Hypersensitivity

• Type 1 hypersensitivity

  • onset within minutes
  • exposure can be inhaled, ingested, injection or direct contact
  • creates IgE to target harmless antigens
  • Spectrum of symptoms/clinical signs - localised (allergic rhinitis, asthma) or systemic (anaphylaxis)
• type 1

  • sensitisation: first exposure - APC- lymph nodes - present to naive T helper cells - become activated Th2 cells - costimulate B cells to make IgE - IgE bound mast cells
  • reaction: second/subsequent antigen exposure - cross binds IgE mast cells - degranulate releasing proinflammatory mediators (e.g. histamines) - smooth muscle contraction, vasodilation and increased permeability
  • late phase reactions
• Type 1 examples

  • anaphylaxis
  • atopy (predisposition to allergy) - asthma, eczema
  • allergy
• Immediate management of anaphylaxis is IM adrenaline (epipen)
• Type I hypersensitivity is an immediate reaction (within minutes) mediated by IgE antibody, which results in allergy, anaphylaxis and atopic disease.
• When an individual first encounters an antigen, their immune system may produce large amounts of IgE antibodies against this specific substance. These IgE molecules attach themselves to mast cells and basophils. The individual is now ‘sensitised’ to the antigen.

  When this antigen is encountered again, it will cause cross-linking of the bound IgE and degranulation of mast cells and basophils, releasing potent vasoactive molecules such as histamine. This leads to the signs and symptoms of allergy, and if severe can cause anaphylaxis.
• Type II hypersensitivity is an IgG or IgM antibody-mediated cytotoxic reaction occurring in hours to days, which results in pathologies such as haemolytic disease of the newborn, autoimmune haemolytic anaemia and Goodpasture’s syndrome.
• An individual may possess or develop IgG and IgM antibodies directed against cell surface or extracellular matrix antigen.

  These antibodies can cause damage to cells or tissues (cytotoxicity) either directly by cell surface receptor binding, via activation of the complement pathway or by antibody-dependent cellular cytotoxicity.

  Pathology is dependent on the target of the antibody. If antibodies are directed to cell surface antigen on red blood cells this can cause haemolytic anaemia, if they are targeted to type IV collagen in the basement membrane this can cause Goodpasture’s syndrome.
• Anaphylaxis is a severe allergic reaction occurring rapidly and causing potentially life-threatening issues with an individual’s airway, breathing or circulation.
• Common allergens that can cause anaphylaxis are foods (most commonly nuts), medications, and insect stings/venom. These allergens trigger a systemic reaction, which via the effects of mediators such as histamine can cause swelling and obstruction of the upper airways, bronchospasm and bronchodilation with respiratory failure, and vasodilation leading to hypotension and cardiac arrest.

  Other systemic features may include widespread urticarial rash (‘hives’) and angioedema(swelling).
• An allergic reaction causing signs and symptoms of anaphylaxis requires urgent treatment with intramuscular (IM) adrenaline (0.5mg 1:1000 in adults) to counteract the vasodilation and bronchoconstriction.
• A classic example of type II hypersensitivity is Goodpasture’s syndrome, a rare autoimmune condition caused by antibodies against the alpha-3 chain of type IV collagen found in the basement membrane.
• Type IV collagen is a major structural component of all basement membranes, but the alpha-3 subtype only occurs in certain tissues, primarily alveoli and glomeruli. There is no consistent trigger for Goodpasture’s disease, but it is associated with certain genetics (HLA-DRB1 or DR4) and cigarette smokers.
• Goodpasture’s commonly presents in men, with bimodal age distribution (20 to 30 years and 60 to 70 years). Symptoms include shortness of breath, haemoptysis and signs of renal dysfunction such as decreased urine output or oedema. Goodpasture’s can lead to rapidly progressive renal failure if untreated.  
• Diagnosis is made by renal biopsy and can be confirmed by blood tests for anti-GBM antibodies.

  Management of Goodpasture’s involves urgent, aggressive treatment with steroids, plasmapheresis (to remove anti-GBM antibodies) and cyclophosphamide. Patients may require long-term dialysis if irreversible renal damage occurs. 
• Type III hypersensitivity is an antigen-antibody immune complex-mediated reaction, which can occur over hours, days or weeks. Examples include serum sickness, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and post-streptococcal glomerulonephritis.
• Soluble antigen in circulation is bound to antibodies (most commonly IgG and IgM) forming immune complexes. These complexes precipitate out of circulation and deposit in certain tissues; blood vessels, synovial joints and glomerular basement membrane.

  These complexes trigger the classical complement pathway, leading to recruitment of inflammatory cells including neutrophils that release enzymes and free radicals causing tissue damage. E.g. In rheumatoid arthritis, where immune complexes damage the filtration systems vital in synovial fluid formation.
• Type IV hypersensitivity is also known as delayed hypersensitivity, as the reaction typically occurs 24 to 72 hours after antigen exposure. Unlike types I to III, it is not antibody-mediated but T cell-mediated. It is involved in the processes of contact dermatitis and the tuberculin skin test (Mantoux).
• When an individual first encounters an antigen, it can be processed by antigen-presenting cells and lead to sensitisation of T helper cells.

  On subsequent exposure to this antigen, these T helper cells will become activated and lead to an inflammatory response involving several immune cells such as macrophages, though there will be a delay of 24 to 72 hours as cells are recruited to the site of antigen exposure.
• Type 2 hypersensitivity

  • onset mins-hours
  • antibody mediated
  • antibody (IgM or IgG) targets specific tissue/organ
• • Membrane attack complex (MAC) inserts into plasma membrane - fluid rushes through - cell lysis
  • chemotaxins attract neutrophils - degranulate releasing granzymes - oxygen radicals - cell damage
  • C3b binds to complex - opsonisation - marks for destruction by macrophages within spleen
• Natural killer cells recognise antigen-antibody complex

  Binds to the Fc tail of the antibody and releases perforins (which form pores in the host cell), granzymes and granulysin (which enter the host cell via the pores and cause apoptosis)
• Type 4

  This can cause local tissue inflammation and damage as seen in contact dermatitis when substances such as nickel or poison ivy contact the skin, or in the Mantoux test where proteins from M. tuberculosis are injected intradermally and an indurated area forms in individuals who have been previously exposed to the bacteria.
• type 3

  immune complex mediated

  (immune complex = soluble antibody-antigen complex)

  IgM or IgG

  Onset within hours

  Antigens can be exogenous or endogenous

  Can be local or systemic (depends on where immune complex deposits)
• Type 3

  soluble antigen - antigen-antibody complex deposit in blood vessels - activates classic complement system - attracts neutrophils - neutrophil degranulation releases enzymes that cause inflammation
• Type 4

  APC - naive T cells - activated T cells - activated macrophages, neutrophils, cytokines - localised tissue inflammation