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Allergy and Hypersensitivity

Introduction

"Hypersensitivity" describes the immune response that is launched against an innocuous antigen, which in unaffected individuals, would not normally be immunogenic. These antigens include common environmental allergens such as pollen or house dust mite, as well as drugs, insect venom and even self cells.

Two key features underlie hypersensitivity disease:

  • Immune system becomes overactive and is capable of launching excessive, inappropriate immune responses against harmless antigens
  • The individual is pre-sensitized to that particular antigen 

 

There is a degree of overlap between hypersensitivity disease and autoimmune disease, which is characterized by a breakdown in tolerance to self cells. The deposition of self-antigen: antibody complexes allows them to become targets for cells of the immune system, which can result in significant tissue damage.

Classification

Gell and Coombs classification has been used since the 1960s to categorise hypersensitivity reactions according to their pathogenesis; this classification identifies four types of hypersensitivity reaction. [1]

Table showing four categories of hypersensitivity reaction with a description of the mechanism invol

Type I hypersensitivity

  • Type I hypersensitivity reactions, commonly referred to as allergy, occur in individuals who have formed allergen-specific IgE antibodies following exposure and sensitization to specific allergens.
  • Allergens are normally proteins derived from food,drugs, house-dust mite, animal dander and grass and tree pollen.
  • The hygiene hypothesis has been propsed to account for the increasing rates of allergic disease in the UK over the past few decades. It states that decreasing rates of infection in children, due to changes in our environment, are associated with increased rates of allergy. A number of mechanisms for this have been propsed, with most evidence supporting a deviation in helper T cell production from Th1 cells (normally active against microbes in childhood) to Th2 cells (active in allergic disease). [2]
  • Atopy is a genetic predisposition towards developing allergic hypersensitivity reactions; it is estimated that 1 in 3 adults in the UK (equating to 21 million people) are affected by allergy. [3]
  • Atopic individuals normally developreactions against multiple allergens, giving rise to the classical "atopic triad" of allergic rhinitis, ezcema and allergic asthma.

Atopic triad

Sensitization

Hypersensitivity reactions depend upon individuals becoming sensitized to the allergen; this involves producing allergen-specific IgE antibodies. IgE antibodies are paramount to the development of type I hypersensitivity and they depend upon IL-4 production by a specialised subset of T cells (Th2 cells) in order for IgE antibody class-switching to occur within B cells. IgE antibodies are found in very low levels in serum; the majority of them are bound to high-affinity Fc receptors on mast cells and basophils.

Mechanism

Type I hypersensitivity reactions can be divided into early-phase and late-phase reactions:

  • Binding of allergens to allergen-specific IgE receptors results in the cross-linking of IgE molecules, which leads to the degranulation of mast cells and basophils as part of the early-phase reaction
  • Degranulation results in the release of histamine which leads to increased vascular permeability and smooth muscle contraction, which may result in the classical allergic symptoms of breathlessness and rhinitis
  • Inflammatory mediators can also be synthesised as part of the late-phase reaction, including eicosanoid lipid mediators (prostaglandins, leukotrienes) and platelet-activating factor (PAF), while enzymes and chemokines can also be released. [4]

Table showing products of type I hypersensitivity reaction

Anaphylaxis

  • Severe, potentially life-threatening form of type I hypersensitivity
  • Systemic anaphylaxis occurs when allergen enters the bloodstream, allowing it to spread to many different organ systems. In severe cases, large quantities of histamine released leads to capillary leak, vasodilation and oedema, typical features of anaphylactic shock.
  • Airway obstruction can also occur due to oedema of the larynx (upper airway obstruction) and smaller airways (lower airway obstruction), presenting as wheezing and dyspnoea which can be life-threatening. [5]

 

 

  • The skin and GI tract can also be affected, resulting in urticaria and nausea and vomiting.
  • Severe anaphylaxis may be treated with adrenaline (epinephrine), airway management and fluid resuscitation.
  • Localised anaphylactic reactions are generally less serious and are restricted to one organ system only. The organ system affected depends on the route of entry of the allergen; ingested allergens normally manifest as GI symptoms (diarrhoea, nausea and vomiting), while inhaled allergens such as pollen present as allergic rhinitis or allergic asthma.

Other types of hypersensitivity

The mechanism of type II and type III hypersensitivity reactions also depend on antibody production, however unlike type I reactions which are IgE-mediated, types II and III typically involve IgG antibodies. The mechanisms of type II and III reactions are similar and can be hard to differentiate.

Blood: a target for type II hypersensitivity?

The most common types of type II hypersensitivity reactions involve antibody-mediated destruction of blood cells.

