• Clinical science

Hypersensitivity reactions

Summary

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).

Overview

  • 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
    • Sensitization: initial asymptomatic contact with an antigen
    • Effect: harmful immune response following sensitization and subsequent antigen contact
  • Types: Hypersensitivity reactions are classified into four types by Gell and Coombs.
Hypersensitivity classification
Type I: immediate Type II: cytotoxic Type III: immune complex Type IV: delayed (T-cell mediated)
Summary of pathophysiology
  • Preformed IgE antibodies coating mast cells and basophils are crosslinked by contact with free antigen
  • Cell degranulation and release of histamine and other inflammatory mediators
  • IgM or IgG antibodies bind to antigens on the cells of particular tissue types
  • Complement system activation and lysis or phagocytosis of cells
  • Antibody-dependent cell-mediated cytotoxicity (e.g., by natural killer cells)
  • Antibody interference with normal cell function
  • Contact of antigen with presensitized T lymphocytes
  • Presensitized CD4+ T cells recognize antigens on antigen-presenting cells → release of inflammatory cytokines
  • Presensitized CD8+ T cells recognize antigens on somatic cells → cell-mediated cytotoxicity
Examples
* 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)

References:[1][2][3][4][5][6][7][8]

Type I hypersensitivity reaction

Overview

Pathophysiology

  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)

Type I is first and fast.

Cross-reactivity

  • Individuals with allergies may also react to substances that contain particles that are similar to the main antigen.
  • Examples (primary allergen – cross-reactant allergen) [9][10]
    • 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

  • 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 greater than 3 mm) [11]
    • Scratch test: comparable to prick test; a scratch (about 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
    • Tryptase in serum (a relatively specific marker of mast cell activation): if elevated → increased risk of severe reactions
    • Allergen-specific IgE
      • Indicated in patients with known allergic triggers and clinical symptoms
      • Preferable to in vivo skin testing in patients in whom the risk of anaphylaxis is high with skin testing
    • Total IgE
      • 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

Treatment of type I hypersensitivity reactions depends on the etiology of the reaction (see the overview of hypersensitivity reactions above).

Prevention

  • 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!

References:[13][14][15][12][16][17][18][19][9][10][20][11]

Anaphylaxis

Antihistamines and glucocorticoids should be administered in anaphylaxis only after the initial dose of epinephrine IM!

In patients presenting with sudden-onset dyspnea, hoarseness, diffuse skin changes (e.g., urticaria), swelling of the face, and/or hypotension, consider anaphylaxis as a differential diagnosis, especially if they have recently been exposed to a known allergen!
References:[21][22][23][24][25]

Type II hypersensitivity reaction

Overview

Pathophysiology

  • IgM and IgG bind to antigens on cells in the body mistakenly detected as foreign and cause:
    1. Complement activation and Fc-mediated immune cell activation
    2. Cellular lysis or phagocytosis
      • Opsonization phagocytosis and/or complement activation
      • Complement-mediated lysis
      • Antibody-dependent cell-mediated cytotoxicity (NK cells or macrophages)
    3. Inhibition or activation of the downstream signaling pathways

Type II is cy-2-toxic.

References:[1][26]

Type III hypersensitivity reaction

Overview

Pathophysiology

  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 → inflammationvasculitis

Examples

Serum sickness

Arthus reaction

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

References:[1][26][29][30][31][7][27][28]

Type IV hypersensitivity reaction

Overview

4 Ts associated with the type IV hypersensitivity: T cells, Transplant rejection, TB skin tests, Touching (contact dermatitis).

Pathophysiology

T cell-mediated reaction

  1. Sensitization: antigen penetrates the skinuptake by Langerhans cellmigration to lymph nodes and formation of sensitized T lymphocytes
  2. Eruption: repeated contact with antigen → secretion of lymphokines and cytokines (e.g., IFNγ, TNFα) by presensitized T lymphocytesmacrophage activation and inflammatory reaction in the tissue

Examples

Allergic contact dermatitis

  • Epidemiology
    • One of the most common dermatological diagnoses
    • Prevalence of ∼ 1–6%
  • Etiology
  • Course
    • First contact with allergensensitization
    • Repeated contact with allergen → development of a rash after 12–48 hours
  • Rash
    • Intensely pruritic, erythematous, papular
    • Vesicles and serous oozing in severe cases
    • Can spread to other parts of the body through antigen transfer by the hands or in the circulation
  • Diagnosis
    • Diagnosis is based on clinical findings.
    • Patch test: testing for specific allergens in allergic contact dermatitis
      • Allergen is fixed on a patch and then attached to the arm or back.
      • Reaction is recorded at two times: at 48 hours and 4–5 days following initial application
      • Positive result: erythema, papules, and vesicles under the area of contact
      • “Angry back” reaction
        • A few strong positive reactions may cause other patch tests to be falsely positive in patients with “angry backs.”
        • Mechanism unknown
        • Separate, sequential testing of allergens is necessary in these patients.[32]
  • Treatment
    • Avoidance of the allergen is the best treatment and preventative measure.
    • Acute phase

Contact dermatitis due to poison oak, poison ivy, or poison sumac is the most likely cause in a patient presenting with itching, burning, red skin lesions arranged in a linear pattern appearing 24 hours after a camping trip.

Type IV drug reactions

Type IV is fourth and last (i.e., delayed).

References:[1][1][26][33][34][35][36][37][38][39][40][41][32]

Nonallergic hypersensitivity

Pseudoallergy

Infection-induced urticaria

References:[42][43][44][45][46][47]