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]

Types of Hypersensitivity Reactions

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 proposed 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 develop reactions against multiple allergens, giving rise to the classical "atopic triad" of allergic rhinitis, ezcema and allergic asthma.

Sensitization and mechanism

Type I 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.

 

Type I hypersensitivity reactions can be divided into early-phase (seconds-minutes following binding of IgE to allergen) and late-phase reactions (8-12 hours later):

  • 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 hypersensitivityr eactions, their time of release and their effect

Anaphylaxis

    • Severe, potentially life-threatening form of type I hypersensitivity
    • Systemic anaphylaxis occurs when allergen enters 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, which can lead to:

     

    1. Hypovolemic shock (tachycardia, vasoconstriction leading to cool, clammy skin)
    2. Airway obstruction (wheezing, dyspnoea)

     

    • 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.

          Type II hypersensitivity

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

          Type II: Autoimmune haemolytic anaemia (AIHA)

          • Involves the production of autoantibodies targeting erythrocytes
          • Can be divided into warm (37°C) and cold (<37°C) 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. [5]
          • 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 [5]

                  Drug-induced thrombocytopenia

                  • Characterised by formation of "drug-dependent" antibodies [6]
                  • 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

                          Differences between type II and III reactions

                          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. In type II reactions, antibodies bind onto antigens on the patient's cell surface whereas in type III they bind onto soluble antigens.

                          Type III hypersensitivity reactions

                          • Characterized by formation of immune complexes- 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- serum sickness) [7]
                          • These immune complexes can then bind complement or phagocytes, leading to significant tissue damage

                          Table showing examples of type III hypersensitivty reactions

                          Rheumatoid arthritis (RA)

                          • Chronic, systemic, inflammatory disease primarily affecting synovial joints, however it can cause extra-articular manifestations
                          • More common in females, particularly those between 25-50 years of age
                          • Aetiology of RA remains unclear; studies using mouse models have identified several potential autoantigens including type II collagen, proteoglycans and cartilage link proteins [5]
                          • There is evidence of a genetic component to RA; individuals with class-II HLA-DRB1 and HLA-DR4 have increased disease susceptiblity [8]

                          Systemic lupus erythematosus (SLE): another example of type III hypersensitivity (SLE)

                          • Systemic, inflammatory disorder characterised by autoantibody formation and deposition of immune complexes.
                          • Autoantibodies are formed against components of self-cells, particularly the nucleus. These autoantibodies can include anti-chromatin and anti-double stranded DNA antibodies.
                          • In order to produce these autoantibodies, autoantigens are released from dead or dying cells. [10]
                          • Once formed, autoantibodies can bind to autoantigens and form immune complexes which deposit in tissues such as renal glomeruli, joints, skin, lungs and eyes.
                          • In SLE, the immune system is defective at clearing these immune complexes. [7]
                          • Fc regions of autoantibodies attach onto phagocytes, which destroy tissue and induces the release of more autoantigens, thus perpetuating the disease process.

                           

                          Type IV hypersensitivity

                          • 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. [7]

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

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

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

                          [8] The Pathogenesis of Rheumatoid Arthritis; McInnes, I. Schett, G. The New England Journal of Medicine (2011); 365

                          [9] The central role of T cells in rheumatoid arthritis; Cope, AP. Schuzle-Hoops, H. Aringer, M. Clinical and Experimental Rheumatology (2007); 25

                          [10] Autoimmune responses directed against self-antigens; Extract from Janeway's Immunobiology (2001) http://www.ncbi.nlm.nih.gov/books/NBK27155/

                          Further reading

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