Autoimmune haemolytic anaemia (AIHA) 

  • Involves the production of autoantibodies targeting erythrocytes
  • Can be divided into warm (37oC) and cold (<37oC) types depending on the temperature at which the antibody binds to the erythrocyte; this also determines which class of antibody binds
  • IgM antibodies are the only antibody to bind in cold AIHA while IgG binds in warm AIHA. [6]
  • Following this, IgM and IgG activate either intravascular or extravascular haemolysis.
  • In cold AIHA, complement proteins can bind onto the Fc region of IgM antibodies, resulting in the lysis of erythrocytes in the circulation (intravascular haemolysis)
  • In warm AIHA, IgG antibodies are not as effective at activating complement and erythrocytes undergo extravascular haemolysis where they are phagocytosed by macrophages in the spleen

Diagram illustrating pathogenesis of AIHA

Further examples

Haemolytic disease of the newborn

  • Caused by incompatability between fetus and mother red blood cell antigens, including rhesus antigens
  • Sensitization occurs when cells from Rh+ baby pass across the placenta into Rh- mothers circulation
  • Mother forms anti-Rh antibodies, however the first pregnancy is not affected
  • In subsequent pregnancies of a Rh+ fetus, these immunoglobulins may pass across the placenta and destroy fetal erythrocytes
  • Anti-D (anti-Rh) is now given intramuscularly following delivery, provided that mother is RhD negative, the fetus is RhD positive and the mother has not already been immunized [6]

Drug-induced thrombocytopenia

  • Characterised by formation of "drug-dependent" antibodies [7]
  • These bind simultaneously to surface glycoproteins on platelets and the drug (ie- drug needs to present for antibodies to bind to platelets)
  • Hundreds of drugs implicated however most common are quinine, quinidine, heparin, penicillin and NSAIDs
  • Following binding, platelets are destroyed by complement proteins which bind to Fc regions of IgG
  • Clinically, this condition leads to clotting disorders, characterised by bruising, abnormal bleeding and purpuric rashes

Immune complexes: Type III hypersensitivity

Table showing examples of type III hypersensitivity diseases
  • Immune complexes are soluble antigen:antibody complexes
  • They can deposit in particular tissues and give rise to either a localized type III hypersensitivity reaction (e.g- Arthus reaction) or a generalized type III hypersensitivity reaction (e.g- rheumatoid arthritis)
  • These immune complexes can then bind complement or phagocytes, leading to significant tissue damage

Type IV hypersensitivity reactions

  • Unlike the previous types of hypersensitivity, type IV reactions are not mediated by antibodies
  • Instead they are mediated by antigen-specific T lymphocytes (CD4+ and CD8+ T cells) which recognise antigens presented by antigen-presenting cells (APCs)
  • Following activation, these T cells can secrete cytokines which can recruit other inflammatory leukocytes to the affected area

 

Contact dermatitis

  •  This consists of an induction phase involving the crossing of allergens across the epidermis into the lower layers of the skin, where they can be presented by dendritic cells (APCs) to naive T cells, which then develop into antigen-specific T cells.
  • Following induction, there is an elicitation phase whereby allergen presentation by dendritic cells results in the activation of antigen-specific T cells and the release of inflammatory cytokines
  • This leads to a localised hypersensitivity reaction in the epidermis, characterised by erythema, cellular infiltrate and intraepidermal abscesses. [8] 

References

[1] Gel and Coombs classification; The Free Dictionary by Farlex

http://medical-dictionary.thefreedictionary.com/classification

[2] The "hygiene hypothesis" for autoimmune and allergic diseases: an update. Okada H. Kuhn C. Feillet H. Bach JF. Clinical and Experimental Immunology (2010); 160

[3] The rise of "homefever"; Allergy UK (2010)

http://www.allergyuk.org/downloads/resources/reports/IAW_Report_2011.pdf

[4] The role of platelet activating factor in allergic respiratory disease; Page CP. British Journal of Clinical Pharmacology (1990); 30

[5] American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergenct Cardiovascular Care; Part 10.6 Anaphylaxis. Circulation (2005); 112

[6] Kumar & Clark's Clinical Medicine: Seventh Edition; Kumar P. Clark M; Saunders Elseview (2009)

[7] Drug-induced thrombocytopenia; Visentin GP. Liu CY. Haematology/Oncology clinics of North America (2007); 21(4)

[8] Janeway's immunobiology: Seventh Edition; Murphy K. Travers P. Walport M. Garland Science (2008)

Further reading

  • Immunology- Hypersensitivity reactions; Dr Abdul Ghaffar; University of South Carolina School of Medicine

http://pathmicro.med.sc.edu/ghaffar/hyper00.htm

  • Janeway's immunobiology: Seventh Edition; Murphy K. Travers P. Walport M; Garland Science (2008) Chapter 13: Allergy and Hypersensitivity (P555-598)
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