Hypersensitivity Type I: Allergy PDF

Hypersensitivity type I: Allergy Learning objectives In these videos I aim to cover: The cause and nature of allergy and allergic reaction. How the cause of allergy leads to specific reactions. How BMSs and medics work together to identify and diagnose allergy By the end of these videos I...

Hypersensitivity type I: Allergy Learning objectives In these videos I aim to cover: The cause and nature of allergy and allergic reaction. How the cause of allergy leads to specific reactions. How BMSs and medics work together to identify and diagnose allergy By the end of these videos I would expect you to be able to explain: How genetic and environmental factors impact on allergy Why certain allergens cause specific reactions How tests are used to diagnose patients and consultations used to investigate their symptoms. Contents Predisposition to allergy (atopy) Mechanisms of allergy Types of reaction Testing for allergy Predisposition to allergy (atopy) Learning objectives 1) Build an awareness of the molecular causes of allergy 2) Understand that there are genetic factors that increase the risk of allergies and how these affect the immune system. Pre-disposition of allergy (atopy) Rates of allergy climbing (Western populations 40%) Allergy caused by immune reaction propensity towards: IgE Th2 cells Requirement for class switching to IgE (B-cells) Increased number of Th2 cells 2 interactions: T-cell differentiation to Th2 cells B-cells class switch to IgE Atopy Over expression of IL-4, 5, 9 and 13 GATA-3 Transcription Factor needed for all these Interleukins IL-4 expression at T-cell activation Suppresses Th1 differentiation Promotes Th2 differentiation IL-4 and Il-13 production prevents Treg production IgE Production Th2 cell + naïve B-cell CD40, CD40L, +IL-13 IgE – Locally produced in germinal centres lymph nodes IgεR – Basophils, eosinophils, mast cells IgE Role of IgE Positive feedback response, promote and intensify IgE response until threat is neutralised Causes degranulation of certain immune cells Mast cells: Histamine, Interleukins, colony stimulating factors, lipid mediators (leukotrienes, prostaglandins, PAF and other thromboxanes) Aim: attract and progenerate immune cells in response Outcome: Exponential response to stimuli Summary Allergy is a misplaced, normal immune response to a non- threatening antigen Allergy uses an escalating immune response to cause a large immune reaction Allergy has genetic risk factors that increase the number and reaction potential towards Th2 cells and an IgE antibody response. Mechanisms of allergy Learning objectives 1) Comprehend the stages that an allergy has to go through from sensitisation through to reaction. 2) Understand the cellular and molecular mechanisms of an allergic reaction. 3) Explore the differences between antigens and allergens. Mechanism of allergy 1. sensitisation First encounter with allergen, immune response created but not overtly misdirected. 2. Reactive Phase Subsequent encounter with allergen produces immunological and physiological responses Cardinal signs of inflammation: Rubor, Calor, Dulor, Tumour, Loss of function Symptoms of allergy Tumour, Patch of localised inflamed area topped with centralised area (bullseye, Flare) Rubour, Patch of red coloured inflammation surrounding flare, Dulour, Calor Wheal and flare is painful, and quite often itchy and warmer Loss of function: Seen primarily in digestive and respiratory tract Tissue activation through antibody mediation IgE, antibody response causes reaction in the tissues Reaction mediated by immune derived tissue cells Mast cells degranulate, release inflammatory molecules Histamines, Interleukins, TNFs, Attracts Anti-parasitic response cells Eosinophils, Basophils, these degranulate too Releasing granzymes and other, causes more inflammation, More mast cell activation, leads to more inflammation Taken from: https://www.frontiersin.org/articles/10.3389/fcell.2021.752350/full accessed 24/10/2022. Comparison of allergens vs parasitic antigens Allergen characteristic Parasitic characteristic Protein Proteins Present in high doses Present in low doses Low MW (10-40 Kda) Low MW (10-40 Kda) Highly soluble Highly soluble Stable Short acting stability Peptides that bind MHC Class II Peptides that bind MHC Class II Frequently have enzymatic activity Varying activity Severity of allergic response Dose of allergen and IgE directly related to response High dose of allergen = High response Amplification of response Mast cells, Eosinophils, Basophils Location of activating nodes, and response; Dictates location and type of response Summary Understand the role of blood and tissue immune cells in allergic reactions Basophils Eosinophils Mast cells We have explored the connection between antigen, allergen and cellular and molecular response causing allergic reactions. Types of reaction Learning objectives 1) Understand the connection between exposure to allergen and symptoms of reaction. 2) Understand that the site of exposure and site of reaction are not always the same 3) Comprehend the difference between localised and centralised reactions. Types of reaction Anaphylaxis (centralised allergy) Allergic rhinitis (sneezing, coughing) Diarrhoea and vomiting Allergic dermatitis Hives (urticartia) What dictates the type of reaction Allergy generally produces localised effects based on the 5 cardinal signs of inflammation Local reaction depends upon: Clustering and concentration of sensitised nodes Speed of allergen to move into blood stream Ubiquity of the allergenic epitope Stability of the allergenic epitope Anaphylaxis Symptoms of anaphylaxis Difficulty breathing Light headedness Fainting Pallor Hives Redness Causes of symptoms Fainting, pallor, :- Histamine, TNF-α, prostaglandins. Lower blood pressure, increased vascular permeability. Difficulty breathing, tracheal, bronchial swelling Histamine, TNF-α, prostaglandins, Heparin Increase vascular permeability, increasing white cell counts; eosinophils & basophils (degranulating cells) Hives, redness,:- TNF, Chemokine, PAF, Heparin, histamine. As above but in small vascular areas just beneath the skin. Centralised response (not localised) Gastro and intestinal Aim is to evacuate the cause of infection ASAP, reaction is localised within the gastrointestinal system. Diarrhoea and vomiting: Leukotrienes and Prostaglandins Smooth muscle contraction Speeds up digestive transit = diarrhoea Compresses stomach and rejects stomach contents = vomiting Loss of function Summary To understand that the mode of exposure can affect or dictate the type of reaction. That anaphylaxis is a centralised response to an allergen not a localised response. Anaphylaxis is demonstrable as a multi-system response. Diagnosis of allergy Learning objectives 1) Understand the role of the laboratory in diagnosing, monitoring and assessing the severity of allergies 2) Comprehend how different tests perform different functions in diagnosing and monitoring allergies. Diagnosis of allergy Clinicians look for evidence of: What causes the reaction Identify causative substances Look for specific epitope Predict severity of response. What causes the reaction Identify episodes of disease Food diary to identify common elements. E.g. Birch tree pollen allergy. Not practical for anaphylactic reactions. Can present as allergy to carrots, apples. ?re-sensitise based on original sensitisation event. Skin Prick test What does this tell us? Epitope determination Determine specific epitope from related substances Der-P1 PR-10 BSA Specific epitope known factors Epitope ubiquity Epitope stability Serum IgE IgE concentration predicts allergy likelihood Taken from https://www.researchgate.net/publication/332749561_Ing estion_of_mammalian_meat_and_alpha-gal_allergy_Clinic al_relevance_in_primary_care 04/07/23 Determination of severity Clinicians responsibility: Factors include: Accounts of previous reactions Epitope stability Epitope ubiquity Site of absorption Summary Understand the relationship between clinicians and the laboratory in provision of patient care. Be able to explain how laboratory tests work together to diagnose allergies Explain the significance of demonstrating the severity and likely type of allergic reaction to patients.