersensitivity and the lung Sympathetic regulation What type of response does the sympathetic nervous system regulate? The fight-and-flight response Which hormone is released by sympathetic nerve fibres? Noradrenaline What receptors are activated by noradrenaline? adrenergic receptors What are the two types of adrenergic receptors? Alpha and beta Where are the adrenergic receptors in the respiratory system? airway smooth muscle cells have beta adrenergic receptors What effect does sympathetic stimulation of beta 2 receptors have on airway smooth muscle? Causes relaxation of smooth muscle and bronchodilation How does activation of beta 2 receptors cause muscle relaxation? by activating adenylate cyclase, raising cyclic AMP Allergy, hypersensitivity and the lung 1  Parasympathetic regulation What neurotransmitter is released by post-synaptic parasympathetic nerve fibres to regulate airway smooth muscle? Acetylcholine What is the effect of parasympathetic stimulation on airway smooth muscle? Smooth muscle constriction On which receptors does acetylcholine act to stimulate airway smooth muscle? muscarinic receptors (M1-5) of the M3 subtype on the muscle cells What is the effect of anti-muscarinics? Block parasympathetic activity by blocking for example M3 receptors What are the two types of anti-muscarinics? Allergy, hypersensitivity and the lung 2  Short acting (SAMA, e.g. ipratropium bromide) Long acting (LAMA e.g. tiotropium) Hypersensitivity types and descriptors Allergy, hypersensitivity and the lung 3  Antibodies What cells produce antibodies? B-lymphocytes (plasma cells) Role of antibodies Neutralises or eliminates pathogens What are the five types of antibodies? IgG, IgA, IgM, IgE, IgD IgG Monomer highly specific antibodies targeting single epitopes IgA Expressed in mucosal tissue. Forms dimers. Protects the neonatal gut (expressed in breast milk) Allergy, hypersensitivity and the lung 4  IgM Circulating tetrameters made at the beginning of infection IgE Likely to have developed in response to parasitic threats. Implicated in allergy, particularly alongside eosinophils IgD Monomers, induction of antibodies in B cells, activates basophils and mast cells Hypersensitivity: Type I What initiates a type I hypersensitivity reaction? Antigen interacts with IgE bound to mast cells or basophils What is the timing of a type I hypersensitivity reaction? Immediate (within 1 hour) Allergy, hypersensitivity and the lung 5  What is the whole process of Type I hypersensitivity reaction? 1. Previous exposure to antigen 2. IgE antibodies produced 3. IgE molecules bind to their receptors on mast cells/basophils 4. Upon re-exposure to antigen, antigen binds to adjacent IgE molecules 5. IgE receptors brought together and trigger signal cascade inducing release of histamine What is the predominant mediator? Histamine What are the effects of mediator degranulation in Type I hypersensitivity? Local effects such as inflammation, itching, and vasodilation. Examples of Type I reactions Type I hypersensitivity (HS) is what most people think of as “allergy.” Hay fever, eczema, hives, and asthma are all considered type I hypersensitivities. Anaphylaxis Allergies: Food (nuts, egg, milk…) Drugs (penicillin…) Pollens, pet dander Allergic bronchial asthma Allergy, hypersensitivity and the lung 6  Case 1: Type I Allergy, hypersensitivity and the lung 7  Hypersensitivity: Type II What initiates a type II hypersensitivity reaction? Previously formed antibodies reacting with antigens on the host cell membrane, marking the cell for destruction Which antibodies are usually involved? IgG or IgM Allergy, hypersensitivity and the lung 8  What does the outcome depend on? whether complement is activated and if metabolism of cell is affected Examples of Type II reactions Autoimmune diseases Haemolytic disease of the newborn What are the outcomes of complement activation? 1. Cell lysis – e.g., Myasthenia. 2. Opsonisation and phagocytosis – e.g., Autoimmune hemolysis. 