hypersensitivity

Hypersensitivity

• An exaggerated response of the immune system to ‘foreign’ antigen causing tissue damage

  •Damage is mediated by the same attack mechanisms that mediate normal immune responses to pathogens

  •Mediated by the Adaptive Immune System

  •Not seen on 1st contact with antigen but appears on subsequent exposure – “senitisation” step

  •Allergy and hypersensitivity are used interchangeably

Type 1

• Also called Immediate or Anaphylactic

  •IgE mediated

  •Immune cell: Mast Cell

  •Release mediators such as histamine and leukotrienes

  •Inflammatory response

   

  •Hay fever

  •allergic asthma

  •Allergic rhinitis

  •atopic dermatitis (eczema)

  •urticaria

  •anaphylaxis

Type 1: phase

• Sensitization

  •Antigen contact,

  •Often low-dose via mucous membranes (respiratory, GI)

  •Primary IgE production

  2. Elicitation (Re-exposure)

  •Pre-formed IgE (allergen-specific) triggers mast cell activation

  •Mediator release immediate (mast cell degranulation) and then early and late-phase synthesis of other inflammatory mediator

Hypersensitivity: sensitisation

• Antigen presented on dendritic cells

  •Activates helper T cell

  •T helper cells secrete Th2 cytokines

  •Activates B-cell

  •Plasma cell – secretes antibodies: IgE (driven by Th2 cytokines)

  •Switch B-cells to produce IgE  

  •Memory B and T cells also formed

Hypersensitivity

• IgE immediately binds to their Fc receptor on mast cells

  •These are Granulocyte /  which can release mediators eg histamine

  •IgE remains bound to mast cell

  •May be no symptoms during sensitisation phase

Mast cell degranulation

• Re-exposure to allergen

  –Allergen binds to IgE on mast cell

  –Cross linking IgE receptor

  –Causes mast cells to degranulate

  –Release of histamine and other inflammatory mediators

  •IMMEDIATE – EARLY PHASE (MINUTES)

  •Histamine

  •Other chemokines / cytokines

  –Leukotrienes, prostaglandins

  •LATE PHASE (HOURS LATER)

  –Other inflammatory mediators

  –Often stimulated by early phase

  –Eg attraction of eosinophils

Type 1L

• Early and late phase

  •Wheal-and-flare reaction

  •(lasts up to 30 min post injection)

  •Raised, red and itchy

  Late-phase reaction

  •(develops approximately

  eight hours later and persists several hours)

  •Painful lump

Allergic rhinitis

Nearly 10% of the population suffer from allergies involving localized

•IgE-mediated anaphylactic reactions

•Most common manifestation is allergic rhinitis – hayfever

•Target organs: mucus membranes of the nose and eyes 

•Congestion, itchiness and sneezing

•eyes red and watery

ATOPY

• Individuals said to be atopic

  •Atopy: clinical presentation of Type I hypersensitivity

  •Usually occur in individuals with family history

  •Show immediate wheal-flare skin reactions to the intradermal injection of common environmental allergens

  •Raised level of serum IgE an atopic individual

  •although a normal IgE serum level does not exclude atopy

  •Effects of IgE mediated allergic reactions vary with the site of mast cell activation

Medications

• Chromoglycate / Nedocromil –

  •inhalational products (asthma)

  •mast cell stabilisers

  •Leukotriene receptor antagonists (asthma)

  •Singulair® / Monteleukast, Accolate®

  •Antihistamines (H1 receptor)

  •Steroids

Type 2

• Also called “Cytotoxic” or “cytolytic” hypersensitivity

  •An appropriate immune reponse to antigen

  •But where antigen is inappropriately situated

  •Damage caused by specific IgG or IgM

   

  Mechanisms

  •Complement-mediated cytolysis (CMC)

  •Antibody-dependent cell mediated cytotoxicity (ADCC)

Complement medicated cytosine

• Antibodies (IgM and IgG) can bind to target cells and activate C1 from the Classical Complement pathway.

  •causing target cell destruction by direct membrane damage

Antibody dependent cell medicated cytotoxicity

• Antibodies (host IgG or IgM) bind to target cells and direct effector cells via Fc receptors (opsonise cells).

  •Effector cells –

  •Phagocytic cells macrophages, neutrophils, eosinophils,

  •Non phagocytic cells – Natural Killer (NK) cells

  •Cells removed by phagocytes or killed by NK cells

Examples

Myasthenia gravis

•Progressive muscle weakness

•auto-antibodies against nicotinic acetyl choline receptors

•failure of muscle to respond to normal neural impulses

•progressive muscle weakness

•(see MSS ISU)

 

•Also transfusion reactions

•ABO blood groups and serum antibodies

Type 3

• Immune complex disease

  •Body may be exposed to an excess of antigen over a protracted period

  •Antibody (IgG) binds to circulating antigen to form a complex.

  •Antibody excess and mild antigen excess, small localised insoluble complexes

  •Localised to site of antigen introduction

  •Moderate to gross antigen excess, soluble complexes are formed

  •Bind to CR1 on erythrocytes, transported to liver and inactivate

Example

• Glomerulonephritis

  •Many cases of glomerulonephritis are associated with circulating complexes.

  •deposited mostly on endothelial side of the glomerular basement membrane

  •Inflammatory process damages the basement membrane

  •leakage of serum proteins and proteinuria

   

Type IV

• •Also called delayed or cell mediated hypersensitivity

  •Exaggerated interaction between antigen and the normal cell mediated immune mechanisms

  •T cell and macrophage response

  •Previously sensitised  T cells exposed to antigen and stimulated

  •Release cytokines to attract macrophages and other cells – cytotoxic t cells

  •Macrophages and other cells will destroy surrounding tissue in an attempt to remove antigen

Type IV examples

• •Mantoux reaction

  •Injection of tuberculin into the skin of an individual previously infected with the mycobacterium

  •have induced a state of cell-mediated immunity (CMI)

  •Erythema (redness) and induration (raised welling)

  •Appears only after several hours (hence the term “delayed”)

  •reaches a maximum at 24–48 h

  •predominantly macrophages