Hypersensitivity & Allergy

• What is a hypersensitivity reaction?

  Overreaction to a harmless substance(s) which results in an immune response that causes inflammation & tissue damage
• What are the different types of hypersensitivity?

  Type I

  Type II

  Type III

  Type IV
• All hypersensitivities involve components of the adaptive immune system.
• What is the normal function of IgE?

  Binds to Fc receptors on the the surface of mast cells, eosinophils & basophils

  Induces responses to get rid of extracellular parasites (esp, multicellular ones that cannot be phagocytosed)

  
• What are the cells involved in Type I hypersensitivity?

  Mast cells

  Eosinophils

  Basophils
• Where are mast cells found?

  Tissue resident cell

  Predominantly in mucosal tissues near body surfaces & in connective tissue near blood vessels
• How does IgE bind to mast cells?

  Binds to FcεR (type of Fc receptor) on mast cell

  1 mast cell can have surface pre-bound IgE that covers a range of specificities
• What happens when pre-bound IgE on mast cells cross links?

  IgE is cross-linked -> mast cells degranulate & release histamine (+ prostaglandins, leukotrienes, cytokines & enzymes)
• What is the hygiene hypothesis?

  Increased cleanliness (usually in 'Westernised' countries) leading to higher rates of allergies and autoimmune diseases.

  There is very little allergy in 'developing' countries

  
• What is atopy?

  A genetic predisposition to develop allergic diseases.
• Atopic individuals have higher levels of IgE & eosinophils in their blood.

  Strong genetic component to risk - polymorphisms of multiple genes on chromosomes 5, 6 & 11
• What is the role of eosinophils in type I hypersensitivity?

  Have FcεRs for IgE on their surface

  Contain pre-formed toxic mediators in granules -> released on receptor crosslinking

  Also can secrete cytokines
• Th2 cells regulate the eosinophil arm of the immune response

  • secrete cytokines (e.g. IL-5) -> promote development & survival of eosinophils
  • promote recruitment of eosinophils to sites of inflammation by stimulating release of chemokines by activated endothelial & epithelial cells
• Where are eosinophils found?

  Present in small numbers in blood

  Resident in connective tissue under mucosal surfaces
• Where are basophils found?

  A minor population in peripheral blood & not usually found in large numbers in peripheral tissues

  Recruited to sites of inflammation
• What is the role of basophils in type I hypersensitivity?

  Have FcεR for IgE

  When activated, receptors crosslink -> release histamine & other mediators

  Cytokine production (IL-4 & IL-13) -> important in initiation of Th2 responses
• What are the different ways that an allergen can enter the body?

  Intravenous

  Subcutaneous

  Inhalation

  Ingestion
• What happens when an allergen is introduced by IV?

  Antigen is distributed widely across the body

  Release of histamine -> systemic increase in blood vessels permeability

  = Anaphylactic shock
• What happens when an allergen is introduced subcutaneously?

  Local release of histamine -> oedema & reddening of the area

  = wheal & flare reaction
• What happens when an allergen is introduced via inhalation?

  In upper airways

  -> nasal irritation & increased mucous production

  In lower airways

  -> contraction of smooth muscle & increased mucous production

  = runny nose & bronchoconstriction
• When happens when an allergen is ingested?

  Contraction of smooth muscle

  Increased fluid loss

  = diarrhoea, urticaria, atopic eczema

  There is a risk of anaphylaxis, due to absorption of allergen into blood
• What happens in a type I hypersensitivity?

  First exposure (sensitisation)

  • allergen is picked up by APC (usually at the mucosal surface) -> antigen presented to Th cells (Th2 response) -> Th cells then activate B cells -> B cells become plasma cells -> IgE production -> IgE 'sticks' to all of the local mast cells (FcεR), but allergen is gone

  Second exposure

  • allergen enters -> becomes bound to IgE pre-bound on mast cells -> cross-linking of IgE -> mast cells degranulate & release its granule contents -> vasodilation & increased permeability
• Atopic individuals have haver levels of IgE & eosinophils in their blood.
• What cytokines are involved in type I hypersensitivity?

  IL-4

  IL-5

  IL-13

  Histamine
• What happens in a type II hypersensitivity?

  IgG antibodies bind to cell surfaces -> their destruction

  2 ways this can be initiated;

  • intrinsic -> antibodies to a self antigen
  • extrinsic -> antibodies to a neo- or foreign antigen (e.g. an infection or drug that attaches to a cell)
• Give an example of a type II hypersensitivity.

  Response to an ABO- incompatible blood transfusion
• What are preformed in mast cell granules?

  Enzymes (e.g. tryptase)

  Histamine

  Heparin

  Cytokines (TNF-a)
• What happens in type III hypersensitivity?

  IgG binds to soluble antigen (not attached to cells) -> forms 'clumps' (immune complexes) -> small immune complexes circulate in the body & deposit in highly vascularised areas (as positively charged complexes are attracted to the negatively charged basement membrane) -> immune complexes activate & deposit complement -> vascular response & phagocytes are recruited -> inflammation is triggered, phagocytes take up immune complexes & ROS are produced -> can result in vasculitis
• What is serum sickness?

  Systemic reaction to an injected foreign antigen

  Antigen is removed & is self-limiting
• In type III hypersensitivity, a reaction to a self-antigen could cause autoimmunity (e.g. SLE).
• What are the differences between the different types of hypersensitivities?

  Type I -> IgE, soluble antigen

  Type II -> IgG, cell-associated

  Type III -> IgG, soluble antigen

  Type IV -> cell mediated
• Fill in the blanks

  A) IgE

  B) IgG

  C) IgG

  D) Cell mediated

  E) soluble

  F) cell-associated

  G) soluble

  H) soluble

  I) cell

  J) mast

  K) complement

  L) phagocytes

  M) complement

  N) phagocytes

  O) macrophage

  P) eosinohpil

  Q) cytotoxicity

  
• Give 2 examples of type I hypersensitivity.

  Allergic asthma

  Eczema
• Give an example of a type II hypersensitivity.

  Chronic urticaria
• Given an example of a type III hypersensitivity.

  Serum sickness
• Give 3 examples of type IV hypersensitivity.

  Allergic contact dermatitis

  Chronic asthma

  Graft rejection
• What is the pathophysiology of allergic (acute) asthma (immediate phase)?

  Immediate phase

  • antigen enters -> taken up by APC -> mast cells activate & degranulate -> releases
  • …histamine -> smooth muscle contraction, increased vascular permeability, increased mucus production
  • …leukotrienes -> promote smooth muscle contraction & increased vascular permeability
  • …cytokines. IL-4 & IL-13 -> Th2 response & mucus production. IL-3 & IL-5 -> eosinophil production & recruitment
• What is the pathophysiology of allergic (acute) asthma (late phase)?

  Late phase

  • Th2 cells -> stimulate mucus production, recruit eosinophils, trigger fibroblasts to synthesise collagen
  • Eosinophils -> produce type 2 cytokines, toxins, enzymes & leukotrienes -> damages airways
  • Smooth muscle cells -> constriction of airways, thickening of airways (chronic)
• When is the immediate phase of allergic asthma?

  Within 30 mins
• When is the late phase of allergic asthma?

  Begins within 12 hours