Hypersensitivity Reactions, Allergy, Anaphylaxis

Question 1

Broad classification of hypersensitivity reactions:

Answer 1

1. Immediate (Type I)
   
   1. Th2 cells, IgE antibodies and mast cells
   2. E.g. anaphylaxis; allergies; bronchial asthma (atopic forms)
2. Antibody mediated (Type II)
   
   1. Production of IgG, IgM inducing phagocytosis of target cells
   2. E.g. Autoimmune haemolytic anaemia, Goodpasture’s syndrome
3. Immune-complex mediated (Type III)
   
   1. Antigen-antibody complexes deposit in tissues, leads to recruitment of leukocytes → release of lysosomal enzymes and toxic free radicals
   2. E.g. SLE, some forms of GN, serum sickness
4. Cell-mediated (Type IV)
   
   1. T lymphocytes (Th1, Th17, CD8+ CTLs) mediated tissue injury
   2. E.g. contact dermatitis, muiltiple sclerosis , type I DM, TB

Question 2

Notes on Immediate (Type I) Hypersensitivity

Answer 2

• Occurs in a previously sensitised individual - triggered by binding of antigen to IgE antibody on the surface of mast cells
• Usually two phases
  
  • Immediate reaction - vasodilation, vascular leakage, smooth muscle spasm within minutes of exposure to allergen
  • Late phase - 2-24 hours after exposure
• Most Type I hypersensitivity responses caused by Th2 responses
  
  • Antigen presented to CD4+ helper T cells → differentiate to Th2 cells
  • Th2 cells produce cytokines → IL-4, IL-5, IL-13. Promote class switching of B cells to IgE (IL-4), IL-5 activates eosinophils.
  • IgE binds to mast cells → degranulate
    
    • Histamine → smooth muscle contraction, increased vascular permeability
    • Enzymes e.g. tryptase), proteoglycans e.g. heparin
    • Cytokines - TNF, IL-1, IL-4
• Late phase reaction:
  
  • Leukocytes (predominantly eosinophils) recruited - amplify and sustain response without repeat exposure to antigen (IL-5 most potent eosinophil activating cytokine)

Question 3

Notes on antibody-mediated (Type II) hypersensitivity

Answer 3

3 mechanisms

• Opsonisation and phagocytosis
  
  • Cells opsonised by IgG recognised by phagocytic cells, IgM/IgG deposited on cells activate classical complement pathway → generate C3b and C4b → deposited on cells for phagocytosis. Complement activation also → formation membrane attack complex which “drills holes” causing lysis of cells
  • Examples
    
    • Transfusion reactions, haemolytic disease of the foetus, autoimmune haemolytic anaemia, agranulocytosis and thrombocytopaenia, certain drug reactions
• Inflammation
  
  • Antibodies deposit in fixed tissues e.g. basement membranes, extracellular matrix → activate complement
  • Examples:
    
    • Some forms of glomerulonephritis, vascular rejection in organ grafts. ANCA associated vasculitis, pemhigus valgaris, goodpasture’s syndrome, acute rheumatic fever
• Cellular dysfunction
  
  • Antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury/inflammation
  • Examples
    
    • Myasthenia gravis - antibodies directed against acetylcholine receptor
    • Grave’s disease - antibodies directed against TSH receptor
    • Neutralisation of intrinsic factor → pernicious anaemia

Question 4

Notes on immune-complex mediated (Type III) hypersensitivity

Answer 4

• Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at sites of deposition
• Examples:
  
  • SLE
  • Post-streptococcal glomerulonephritis
  • Polyarteritis nodosa
  • Reactive arthritis
  • Serum sickness

Question 5

Notes on serum sickness

Answer 5

• Uncommon now - previously seen more in the setting of administration of large amounts of foreign serum (e.g. serum from immunised horses for protection against diphtheria)
• 3 phases
  
  • Formation of immune complexes - one week after injection of antigen - antibodies produced which than react with antigen still present in circulation → antigen-antibody complexes
  • Deposition of immune complexes - deposited in vessels, often glomeruli and joints affected
  • Inflammation and tissue injury - approx. 10 days after antigen admin → acute inflammatory reaction - fever, arthralgias, urticaria, lymphadenopathy, proteinuria

