Allergies.pdf

Allergy and Hypersensitivity Simon Powis Definitions • Allergy: originally defined as ‘an altered capacity of the body to react to a foreign substance’. Maybe a bit too broad, so now a more restricted definition is ‘disease following a response by the immune system to an otherwise innocuous antige...

Allergy and Hypersensitivity Simon Powis Definitions • Allergy: originally defined as ‘an altered capacity of the body to react to a foreign substance’. Maybe a bit too broad, so now a more restricted definition is ‘disease following a response by the immune system to an otherwise innocuous antigen’ • Allergies reside within Hypersensitivities, defined as ‘harmful immune responses that produce tissue damage’ The Four Types of Hypersensitivity Reaction Type I Type II Immune reactant IgE IgG Antigen soluble Effector mechanism Example Mast cell activation Allergy, Asthma cell or matrix Cell surface associated receptor Complement, Ab alters FcR+ cells Drugs signalling chronic urticaria Type III Immune reactant Antigen IgG soluble Type IV Th1 cells soluble Th2 cells soluble CTL cell- associated antigen Effector mechanism Example dermatitis complement, macrophage eosinophil phagocytes activation activation arthus reaction cytotoxicity contact dermatitis chronic asthma tuberculin reaction & allergic rhinitis contact • Allergy is IgE mediated, and always occurs on secondary exposure to an allergen, so an initial exposure event has always taken place. • Allergies very common in West, often between 25 and 50% of population have allergy. This fact has driven IgE research; we know more about IgE’s role in allergy than its normal pathophysiology. Serum IgE levels are normally very low Immunoglobulin Class IgG IgM Size (kDa) 150 970 160 Serum level (mg/ml) 15 1.5 3 0.03 0.0003 10 6 3 2 1/2 life (days) 21 IgA IgD IgE 185 190 Allergy occurs when IgE triggers Mast cell degranulation. Production of IgE • IgE produced by plasma B cells in lymph nodes, or locally at site of inflammation • IgE located mostly in tissue (hence low serum concentration), bound to Mast Cell surface through high affinity IgE receptor Fc!RI • Certain antigens and routes of delivery appear to favour IgE production. Transmucosal at low doses is often a common route. • CD4+ T cells of the Th2 phenotype that produce IL4 cytokines favour IgE responses • Th2 T cells also force B cells to switch the isotype of the Ig they secrete from IgM to IgE Effector T cells produce distinct molecules CD8 cytotoxic IFN", TNF# Target cell lysis CD4 Th1 IFN" GM-CSF TNF# macrophage activation CD4 Th2 IL4, IL5 B cell activation Common allergens Features of some inhaled allergens. Protein: only proteins induce T cell responses Enzymatically active: allergens are often proteases Low dose: favours IL4 producing CD4 T cells. Small size: allergens can diffuse out of particle Highly soluble: Stable: elutes readily from particle allergen can survive dessication. Enzymes as Allergens • IgE is thought to be crucial in in host defence against parasites, many of which gain access by secreting proteolytic enzymes Many allergens are enzymes. Major allergen in feces of house dust mite is Der p 1, which can cleave tight junctions between epithelial cells in airway, thus enhancing access. Der p 1 then taken up by Dendritic Cells, presented to T cells, which become Th2, and cause B cells to secrete IgE. Route of allergen delivery is crucial to symptoms • The location and distribution of the antigen is the most important factor in what symptoms occur • Inhaled antigens will affect nasal epithelium, causing allergic rhinitis, ie hay fever etc. due to seasonal pollens. Local edema, nasal discharge, often containing eosinophils • Allergen induced degranulation further down airway results in allergic asthma Allergic Asthma • Bronchial constriction • Increased secretion of fluid and mucus, trapping inhaled air • Chronic inflammation may ensue with continued presence of Th2 T cells, eosinophils, neutrophils. • Chronic asthma driven originally by specific allergen, but may then result in hyperreactive airways to other irritants such as cigarette smoke and other pollutants Asthmatic response in lungs: air expulsion capacity Skin allergy • Allergens entering at skin sites cause rashes. • Wheal and Flare, first appearing within a few minutes as a result of vasodilation after Mast Cell degranulation, localised redness • Around 8 hours later more diffuse edema at site due to