Allergy and hypersens

• Hypersensitivity


  An overreaction to harmless molecules which results in an immune response that causes inflammation and tissue damage
• Allergy


  Often used as a term to refer to IgE mediated hypersensitivity reactions
• Types of Hypersensitivity


  • Type I (IgE)
  • Type II (IgG Antibody binding to cell associated antigen)
  • Type III (Immune complex deposition)
  • Type IV (Cell mediated)
• Type I Hypersensitivity


  • IgE antibody binding to soluble antigen
  • Mast Cell Activation
• Type II Hypersensitivity


  • IgG Antibody binding to cell associated antigen
  • Complement and Phagocytes
• Type II Hypersensitivity Reactions

  • Serum sickness
  • Arthus reaction
• Type III Hypersensitivity


  • Immune complex deposition
  • Complement and Phagocytes
• Type III Hypersensitivity Reactions

  • Serum sickness
  • Arthus reaction
• Type IV Hypersensitivity


  • Cell reactions to soluble and cell associated antigens
  • Eosinophil activation
  • Macrophage activation
  • Cytotoxicity
• Type IV Hypersensitivity Reactions

  • Allergic contact dermatitis
  • Chronic asthma
  • Chronic allergic rhinitis
  • Graft rejection
• Allergy incidence is increasing
• Common causes of allergies

  • Inhaled - Dust mite faeces, Plant pollen
  • Injected - Insect venom, drugs
  • Ingested - Peanuts, shellfish
  • Contacted - Plant oil, metal
• Many allergens share molecular similarities to pathogen antigens
• The dose and site of exposure to allergens influences the type of response seen
• IgE


  Promotes responses like sneezing, coughing, diarrhoea, vomiting, increased mucus flow, increased peristalsis, itch induced scratching
• The function of IgE induced responses is to get rid of extracellular multicellular parasites which are too large to be phagocytosed
• Mast Cells


  • Tissue resident cell that is abundant around vasculature and in mucosal tissues
  • Have pattern recognition receptors and can synthesise cytokines
  • The Fc??RI on mast cells binds to multiple IgE molecules and allows it to respond to antigens
  • Contain granules with enzymes and vasoactive mediators
  • Potent source of Th2 cytokines
• Mast Cell Mediators


  • Preformed granules - Tryptase, chymase, cathepsin G, carboxypeptidase, Histamine, Heparin
  • Synthesised after activation - TNF-??, IL-4, IL-13, IL-3, IL-5, GM-CSF, CCL3, Leukotrienes C4,D4 and E4, Prostaglandins D2 and E2, Platelet activating factor
• Mast cell activation


  Varying effects dependent on site - Intravenous, Subcutaneous, Inhalation, Ingestion
• Anaphylaxis


  Serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention
• Anaphylaxis Symptoms


  • Feeling lightheaded or faint
  • Breathing difficulties - such as fast, shallow breathing
  • Wheezing
  • A fast heartbeat
  • Clammy skin
  • Confusion and anxiety
  • Collapsing or losing consciousness
  • Other allergy symptoms, including an itchy, raised rash (hives); feeling or being sick; swelling (angioedema) or stomach pain
• If the allergen enters the blood stream it can cause systemic activation of mast cells throughout the body, resulting in widespread vascular permeability and smooth muscle constriction
• Causes a catastrophic reduction in blood pressure leading to reduced oxygen perfusion to organs and constriction of the airways culminating in respiratory failure
• Two phase response in IgE allergy

  1. Immediate Phase - Within 30 minutes the mast cells have reacted to the presence of the allergen, releasing granule contents resulting in increased blood vessel permeability

  2. Late Phase - Within 12 hours the late phase begins, with mast cells now producing synthesised mediators, resulting in the recruitment of eosinophils, monocytes and more T cells leading to exacerbation of the bronchoconstriction and oedema, tissue damage and mucus production
• Immediate Phase


  • Histamine - Smooth muscle contraction, ↑Vascular permeability ↑mucus production
• Late Phase


  • Cytokine secretion - IL-4, IL-13 (mucus and TH2 recruitment), IL-3, IL-5 (Eosinophil production and recruitment), IL-13 (Stimulate mucus production, eosinophil recruitment, collagen synthesis by fibroblasts)
  • Eosinophils - Produce type 2 cytokines, enzymes which degrade tissue, neurotoxins, and leukotrienes, damage the airways
• Leukotrienes


