Allergy & Hypersensitive Reactions

• IgE


  Mediates Type I allergic reactions; asthma, hay fever, food allergy and anaphylaxis
• IgE


  • Binds to high affinity FcεR1 receptors on mast cells
  • No mast cell activation
• Allergic reaction


  1. Exposure to specific antigen cross-links IgE bound to the mast cell surface

  2. Triggers release of histamine and other mediators
• Allergic reactions


  Occur when an individual who has produced IgE antibody during the initial response to an innocuous antigen, or allergen, in the sensitisation phase subsequently encounters the same allergen in the effector phase
• IgE


  • Bound to the surface of mast cells through high affinity IgE receptors called FcεR1 receptors
  • Most non-allergic individuals have ≈500 molecules of IgE bound to their mast cell surface, mainly directed against bacterial antigens
  • Allergic individuals can have as many as 500,000 molecules of IgE bound to their cell surface, directed against the allergen
• Allergens


  • Soluble and continuously diffuse across epithelia at very low doses, especially in the airway and gut
  • Responsible for activation of Th2 cells and IL-4 production that favours the synthesis of IgE
  • In the skin, allergens may be injected by stinging insects (bees and wasps)
• Allergic reaction


  1. Allergen cross links preformed IgE bound to IgE receptors on mast cells

  2. IgE is nearly always found bound to mast cells in tissues even in the absence of allergen and levels of IgE in the circulation are very low

  3. Mast cells line the body surfaces and alert the immune system to local infection
• Early phase of allergic reaction

  • Degranulation and release of histamine
  • Histamine causes rapid increase in the permeability of blood vessels and contraction of smooth muscle
  • Increased vascular permeability leads to oedema and blocked nose associated with hay fever
  • Smooth muscle contraction leads to bronchoconstriction (airway narrowing) in asthmatics
• Late phase of allergic reaction

  • Release of mast cell cytokines and sustained inflammatory response (develops after 8-12 hours)
  • Recruitment of T-cells and eosinophils leads to a chronic inflammatory response and tissue damage
  • In the skin this causes eczema
• Systemic anaphylaxis


  • Response to allergen introduced into the blood
  • Widespread activation of mast cells leads to widespread increased vascular permeability, loss of blood pressure, circulatory collapse and respiratory failure
• Type I allergic reaction

  • A wheal and flare reaction develops within a minute or two of intradermal injection of allergen and lasts for up to 30 minutes
  • Immediate reaction due to IgE-mediated mast cell activation
  • Results from the release of histamine, prostastaglandins and other pre-formed or rapidly synthesised mediators released by mast cells
  • Causes a rapid increase in vascular permeability resulting in visible oedema (the wheal) and reddening of the skin (the flare)
• Symptoms of allergic reaction

  Local swelling of the tissue, itch, hypotension (drop in blood pressure as a result of vasodilation, wheezing due to bronchoconstriction and diarrhea (effects of histamine on the gut)
• Late phase response


  • More widespread oedematous response which occurs about 6 hours later and can last several hours
  • Peak can be between 3 and 9 hours after allergen exposure
  • Characterised by the continued synthesis and release of inflammatory mediators by mast cells, especially vasoactive mediators such as vascular endothelial growth factor (VEGF) which causes vascular leakage and tissue oedema
• Systemic anaphylaxis


  • Rapid response to allergen introduced in the blood (eg. bee or wasp sting, or foods such as nuts)
  • Widespread activation of mast cells leads to increased vascular permeability, loss of blood pressure, circulatory collapse and respiratory failure
• Treatment for anaphylaxis


  1. Immediate subcutaneous treatment with adrenaline (Epipen)

  2. Anti-histamines, eg injectable diphenhydramine HCl (Benadryl)

  3. Corticosteroids ,eg prednisone
• Adrenaline


  Acts on α1 receptors on blood vessels to cause vasoconstriction and raise blood pressure, and on β1 receptors to increase heart rate and on β2-receptors to induce bronchial relaxation and bronchodilation
• Type II (cytotoxic) reactions

  • Caused by antibodies (IgG or IgM) directed against antigens on a person's blood cells (red blood cells (RBC), lymphocytes or platelets) or tissue cells
  • Reaction of antibody with antigen on the cell surface usually leads to activation of complement and cell lysis or clearance by phagocytes carrying the FcγR
• Blood group systems


  • ABO
  • Rhesus
• ABO blood group system

  • Two different antigens (A and B) and four possible blood groups (A, B, AB, O), depending on which antigens are present on the RBC
  • Blood plasma usually contains IgM antibodies called agglutinins that react with the A or B antigen (the anti-A and anti-B antibodies)
  • You do not have antibodies for the antigens that are present on your RBC
• Transfusion


  • Transfer of whole blood or blood components (RBC or plasma) into a donor to alleviate anemia, increase blood volume or improve immunity
  • Transfusion of incompatible RBC into a person who already has antibodies against them, will result in the binding of antibodies in the recipients blood to antigens on the donated RBC to cause agglutination, or clumping
• A person of blood group A can not receive blood from a person with blood group B or blood group AB, since the RBC in the donated blood have the B antigen and will be agglutinated by the anti-B antibodies in the recipient's blood
• IgM antibodies are large and do not cross the placenta, therefore there can be no incompatibility between mother and fetus during pregnancy
• Hemolytic disease of the newborn

  • Occurs if blood from Rh+ fetus contacts Rh-mother during birth, anti-Rh antibodies made
  • Affects is on second Rh+ baby and causes red blood cell lysis
• Rhesus antigens


  There are 3 rhesus antigens, C,D and E but only the rhesus D antigen is a strong immunogen and therefore important clinically
• Hemolytic disease of the newborn

  1. During the first pregnancy, RhD antigens on RBC in the fetal circulation leak into the maternal circulation, usually at the time of birth

  2. These RhD+ red blood cells sensitise the mother, who starts producing anti-RhD antibodies after the birth of the first child

  3. Anti-RhD antibodies are of the IgG class and are able to cross the placenta and react with RhD+ fetal red blood cells in subsequent pregnancies, causing hemolysis of RBC in the unborn child

  4. Prophylactic treatment involves giving the Rh- mother preformed anti-RhD antibodies immediately after the birth of the first child, so that these can destroy the fetal RhD+ red blood cells before they sensitise the mother to produce anti-RhD antibodies
• Type III hypersensitivity reaction

  • IgG mediated immune complex reaction to a soluble antigen
  • Antigen-antibody complexes that are not cleared normally because of their small size, deposit in the blood vessel wall where they stimulate complement activation, and activate both Fc and complement receptors on inflammatory cells, inducing inflammation in blood vessel walls
• Type IV hypersensitivity reaction

  • Delayed-type hypersensitivity reaction eg celiac disease, rheumatoid arthritis
  • Mediated by T-cells and NOT antibodies
  • Allergens in tissue are taken up, processed and presented by APCs such as macrophages
  • Allergen specific Th1-cells that were primed by a previous exposure to the antigen, migrate to the tissue site and are stimulated by antigen-presenting macrophages, to release cytokines that stimulate the endothelial cells and stimulate a delayed inflammatory response