Hypersensitivity reactions

Last updated: April 28, 2022

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Hypersensitivity reactions occur when the normally protective immune system responds abnormally, potentially harming the body. Various autoimmune disorders as well as allergies fall under the umbrella of hypersensitivity reactions, the difference being that allergies are immune reactions to exogenous substances (antigens or allergens), whereas autoimmune diseases arise from an abnormal immune response to endogenous substances (autoantigens). A symptomatic reaction only occurs in sensitized individuals, i.e., they must have had at least one prior asymptomatic contact with the offending antigen. Hypersensitivity reactions are commonly classified into four types. Type I hypersensitivity reactions are immediate allergic reactions (e.g., food and pollen allergies, asthma, anaphylaxis). Type II hypersensitivity reactions are referred to as cytotoxic, as they involve antibodies that are specific to particular tissues within the body and cause destruction of cells in these tissues (e.g., autoimmune hemolytic anemia, Goodpasture syndrome). Type III hypersensitivity reactions are immune complex-mediated, with tissue damage caused by antigen-antibody complex deposition (e.g., many vasculitides and glomerulonephritides). Type IV hypersensitivity reactions (e.g., TB skin tests, contact dermatitis) are delayed and cell-mediated and are the only hypersensitivity reaction that involves sensitized T lymphocytes rather than antibodies. Unlike true hypersensitivity reactions, which occur after sensitization, nonallergic hypersensitivity reactions (e.g., pseudoallergies) cause mast cell activation and histamine release after initial exposure to a trigger substance (e.g., radiocontrast media).

See also “Anaphylaxis.”

  • Definitions
    • Hypersensitivity reaction: a condition in which the normally protective immune system has a harmful effect on the body
    • Allergy: an abnormal immunological response to an otherwise harmless environmental stimulus (e.g., food, pollen, animal dander)
    • Autoimmune disease: an abnormal immunological response directed against an antigen that is actually part of the body itself
  • Stages
  • Types: Hypersensitivity reactions are classified into four types.
Hypersensitivity classification [1][2]
Summary of pathophysiology Examples
Type I: immediate
Type II: cytotoxic
Type III: immune complex

Type IV: delayed (T-cell mediated)

* Autoantibodies present

Drugs can cause all four types of hypersensitivity reactions.

The hypersensitivity reactions can be memorized with the mnemonic ACID: AAllergic/Anaphylactic/Atopic (Type I); CCytotoxic (Type II); IImmune complex deposition (Type III); DDelayed (Type IV)



  1. IgE is formed as a result of prior sensitization (i.e., previous contact with the antigen) and coats mast cells and basophils.
  2. Subsequent encounter with antigen results in an IgE-mediated reaction by preformed IgE antibodies: free antigen binds to two adjacent IgE antibodies (crosslinking) → degranulation of cells
  3. Release of histamine and other mediators (e.g., prostaglandin, platelet-activating factor, leukotrienes, heparin, tryptase), leading to:
  4. Mast cell secretion of cytokines and other proinflammatory mediators → eosinophil and neutrophil chemotaxis late-phase reaction → inflammation and tissue damage

Type I is Fast and Furious.

Cross-reactivity [5][6]

  • Description: Individuals with allergies may also react to substances that contain particles that are similar to the main antigen.
  • Examples (primary allergen – cross-reactant allergen)
    • Pollen – various foods (e.g., apple, hazelnut, carrot, kiwi, apricots, peaches)
    • Mites – crustaceans
    • Latex – exotic fruits (e.g., banana, avocado, kiwi)
    • Bird dander – egg yolk
    • Cat dander – pork

Clinical findings

Diagnostics [10]

In vivo skin testing

  • General principle: Small amounts of allergens (e.g., pollen) are introduced into the skin to test for a local allergic reaction.
    • Higher sensitivity may be achieved with more invasive testing. However, the more invasive the test, the higher the risk of anaphylactic shock.
    • Test results are usually available after 20 minutes.
    • Evaluation: skin reddening and size of wheals
  • Skin prick test
    • Tiny amounts of various allergens are applied to the skin; a lancet is then used to prick the surface of the skin so that allergen extracts may enter.
    • Positive result: wheal equal to or larger than histamine control (or > 3 mm)
  • Scratch test
    • Comparable to prick test
    • A scratch (∼ 1 cm) is made and the allergen subsequently applied.
  • Intradermal test: intradermal injection of small amounts of the allergen on the back or arm

In vitro testing (blood tests)

  • Tryptase in serum (a relatively specific marker of mast cell activation): Elevated levels indicate an increased risk of severe reactions.
  • Allergen-specific IgE test
  • Total IgE levels
    • Often elevated in patients with allergic conditions
    • Because normal levels of IgE do not exclude allergy, in vitro testing should not be used as a definitive test for allergy diagnosis.


Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see “Hypersensitivity classification” above).

Allergen immunotherapy (desensitization)

  • Indication
  • Method
    • Only available for some allergens but can be quite effective
    • Application of specific antigen in subclinical dose (subcutaneous, mucosal)
    • Slow escalation of dose
    • Goal: ↑ production of IgG antibodies instead of excessive IgE production (isotype switching) [11]
    • Duration of treatment: at least 3 years
  • Prognosis
    • Success in up to ⅔ of patients
    • Younger patients see comparatively more benefits.
    • Higher success rates in patients with sensitivity to only one allergen (monovalent) as opposed to patients with sensitivity to many allergens (polyvalent)


Contact prevention and avoidance of offending agents is the best treatment for allergies.



IgM and IgG mistakenly bind to surface antigens of the cells in the body, which results in:

Type II is cy-2-toxic and consists of 2 components (antigen and antibody)



  1. Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex (antigen-antibody complex)
  2. Immune complexes are deposited in tissue, especially blood vessels initiation of complement cascade release of lysosomal enzymes from neutrophils cell death inflammation vasculitis

Type III means three things stuck together: antigen + antibody + complement

Examples [12][13]

Serum sickness

Arthus reaction

Other examples



Compared to type I-III hypersensitivity reactions, which are antibody-mediated, type IV reactions are mediated by T cells. Type IV hypersensitivity reactions involve two major steps:

  1. T cell sensitization: : skin penetration by the antigen uptake of the antigen by Langerhans cell → migration to lymph nodes → formation of sensitized T lymphocytes
  2. Presensitized T cell response (after repeated contact with the antigen)

To remember the specifics of type IV hypersensitivity reaction, think of the 5 Ts: T cells, Transplant rejection, TB skin tests, “Touching” (contact) dermatitis, Terminal (last; delayed).


Type IV drug reactions

Other examples


Infection-induced urticaria

  1. Mandallaz et al.. Bird-egg syndrome. Cross-reactivity between bird antigens and egg-yolk livetins in IgE-mediated hypersensitivity. International Archives of Allergy and Applied Immunology. undefined; 87 (2): p.143-50.
  2. Relationship of Dust Mites and Crustaceans. https://www.worldallergy.org/ask-the-expert/answers/relationship-of-dust-mites-and-crustaceans-fernandez-caldas. Updated: July 13, 2013. Accessed: April 17, 2019.
  3. Kanani A, Schellenberg R, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2011; 7 (Suppl 1): p.S9. doi: 10.1186/1710-1492-7-s1-s9 . | Open in Read by QxMD
  4. Luskin, Luskin. Anaphylaxis and Anaphylactoid Reactions: Diagnosis and Management. American Journal of Therapeutics. undefined; 3 (7): p.515-520.
  5. Riedel MA, Casillas AM. Adverse Drug Reactions: Types and Treatment Options. Am Fam Physician. 2003; 68 (9): p.1781-1791.
  6. Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010; 126 (6 Suppl): p.S1-58. doi: 10.1016/j.jaci.2010.10.007 . | Open in Read by QxMD
  7. Fujita et al.. Mechanisms of allergen-specific immunotherapy. Clinical and translational allergy. 2012; 2 (2). doi: 10.1186/2045-7022-2-2 . | Open in Read by QxMD
  8. Adverse Events following Immunization: Interpretation and clinical Definitions Guide.
  9. Stratton KR, Howe CJ. Adverse Events Associated with Childhood Vaccines, Evidence Bearing on Causality. National Academies ; 1994
  10. Liang, et al.. Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2018 .
  11. Lee et al.. Clinician's Handbook of Preventive Services: Put Prevention Into Practice. DIANE Publishing
  12. Choudhary S, McLeod M, Torchia D, Romanelli P. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. J Clin Aesthet Dermatol. 2013; 6 (6): p.31-7.
  13. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Elsevier Saunders ; 2015
  14. Murphy KM. Janeway's Immunobiology. Garland Science ; 2011
  15. Lum G, Szuflad P, D'Amarino M. A Patient With a Low IgA Level Requiring Transfusion During CABG Surgery. Lab Med. 2015; 36 (6): p.353-356. doi: 10.1309/1BTM2E2H81C9DVJN . | Open in Read by QxMD
  16. Latex Allergy. http://www.aafa.org/page/latex-allergy.aspx. Updated: October 1, 2015. Accessed: March 9, 2017.

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