Hypersensitivity: Immunological


Immunological hypersensitivities are immunological states where the immune system produces harmful responses upon reexposure to sensitising antigens. There is a sensitisation phase where the memory T and B cells develop and an effector phase where they elicit inflammatory responses. In 1963, Gell and Coombs classified hypersensitivity into four types by their different effector mechanisms. Type 1 encompassed the IgE‐mediated hypersensitivities, type II the action of antibodies on cells, type III the action of antigen–antibody complexes and type IV the direct action of lymphocytes exemplified by delayed hypersensitivity. A category of type V, introduced by others, is sometimes used to describe noncytotoxic responses mediated by antibodies to affect cell function, especially applied to the endocrine system. Subcategories of type IV were introduced to categorise the clinically distinct hypersensitivities induced by different types of T‐cell response and are elaborated here in terms of Th1, Th2 and Th17 differentiation lineages.

Key Concepts

  • Type I hypersensitivity consists of the IgE‐mediated immediate hypersensitivity responses found in anaphylaxis and asthma attacks and slower responses caused by inflammatory cascades triggered by mediators released in the immediate reaction and by accompanying Th2 responses.
  • Type II hypersensitivity is mediated by the direct effects of antibody and killing mediated by complement or antibody‐dependent cytotoxicity.
  • Type III hypersensitivity is mediated by the formation of antigen–antibody complexes that either activate complement for direct toxic effects or attract inflammatory cells, especially neutrophils that bind the complexes by Fc receptors and cause tissue damage.
  • Type IV hypersensitivity can be subdivided depending on the differentiation lineage of the sensitised T cells. The Th1, Th2 and Th17 lineages are determined by innate immune mechanisms activated by tissue damage and direct interactions with innate immune receptors and are typically respectively determined by the production of IL‐12, IL‐4 and IL‐23.
  • Type IVa corresponds to the classical monocytic tuberculin‐type delayed hypersensitivity mediated by Th1 cells and Th17/Th1 cells.
  • Type IVb corresponds to the eosinophilic inflammation produced by Th2 cells.
  • Type IVc corresponds to tissue damage produced by cytotoxic T cells and can have either granzyme B/perforin or Fas/FasL killing mechanisms.
  • Type IVd hypersensitivity produces tissue damage by the infiltration of neutrophils attracted by IL‐8 from Th17 responses.
  • Type V hypersensitivity categorises direct effects of antibodies on cell functions for example the agonist effects of antibodies binding to endocrine receptors.
  • The tissue damage in individual hypersensitivity reactions is often caused by a mixture of the types of hypersensitivity reaction, for example, a combination of types I and IVa, IVb and IVc in contact hypersensitivity.

Keywords: hypersensitivity; allergy; Gell and Coombs; immediate hypersensitivity; delayed hypersensitivity; type I hypersensitivity; type II hypersensitivity; type III hypersensitivity; type IV hypersensitivity; type V hypersensitivity

Figure 1. Development of Th1, Th2 and Th17 lineages during antigen‐induced sensitisation. The interaction of antigen mainly with epithelial cells (EC) induces cytokines that activate further cytokines from innate lymphoid cells (ILC). The EC and ILC‐produced cytokines along with the direct affect of the antigens program dendritic cells to affect the differentiation of the Th lineages leading to Th1, Th2 and Th17 cells. The Th17 lineage is very plastic (see text) and under Th1 and Th2 conditions can further differentiated into Th17‐Th1 and Th17‐Th2 subtypes respectively.
Figure 2. Outline of mechanisms leading to Types 1–V hypersensitivities and participation of different Th and Tc lineages. The Th cells act directly for type IV hypersensitivities and through antibody production for the others.
Figure 3. Passive cutaneous anaphylaxis (PCA) is used to detect IgE antibodies. Serum from an immune mouse was injected intradermally into rat skin where the IgE antibodies were able to arm the local mast cells. The antigen was then injected intravenously with Evans blue dye. The oedema produced by the release of the mast cell mediators is detected by the extravasation of the dye. IgE antibodies can only bind to the FcεRI of the same or closely related species, and were once called homocytotrophic antibodies. IgE antibodies can also be measured by enzyme‐linked immunosorbent assay (ELISA) and other solid‐phase assays such as the radioallergosorbent test (RAST).
Figure 4. Histology of lung inflammation in responses to an aeroallergen. Section (a) is of a lung from a naïve mouse. Section (b) is from a mouse sensitised to an inhaled allergen (papain). Disruption of the airway epithelium and eosinophilic subepithelial inflammation is evident.
Figure 5. Histology of the contact hypersensitivity reaction to oxazolone painted on the ear. (a) Section of an ear of mouse sensitised to oxazolone showing a mononuclear cell infiltration and oedema. (b) Section of an ear from a nonsensitised mouse after the application of oxazolone that does not show the inflammatory infiltrate and swelling. Haematoxylin and eosin staining; resolution, ×125.
Figure 6. Eosinophilia. Cells collected from the airway fluid of allergen sensitised mice and stained with haematoxylin and eosin are shown. The distinctive eosinophils with pink staining cytoplasm were present in increased numbers in sensitised mice ((a) 20×magnification and (b) 100×magnification).


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Further Reading

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Siracusa MC, Kim BS, Spergel JM and Artis D (2013) Basophils and allergic inflammation. Journal of Allergy and Clinical Immunology 132: 789–801.

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Thomas, Wayne R, and Cunningham, Paula T(Nov 2015) Hypersensitivity: Immunological. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000964.pub3]