T1 L23. Allergy (MTz) (1).pptx

Module 204 Immunology Allergy Dr Michael D Tarzi Senior Lecturer&Honorary Consultant Immunologist Aims • This lecture will cover: – The mechanism of type I (IgE-mediated) reactions – The clinical features of type I allergic reactions – The immunology of allergic sensitisation – The immunology of...

Module 204 Immunology Allergy Dr Michael D Tarzi Senior Lecturer&Honorary Consultant Immunologist Aims • This lecture will cover: – The mechanism of type I (IgE-mediated) reactions – The clinical features of type I allergic reactions – The immunology of allergic sensitisation – The immunology of chronic allergic inflammation – The epidemiology of allergic diseases – Aetiology of allergic disease – Tests for sensitisation Learning outcomes • You should be able to: – Describe the immunology of early phase allergic reactions – Give examples of allergens – Discuss how this immunology relates to the clinical features of acute allergic reactions with examples – Explain the role of T cells in sensitisation to environmental allergens and their contribution to allergic disease – Discuss the ‘atopic march’ – Describe some factors that may be important in the development of allergic diseases – Describe the immunology of skin prick testing and serological detection of allergen-specific IgE – List various treatment options for allergic diseases • Part 1: The early phase reaction The early phase allergic reaction • In allergic individuals, exposure to allergens* leads to the rapid development of symptoms • This reaction develops within seconds or minutes of exposure and results from the binding of allergens to pre-formed IgE antibodies on the surface of mast cells and basophils *Allergen=substance to which IgE antibodies may be produced Basic mechanism of the early phase allergic reaction Mast cell FcεR1 (high affinity IgE receptor) Allergen-specific IgE antibodies Events the follow mast cell IgE ligation Mast cell Histamine • IgE binds its specific allergen • Cross-linking of IgE antibodies by allergen leads to clustering of FcεR1 receptors • The intracellular portion of the receptor becomes phosphorylated • The resulting intracellular cascade leads to cellular activation • Mast cell ‘degranulates’ releasing histamine, tryptase Delayed mediators – leukotrienes The leukotrienes produced have similar pharmacological effects to histamine Inflammation mast cell activation Membrane phospholipids Phospholipase A2 Arachidonic acid 5 Lipoxygenase Leukotrienes COX1 Prostoglandins Pharmacological effects of mast cell mediators and leukotrienes Skin Wheal and flare Nose (discharge, Sneezing etc) Eyes (conjunctivitis) Lung (wheeze) • Part 2: Allergens and allergy syndromes Examples of allergen sources Pollens House dust mite faeces Stinging insect venom • Allergens are almost always otherwise innocuous environmental proteins • Of the thousands of environmental proteins that we meet, only a few hundred are recognised as allergens General characteristics of allergens Characteristic Proteins (there are a few minor exceptions) Discussion Only protein can produce a T cell (and therefore B cell) response Physical properties that favour Need to cross mucus transition across mucus membranes to activate membranes immunity. Typically soluble and low molecular weight Biologically active, often enzymes Interesting, but ?important or coincidence Clinical allergy syndromes: anaphylaxis • Potentially life-threatening generalised allergic reaction • Systemic release of histamine: – Cutaneous: hives, angioedema – Gut histamine release: vomiting, diarrhoea – Mucosal histamine release: laryngeal oedema, bronchoconstriction – Circulation: vasodilatation, hypotension • Food, drugs and insect venom commonest triggers in UK • Cardinal features: – – – – typical symptoms multi-system and dramatic rapidly follows exposure to credible allergen Rapidly improves thereafter Clinical allergy syndromes: oral allergy syndrome • Most common type of food allergy amongst UK adults • IgE directed against pollen proteins cross-reacts with homologous proteins in plant-derived foods • Oral itching upon exposure to raw fruit, nuts and vegetables • In UK: – Pollen = mainly birch – Food = mainly Rosaceae fruits Clinical allergy syndromes: airway disease • Rhinitis – Sneezing, rhinorhoea, blockage due to a type 1 allergy • Lower airway obstruction – Wheeze due to type 1 allergy • Allergens/ symptoms may be: • Seasonal: pollens, moulds • Episodic: occupational, animal dander • When symptoms are chronic, the inflammation becomes established and cannot be explained simply in terms of mast cell degranulation • Part 3: Mechanisms - sensitisation and chronic allergic inflammation The immunological tightrope • The immune system is constantly challenged with antigens&must somehow decide how to respond – Self antigens vs non-self – Dangerous infections vs commensal organisms – Environmental allergens such as foods and pollens Activation Tolerance Required for defence against infection and cancer Required to prevent autoimmune and inflammatory diseases Chronic allergic inflammation: asthma • Patients with chronic asthma have on-going symptoms • Most patients are sensitised to a variety of airborne allergens • Biopsy shows inflammatory infiltrate and airway changes known as ‘re-modelling’ – thickened basement membrane and smooth muscle hyperplasia • The ‘early allergic reaction’ model does not provide a good The late phase allergic reaction • The early phase reaction to allergen is followed some hours later by a second ‘late phase reaction’ • Biopsy of the late phase shows infiltration with inflammatory cells – particularly CD4 T cells, eosinophils and mast cells; provides some insight into chronic allergic inflammation, and often used as an experimental model T cell subsets Th1 Naiv e CD4 Th2 Th17 Treg IFN-g IL-4, 5, 9 &13 IL-17 IL-10, contactdependent mechanisms T cell subsets and the Th2 hypothesis • Th2 responses to allergens have been consistently associated with allergic disease – Biopsies of allergic inflammation are rich in T cells expressing Th2 cytokines – T cells from allergic patients stimulated with allergen in the