Allergy and Hypersensitivity

Hypersensitivity occurs when the immune system over-responds to harmless antigens that result in harm to the body. There are four types of hypersensitivity reaction:

  • Type I: Classical allergy, mediated by the inappropriate production of specific IgE antibodies to harmless antigens
  • Type II: Caused by IgG and IgM antibodies that bind to antigens cells or tissues leading to cell or tissue damage
  • Type III: Caused by antibody-antigen complexes being deposited in tissues, where they activate the complement system and cause inflammation
  • Type IV: A delayed type hypersensitivity reaction caused by T helper cells traveling to the site of antigens, recruiting macrophages and causing inflammation

 

Type I Hypersensitivity (allergy)

Allergens are antigens that produce allergic reactions (e.g. peanuts, penicillin, pollen, house dust mite).

IgE mediated allergy is responsible for a number of atopic conditions:

  • Food or drug allergy
  • Asthma
  • Allergic rhinitis
  • Hayfever
  • Eczema

Sensitisation is the term to describe the initial event that lead to the specific IgE being developed for that allergen

  • CD4 cells recognise the allergen
  • They proliferate and differentiate into T Helper 2 cells
  • These Th2 cells release IL-4, that stimulates the production of IgE by B Cells specific to that allergen
  • The IgE then circulates the blood and binds to mast cells

The Allergic Response involve activation of mast cells

  • On re-exposure to the allergen, it binds to the IgE and causes mast cell degranulation, releasing cytokines including histamine and TNF-α.
  • Histamine causes vasodilation, increased vascular permeability and broncho-constriction, causing symptoms of allergy (itch, flushing, rash, angioedema and wheeze). This happens within minutes of exposure to the allergen.
  • TNF-α causes a localised inflammatory process at the site of exposure. This takes a few hours and is called the late phase reaction.
  • The allergic response can vary from mild reactions involving itch, mild swelling and hives to severe reactions called anaphylaxis that can lead to systemic shock (from severe vasodilation) and complete airway closure from broncho-constriction and oedema.
  • Allergic responses to allergens tend to get worse on repeat exposures due to increased sensitisation.
  • Mast cell tryptase can be measured to confirm the diagnosis of anaphylaxis, and will be raised after an anaphylactic reaction.

 

Type II Hypersensitivity

This involves IgG and IgM antibodies that bind to the antigens on cells or tissues that result in a reaction that is damaging to the person. Here are three examples:

  • Blood transfusion reactions: When blood is transfused and the ABO group of the donor does not match the recipient, the antibodies in the recipients blood attack the donors blood causing haemolysis of the donor red blood cells, rapidly releasing the contents of those cells and causing a toxic reaction.
  • Haemolytic Disease of the Newborn: When a rhesus negative mother has a rhesus positive baby, exposure to the babies blood during birth will cause the mother to produce IgG to rhesus. If she has another rhesus positive baby, that IgG will cross the placenta into the babies bloodstream and cause haemolysis of the babies red blood cells.
  • Goodpastures Syndrome: antibodies specific to a type of collagen in the the glomerular basement membrane in the kidneys and lungs lead to inflammation and destruction of the basement membrane leading to pulmonary haemorrhage and kidney failure.

 

Type III Hypersensitivity

This involves antibodies (mainly IgG and IgM) binding to antigens, which forms immune complexes. These immune complexes then become deposited in tissues, where they activate the complement system and cause inflammation.

The difference compared with Type II, is that in Type II it is the antibodies binding to the target that causes inflammation and damage of the target, whereas in type III, the antibodies bind to antigens, and it is the antibody-antigen complexes that travel to their target organs where they cause inflammation and damage.

Here are two examples:

  • Rheumatoid arthritis: Rheumatoid factor is IgM antibody that recognises IgG antibodies as an antigen, specifically the Fc portion. It is IgM against IgG. This leads to formation of antibody-antigen complexes in the blood. These become deposited in joints, skin, lungs and other organs where they activate the complement system and lead to chronic inflammation.
  • Farmers lung: Mould and hay spores are breathed into the lungs. Antibodies against the mould or hay antigens form antibody-antigen complexes. These are deposited in the lung tissues and alveoli where they activate the complement system and lead to inflammation of the lung tissue.

 

Type IV Hypersensitivity

This is also called delayed type hypersensitivity. This is because it takes 24-72 hours for a reaction to occur. It is a “cell mediated” hypersensitivity reaction. This is what happens:

  • Antigens enter tissues
  • They get picked up by dendritic cells
  • Dendritic cells deliver the antigens to the relevant CD4 cell
  • CD4 cells proliferate and differentiate into T helper cells
  • T helper cells travel to the tissues where to original antigen presented
  • T helper cells release cytokines that recruite macrophages and both cells release proinflammatory cytokines that result in localised inflammation
  • In skin this presents as a contact dermatitis

Some examples of this are:

  • Poison Ivy: contact with poison ivy antigens leads to a delayed contact dermatitis via the
  • Nickel and gold: some people react to nickel or gold. Small chemicals from the metal enter the skin and alter proteins in a way that turns them into antigens. These antigens then lead to contact dermatitis
  • Mantoux test: this is a test for TB contact. TB antigens are injected superficially into the skin. If the person has had previous TB contact, these antigens stimulate an immune response from T cells in the way described above, leading to a localised inflammation around the infection site.
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