influx of lymphocytes and other leukocytes, attracted by chemokines. Commonly used method for testing for allergen sensitivity Ingested allergens • Ingested allergens leads to two main symptoms • Activation of GI Mast cells results in transepithelial fluid loss and smooth muscle contraction: diarrhea and vomiting • If allergen enters bloodstream, generalised disseminated rash, Urticaria, (hives). • In severe cases of food allergy, eg nuts and shellfish, life threatening generalised anaphylaxis and cardiovascular collapse may occur Chemical mediators of allergic responses • Mast cells granules contain a wide range of inflammatory mediators • Lipids • Toxic mediators • Cytokines • enzymes Lipids • Prostaglandins, $ vascular permeability, $ body temperature. Platelet activating Factor, $ adhesion between endothelium and neutrophils. Leukotrienes, attract and activate neutrophils, $ vasc permeability Toxic mediators Histamine, $ vascular permeability, and promotes movement of fluid from the vasculature by constricting vascular smooth muscle. • Heparin, inhibits coagulation Cytokines • IL-4, IL-13; amplify Th2 response • IL-3, IL-5, GM-CSF; promote eosinophil activation and production • TNF-#; pro-inflammatory, activates endothelium Chemokine MIP-1#; attracts macrophages and neutrophils Enzymes • Tryptase • Chymase • Cathepsin G • Carbopeptidase • Remodel connective tissue matrix Treatment of allergy • Two main types of treatment currently used, desensitisation, and blockade of effector pathways • Future therapies may involve recombinant allergens, hypoallergenic derivatives, T cell peptides, B cell peptides, DNA vaccines. Desensitisation and blockade • Aim to shift response from IgE dominated to IgG dominated • Patients injected with escalating doses of allergen, gradual shift from Th2 to Th1 T cells. • Potential risk of inducing anaphylaxis! • Anti-histamines, H1 receptor blocking. • Topical or systemic corticosteroids to supress chronic inflammation in asthma and rhinitis Severe anaphylaxis • Potentially life threatening reactions should be treated with epinephrine (adrenaline) injection • Affected individuals often carry selfadmin inject devices, Epi-pen or Ana-pen. • 0.15mg dose for child, 0.3mg dose for adults. Delivered in thigh. Second dose possible if no signs of improvement within 10-15 mins. Seek professional advice ASAP! • Do not inject in thumb!!! Why? Risk vs benefit? The Hygiene Hypothesis • Why are economically developed societies more prone to allergies? • Exposure to infectious diseases in childhood? Early childhood exposure to Th1 inducing pathogen (bacterial or viral) may prevent bias towards Th2 responses later. • Allergen levels? • Dietary change? • Pollution levels? Pollution • Environmental pollution, does it increase allergic asthma? • East German children exposed to high levels of air pollution had lower levels of asthma than West German children. • This does not mean air pollution is good for you, the East German children had higher levels of respiratory disease, but mostly not allergic type. Infection control of Allergy • Allergies and asthma is lower in areas with high Helminth burdens. • IgE is a key defense in Helminth expulsion. • 300 Gabonese children treated with anti-helminth drugs, followed over 30 months; increase observed in house dust mite allergy • Is immune system diverted by presence of helminth, or does helminth actively suppress allergy? • Latest data suggest that helminth infection induces a new set of T cells, regulatory T cells (Tregs) that actively suppress Th2 cells. Genetic influences on allergy • Over 35 genes now thought to influence allergy and asthma. • IL-4; promoter variants affect levels of IL-4 secretion • IL-4 receptor: variants have different signalling response • B2 -adrenergic receptor: variants increase bronchial hyperreactivity • 5-Lipoxygenase; variation in leukotriene levels. • Possibility of epigenetic influences; modifying gene behaviour by methylation, either in utero, or in childhood, may effect subsequent responses. Familial heredity? Summary • Allergic reactions result in IgE responses • Allergens usually small antigens that enter body at low doses, often mucosally. • Promotion of Th2 T cells favours IgE response • Mast cells strategically placed at mucosal surfaces. • Engagement of IgE on Mast cell results in degranulation, also basophil and eosinophil involvement. • Late phase of allergic response can involve tissue damage.