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. 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.”
- 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
- Types: Hypersensitivity reactions are classified into four types.
|Hypersensitivity classification |
|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: A – Allergic/Anaphylactic/Atopic (Type I); C – Cytotoxic (Type II); I – Immune complex deposition (Type III); D – Delayed (Type IV)
- Type I hypersensitivity reactions are referred to as “immediate reactions”; they are antibody-mediated and include anaphylactic and atopic immune responses.
- For the specific causes of type I hypersensitivity, see “ ” above.
- IgE is formed as a result of prior sensitization (i.e., previous contact with the antigen) and coats mast cells and basophils.
- 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
- Release of histamine and other mediators (e.g., prostaglandin, platelet-activating factor, leukotrienes, heparin, tryptase), leading to:
- 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.
- 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
- Main symptoms: : pruritus, edema, rash, rhinitis, bronchospasm, and abdominal cramping
Specific manifestations 
- Urticaria (hives)
- : due to mast cell activation in the dermis and/or subcutaneous tissue
- can be caused by: 
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.
- Skin prick test
- Scratch test
- 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
Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see “ ” above).
- Drug reactions
- Emergency (self‑) medication: : Patients with known allergic reactions to food or insect venom, for example, may be provided with antihistamines, corticosteroids, and epinephrine auto-injectors for self-treatment
Allergen immunotherapy (desensitization)
- Breastfeeding: There is conflicting data regarding the beneficial effect of breastfeeding in preventing asthma and atopic dermatitis.
Contact prevention and avoidance of offending agents is the best treatment for allergies.
- Type II hypersensitivity reactions, or “cytotoxic reactions,” are antibody-mediated and responsible for a number of autoimmune disorders.
- Clinical features, diagnostics, and treatment depend on the underlying etiology (see “” above).
- Distribution of disease: often limited to a particular tissue type
- Diagnosis may involve autoantibody testing (see “ ”) and the .
- Cellular destruction
- Impaired cellular function
- Type III hypersensitivity reactions, also referred to as immune complex reactions, are antibody-mediated.
- Clinical features, diagnostics, and treatment depend on the underlying etiology (see “” above).
- Distribution of disease: systemic
- Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex (antigen-antibody complex)
- Immune complexes are deposited in tissue, especially blood vessels → initiation of complement cascade → release of lysosomal enzymes from neutrophils → cell death → inflammation → vasculitis
- Definition: Serum sickness is a classic example of a type III hypersensitivity reaction, which usually develops as a complication of antitoxin or antivenom administration.
- Antivenom or antitoxin containing animal proteins or serum (→ “serum” sickness), such as:
- Medications most frequently antibiotics (e.g., penicillin, amoxicillin, cefaclor, trimethoprim-sulfamethoxazole)
- Infections: Hepatitis B virus
- Pathophysiology: exposure to an antigen (e.g., antivenom, drug) → formation of antibodies → deposition of antibody-antigen complexes in tissue → activation of the complement cascade → tissue damage and systemic inflammation
- Clinical features: Symptoms appear 1–2 weeks following initial exposure (because antibodies take several days to form), and usually resolve within a few weeks after discontinuation of the offending agent.
Subtypes and variants: serum sickness-like reaction
- Epidemiology: much more common than actual serum sickness
- Etiology: similar to that of serum sickness
- Pathogenesis is unclear (likely not the result of a type III hypersensitivity reaction).
- Clinical features: difficult to distinguish from classic serum sickness, as they both present similarly (see “Clinical features” above)
- Diagnostics: Urinalysis may show mild proteinuria.
- Treatment: : Stop the offending agent.
- Prognosis: excellent once the offending drug is stopped or the causative infection has resolved clinically
- Definition: local subacute type III hypersensitivity reaction
- Etiology: : vaccination against tetanus, diphtheria
- Pathophysiology: intradermal antigen injection in a presensitized individual (previously exposed to the antigen, with preformed, antigen-specific IgG in the serum) → formation of antigen-antibody complexes in the skin → complement activation → local inflammation and possibly necrosis
- Clinical features
- Prevention 
- Type IV hypersensitivity reactions are referred to as delayed and cell-mediated.
- For the specific causes of type IV hypersensitivity, see “” above.
- Clinical features, diagnostics, and treatment depend on the underlying etiology.
- T cell sensitization: : skin penetration by the antigen → uptake of the antigen by Langerhans cell → migration to lymph nodes → formation of sensitized T lymphocytes
- Presensitized T cell response (after repeated contact with the antigen)
Type IV drug reactions
- Local drug reaction following topical application of drug; see “ .”
Exanthematous drug eruption: maculopapular or morbilliform (measles-like) drug eruption
- Most commonly develops 5-14 days after receiving an offending drug (most commonly antibiotics, e.g.,“ampicillin rash” following ampicillin administration for infectious mononucleosis)
- Typically manifests with erythematous macules and papules on the trunk and proximal extremities that resolve after discontinuation of the offending drug
- Associated symptoms include pruritus and low-grade fever
- DRESS syndrome (drug reaction with eosinophilia and systemic symptoms syndrome; also known as drug-induced hypersensitivity syndrome) 
- Description: : an IgE-independent reaction that is clinically indistinguishable from type I hypersensitivity
- Substances cause direct (or complement-mediated in case of anaphylactoid reaction) mast cell activation and subsequent release of histamine not mediated by immunoglobulin.
- In contrast to true anaphylactic reactions, no sensitization to allergens is required (i.e., first contact can already lead to anaphylactic shock)
- Clinical features: urticaria, pruritus, edema, hypotension, or even symptoms of anaphylactic shock
- Diagnostics: clinical diagnosis
- Pathophysiology: mast cell activation and subsequent release of histamine, most likely IgE-independent
- Clinical features: See “
- Diagnostics: clinical diagnosis based on physical examination and patient history