Question 6

Notes on T cell mediated (Type IV) hypersensitivity

Answer 6

CD4+ T cell mediated hypersensitivity (majority)

• Cytokines produced by T cells induce inflammation
• Mediated by T1 and T17 cells (differentiate from CD4+ cells on recognition of antigen) - secrete cytokines (mainly IFN-y)
• Examples:
  
  • Tuberculin skin test
    
    • Note granuloma formation from commonly associated with Th1 activation and production of cytokines such as IFN-y
  • Contact dermatitis
  • RA, MS, IBD, psoriasis

CD8+ T cell mediated hypersensitivity

• CD8+ CTLs kill antigen expressing target cells (also play a role in reactions to viruses)
• E.g. T1DM

Question 7

Criteria for anaphylaxis:

Answer 7

• Skin symptoms or swollen lips and either:
  
  • Difficulty breathing or
  • Reduced bp (<100mmHg or >30% decrease)
• Exposure to a suspected allergen and ≥2 of the following:
  
  • Skin symptoms or swollen lips
  • Difficulty breathing
  • Reduced BP
  • GI symptoms with suspected food allergy (vomiting, diarrhoea, cramping)
• Exposure to a known allergen for that patient and:
  
  • Reduced BP (<100mmHg systolic) or a decrease in systolic BP >30%

Question 8

Notes on IgE

Answer 8

• Low levels compared to other antibodies
• 50% free, 50% bound to IgE receptors (on mast cells and basophils)
• Bound IgE responsible for allergic reactions

Question 9

Classification of anaphylaxis:

Answer 9

See diagram

IgE dependent mechanisms:

Foods - peanuts, shellfish, stinging insects/venom, beta lactam antibiotics, NSAIDs, biologics, latex, seminal fluid, aeroallergens, radiocontrast media

Immunologic mechanisms - IgE independent

Radiocontrast media, NSAIDs, dextrans, biologics

Non-immunological mechanisms - direct mast cell activation

Physical factors, ethanol, medications

Question 10

Role of adrenaline in anaphylaxis and dose.

Answer 10

• Dose - 0.5mg 1:1000 IM
• Mechanism of action
  
  • Beta 2 agonist - bronchodilation
  • A1 agonist
  • B1 agonist

Question 11

Notes on tryptase in anaphylaxis:

Answer 11

• Present in mast cell granules
• Peaks 1-2 hours after anaphylaxis → back to baseline 6-24 hours (histamine peaks within 5-10 minutes)
• Most specific test for mast cell activation

Question 12

Notes on biphasic reaction anaphylaxis:

Answer 12

• 30% anaphylaxis deaths related to this
• Should observe for 4 hours after initial reaction
• No role for steroids
• Risks for biphasic reaction:
  
  • Severe initial presentation
  • Need for >1 dose adrenaline
  • Delayed initial administration of adrenaline

Question 13

Clues in assessing type of drug reaction

Answer 13

• Urticaria, angioedema, bronchospasm, anaphylaxis → mast cell activation
  
  • Usually IgE mediated (usually immediate reaction)
  • Can get direct mast cell activation without IgE → vancomycin, radiocontrast
• Maculopapular exanthems/non-specific rashes often T cell mediated, T cell mediated often delayed

Question 14

Examples of allergy tests

Answer 14

• Skin prick test
  
  • Most common, easy, cheap, drops of diluted antigen placed on skin, then skin pierced. Can test large number of allergens in one session
  • Wheal if allergic (IgE) read at 15 minutes
  • Useful for food allergies and aeroallergens
• Intradermal testing
  
  • Intradermal injection of diluted allergens
  • More sensitive than skin prick, more likely false positives
• Specific IgE testing (RAST/ELISA)
  
  • Less sensitive, longer turnaround, more expensive - not first choice in allergy
• Oral food challenge - gold standard for food allergy
• Skin patch testing - useful for contact dermatitis

Question 15

Type A vs Type B drug reactions:

Answer 15

Question 16

Notes on latex allergy and plant panallergens

Answer 16

• Proteins in certain foods cross react with antigens found in latex
• Banana, potato, avocado, kiwi, tomato, chestnut, passionfruit, mango, apple, peach, watermelon
• Reaction classically limited to mouth, throat, lips