3. Neutrophil activation and tissue damage – e.g., Anti-GBM (Goodpasture’s) disease. What functional activities occur in Type II hypersensitivity? Metabolic activation – e.g., Graves’ disease. Growth stimulation – e.g., Euthyroid goiter. Receptor blocking – e.g., Addison’s disease. Allergy, hypersensitivity and the lung 9  Case 2: Type II What type of hypersensitivity reaction is Anti-Glomerular Basement Membrane (aGBM) disease? Type II Which organs are primarily affected in aGBM disease? Kidneys (glomeruli) and lungs (alveoli). What syndrome occurs when aGBM disease involves the alveoli? Goodpasture syndrome. What is the composition of the glomerular basement membrane (GBM)? Type IV collagen. Allergy, hypersensitivity and the lung 10  What is the antigen causing Goodpasture syndrome? Alpha-3 subunit of type IV collagen Hypersensitivity: Type III What mediates Type III hypersensitivity? Formation of antibody-anitgen aggregates Which antibodies are mainly involved? IgG/IgM, predominantly IgG Where can immune complexes precipitate? Various tissues e.g. skin, joints, vessels, or glomeruli What pathway is triggered by the antigen-antibody aggregates? Classical complement pathway Overall aim of complement system Marks pathogens for destruction - opsonisation What does complement activation lead to? Recruitment of inflammatory cells (monocytes and neutrophils) that release lysosomal enzymes and free radicals at the site of immune complexes, causing tissue damage Allergy, hypersensitivity and the lung 11  Examples Autoimmune disease Serum sickness - complexes deposited in walls of blood vessels, triggering inflammation/vasculitis Arthus reaction Case 3: Type III; hypersensitivity pneumonitis What is hypersensitivity pneumonitis (Type III hypersensitivity)? An inflammation of the alveoli in the lungs caused by hypersensitivity to inhaled antigens, formerly called "extrinsic allergic alveolitis" (EAA). What causes hypersensitivity pneumonitis? Formation of immune complexes with various antigens, leading to airway deposition, acute inflammation, and chronic scarring. What are the forms of hypersensitivity pneumonitis? Acute, subacute, and chronic forms, which can be fibrotic or non-fibrotic. What type of immune response is involved in hypersensitivity pneumonitis? A predominantly IgG-mediated response. Name some examples of hypersensitivity pneumonitis. Farmer's Lung (from moldy hay) Allergy, hypersensitivity and the lung 12  Bird Fancier's Lung (from bird droppings) Exposure to metal working fluids What is the treatment for hypersensitivity pneumonitis? Removal of the antigen and, if necessary, immunosuppression. Allergy, hypersensitivity and the lung 13  Hypersensitivity: Type IV What mediates Type IV hypersensitivity? T-cells releasing cytokines such as IL-2 and IFN-γ. What is required for Type IV hypersensitivity to occur? Primary sensitisation to the antigen. Allergy, hypersensitivity and the lung 14  How long does it take for a secondary Type IV hypersensitivity reaction to develop? 2-3 days What is the role of cytokines in Type IV hypersensitivity? recruit and activate macrophages and other immune cells, causing localised inflammation What happens if macrophages cannot destroy a pathogen in Type IV hypersensitivity? Macrophages fuse to form giant cells and create granulomas. Examples Contact dermatitis Tuberculosis skin test Tissue rejection Allergy, hypersensitivity and the lung 15  Case 4: Type IV; sarcoidosis Possibly reaction to mycobacteria Multisystem disease, causing granuloma Eyes, skin, lungs, heart, nervous system… 80% regress spontaneously Some require systemic treatment – steroids, methotrexate, others Mantoux/Tuberculin skin testing How is the test performed? Allergy, hypersensitivity and the lung 16  Subcutaneous injection of tuberculosis protein When should the Mantoux test be interpreted? 48-72 hours after injection. What determines a positive Mantoux test? The diameter of induration (raised area) at the injection site. What does a positive Mantoux test indicate? Positive only if exposed to TB or vaccine previously Allergy, hypersensitivity and the lung 17