  Synthesised later, promote smooth muscle contraction and ↑Vascular permeability
• Treating anaphylaxis


  1. Adrenaline given IM (stimulates β2 adrenoreceptors to relax airway smooth muscles and reverses cardiovascular effects)

  2. Oxygen and monitoring (ECG, pulse oximetry and blood pressure)

  3. IV fluid (counter low blood pressure, signs of shock)
• Skin


  • Highly vascularised making it reactive to systemic influences as well as quick to respond to inflammation
  • Smooth muscle cells are present around vessels and allow vasculature to respond
  • Langerhans cells are specialised epidermal dendritic cells
• Urticaria


  • Affects 15-20% population, more common in adults and women
  • Dermal oedema causing red blotchy patches which are itchy
  • Rashes can be small patches or coalesce into larger wheals, usually resolves within 24hrs
  • Sometimes accompanied by angioedema – swelling in submucosal and subdermal layers
  • Can be acute or chronic (> 6 weeks)
  • Immunological – food, medications, venom and environmental allergens
  • Non immunological – Heat, cold, pressure
  • Autoimmune responses can also present with urticaria
• Immune response in urticaria

  1. Allergen triggers mast cells in the skin from the systemic vasculature

  2. Type I cases of urticaria are driven by mast cell recognition of antigen through IgE

  3. In acute cases this is broadly self limiting and resolves after a few hours. Symptoms can be relieved by anti histamines

  4. Non immunological triggers can also activate mast cells by alternative receptors - Neurotransmitters, C3a&C5a, Toll like receptors, Cytokine receptors
• Delayed Type Hypersensitivity Reactions

  • Type IV response driven by cell responses rather than antibodies
  • Mediated by antigen specific T Cells which have previously been sensitised to the allergen
  • Takes 24-72 hours to develop as the antigen is recognised and presented
• Allergic Contact Dermatitis


  1. Activation of CD4 or CD8 cells by highly reactive small molecules which penetrate intact skin

  2. The reactive molecule binds as a hapten to an endogenous protein

  3. This is recognised and taken up by Langerhans cells

  4. Peptides are recognised by T helper cells which secrete IFN-γ

  5. Keratinocytes are activated and secrete pro-inflammatory cytokines and chemokines

  6. Cytokines from keratinocytes and T Cells activate macrophages which cause further inflammation and release NO
• Atopic Dermatitis - Eczema

  • Dry skin, flaky or scaly patches and itching, usually around joints and occurs in flare ups of irregular cycles
  • More prevalent in children and symptoms typically appears early in life
  • The skin is deficient in lipid molecules and antimicrobial peptides, allowing S.aureus to often be found colonising patients (90% of AD patients)
  • Complex mix of reduced barrier function, immune dysregulation and environment
  • Children with atopic dermatitis are more at risk of developing food allergies and allergic rhinitis
• Drug Hypersensitivity


  • Immune mediated reaction to a drug in a sensitised patient
  • Can be induced by a variety of hypersensitivity mechanisms and occur in any age and gender
  • Rates are low but common drugs are antibiotics, anticonvulsants, biologicals & anti retrovirals with rates between 1-5%
  • Certain drugs are more likely because of their ability to act as haptens or covalently bind to receptors
  • Administration route can also affect frequency – Topical, IM and IV are more likely to induce a reaction than oral
• Mechanisms of Drug Reactions

  • Type I - IgE mediated urticaria predominantly on trunk and sometimes anaphylactic reaction minutes to hours
  • Type II - Cytotoxic - Haemolytic anaemia, neutropoenia, thrombocytopaenia
  • Type III - Serum sickness, vasculitis 1 to 3 weeks after exposure
  • Type IV - Allergic contact dermatitis, maculopapular with eosinophilia, Stevens Johnson-syndrome, bullous exanthema
• Non severe drug reactions present with an exanthematous or urticarial rash. Life- threatening reactions present with skin detachment or necrosis of large areas of the body e.g. Stevens-Johnson syndrome
• Drug induced reactions can also present as purpura, vasculitis or drug induce thrombocytopaenia, blistering lesions with mucous membrane involvement, or a circumscribed erythematous raised lesion (fixed drug eruption)