laboratory produce Th2 cytokines • Plenty of reasons to believe that Th2 responses may be important in allergy: – IL-4 is required for B cell class switching to IgE – IL-4 and IL-13 promote mucus hypersecretion – IL-5 is required for eosinophil survival – IL-9 recruits mast cells Number of Cells with Positive Signals for mRNA for Interleukin-2, 3, 4, and 5, GM-CSF, and Interferon Gamma in BAL Fluid from 10 Subjects with Asthma and 10 Control Subjects. Th2-biased infiltrate in asthmatic lung Robinson DS et al. N Engl J Med 1992;326:298304. Chronic allergic disease: asthma Chronic allergic disease: asthma • Activated Th2 cells and other inflammatory cells accumulate • Th2 products lead to chronic disease – IL4: mucus hypersecretion – IL-13: bronchial hyperresponsiveness – IL-5: eosinophil recruitment – IL-9: mast cell recruitment • This model suggests a true role for T cells in chronic inflammation rather than just in Potential factors in the aetiology of allergy: genetics • Childhood allergy is strongly predicted by presence of allergy in parents, but difficult to unpick relative contribution of environment • Numerous genetic risk factors identified, but none particularly compelling • Notable that the allergy epidemic has occurred too quickly to be explained entirely by genetics Hygiene hypothesis: Strachan 1989 Hygiene hypothesis: immunology • Low hygiene levels, high pathogen load, helminth infection proposed to: – Skew immunity from Th2 to Th1 – Induce regulatory T cells • High hygiene levels, low pathogen load, absence of helminth infection proposed to: – Skew immunity towards Th2 – Reduce production of regulatory T cells • See module 302 for more discussion • Has proved resilient as a theory, but remains somewhat theoretical LEAP study: is early exposure to peanuts protective? (nb not examinable) • High-risk infants recruited • Tested for peanut allergy at baseline • From age 6 months, randomised to either peanut avoidance or regular consumption • Followed to age around 5 Testing for allergic sensitisation: skin testing and serology Detection of allergen-specific IgE in vivo: skin testing Skin prick testing • Allergen extract applied as drops • Top layers of epidermis punctured with lancet • A wheal with flare response after 15 minutes is positive • Result needs interpretation in clinical context Detection of allergen-specific IgE in vitro • Performed by radioallergosorbant (RAST) assay a very long time ago • Now usually by ELISA, but term ‘RAST’ still widely used clinically Patient serum Plastics coated with purified allergen of interest. Incubate with patient serum IgE antibodies in sera of sensitised patient bind to allergens Immobilised IgE antibodies detected with polyclonal antiIgE detection antibody Treatment of allergy: Pure symptom relievers (don’t act on mediators, but act on other pathways that oppose actions of mediators) Nasal decongestants eg oxymetazoline Act on α1 adrenoreceptors to cause vasoconstriction Only for short-term use Topical and systemic B2 agonists Eg salbutamol Act on lung B2 adrenoreceptors, cause smooth muscle relaxation Epinephrine Systemic adrenergic effects oppose vasodilatation and bronchoconstriction Treatment of allergy: drugs acting on early-phase mediators H1 Antihistamines Mast cell Histamine Leukotrienes Leukotriene receptor antagonists Mast cell stabilisers Mast cell stabilisers • Eg sodium cromoglycate • Reduce mast cell degranulation by unknown mechanism • Not orally absorbed – topical use only • Short half-life requires frequent dosing • Main benefit is steroid-free, but efficacy very poor H1 Antihistamines • Inverse agonists at H1 histamine receptor • Best used before exposure to allergen • 1st generation eg chlorpheniramine – Considerable sedation, drug interactions • 2nd generation eg cerizine, loratidine, desloratidine, fexofenadine – Constipation/ dry mouth and sometimes sedation Leukotriene receptor antagonists • Only UK drug is montelukast • Effective in reducing early allergic responses, but inferior to H1 antihistamines • Unlike anti-histamines, beneficial in chronic asthma, which is the main indication for their use Treatment of allergic disease: corticosteroids Steroids reduce immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system. Their onset of action is delayed and they must be taken regularly Corticosteroids Inhaled Eg beclamathosome, fluticasone Nasal Eg beclamathasone, mometasone, fluticasone Also for skin (eg hydrocortisone) and ophthalmic drops Topical preparations may cause local and even systemic side effects Oral , intravenous and depot preparations available Treatment of allergic disease: Omalizumab Omalizumab is a monoclonal antibody directed against IgE, used for atopic asthma (amongst other things) Treatment of allergic disease: allergen-specific immunotherapy • Allergen doses administered by subcutaneous injection or sublingually • Provide long-term protection • Mainly venom allergy and rhinitis • Multiple immunological effects: – Induce regulatory T cell responses to allergens – Reduce Th2 responses – Induce allergen-specific IgG antibodies – Reduction in mast cell responsiveness – Reduce allergen-specific IgE levels Oral peanut desensitisation • ‘Palforzia’ = defatted peanut protein for oral desensitisation in children • In clinical trial, median tolerated dose in DBPC food challenge increased from 5mg to 5000mg (approx 20 peanuts) • Daily peanut exposure needs to continue after treatment or tolerance is lost Mechanism of allergen immunotherapy (?and natural tolerance) Akdis M KJP 2013 Learning outcomes • You should be able to: – Describe the immunology of early phase allergic reactions – Give examples of allergens – Discuss how this immunology relates to the clinical features of acute allergic reactions with examples – Explain the role of T cells in sensitisation to environmental allergens and their contribution to allergic disease – Discuss the ‘atopic march’ – Describe some factors that may be important in the development of allergic diseases – Describe the immunology of skin prick testing and serological detection of allergen-specific IgE – List various treatment options for allergic diseases