Inappropriate or exaggerated immune response to an antigen (allergen or self) that causes host tissue damage; classically categorized into four types (I–IV) by the Gell–Coombs system.
Hypersensitivity mechanisms underlie extremely common conditions (e.g. hay fever affects ~1 in 10 people worldwide, asthma hundreds of millions, autoimmune diseases ~1 in 12). They can also be life-threatening (e.g. anaphylaxis). Recognizing the type of reaction guides diagnosis (allergy testing vs autoantibody assays) and appropriate therapy (e.g. epinephrine for anaphylaxis vs immunosuppression for autoimmunity). These classifications are frequently tested on exams.
🔴 Type I (Immediate IgE-mediated) – Classic allergic reactions occurring within minutes of exposure: urticaria (hives), itching, bronchospasm (wheezing), angioedema (swelling), hypotension. Triggers are typically environmental allergens (foods, pollen, insect stings, drugs, latex, etc.), and severe cases present as anaphylaxis.
🟠 Type II (Cytotoxic IgG/IgM-mediated) – Organ-specific autoimmune or drug-induced reactions. Antibodies target cells or ECM, causing tissue-specific damage. Examples: hemolytic anemia or thrombocytopenia (antibody-coated cells destroyed → pallor, jaundice, bleeding), Goodpasture syndrome (anti-GBM antibodies → lung hemorrhage + glomerulonephritis with hemoptysis and hematuria), or pemphigus/bullous pemphigoid (antibodies to skin components → blistering).
🟡 Type III (Immune complex-mediated) – Immune complex deposition causes systemic or localized inflammation, typically with a delayed onset (days to weeks after antigen exposure). Presents with vasculitic features: e.g. serum sickness (fever, rash, arthritis ~1 week after antiserum/drug exposure), post-streptococcal glomerulonephritis (hematuria after strep infection), or lupus (immune complexes affect joints, kidneys, etc.). Findings often include complement activation (potentially low C3/C4) and neutrophil-rich inflammation.
🟢 Type IV (Delayed T-cell-mediated) – Delayed (>48h) inflammatory reactions mediated by sensitized T lymphocytes, not antibodies. Examples: contact dermatitis (e.g. poison ivy or nickel rash developing 1–2 days after contact), tuberculin skin test (induration peaks ~48–72h), transplant rejection and granulomatous inflammation (like in TB or sarcoidosis) due to Th1-cell activation of macrophages. Often presents with erythema, itching or tissue-specific damage without any detectable antibodies.
Timing is key: classify by onset after exposure – minutes suggests Type I; hours suggests Type II or III; 48–72 hours suggests Type IV.
Identify the immunologic mechanism: look for evidence of IgE (allergy test positive → Type I), specific autoantibodies (e.g. Coombs or anti-tissue antibody → Type II), circulating immune complexes (low complement levels, granular immunofluorescence on biopsy → Type III), or T-cell involvement (e.g. contact patch test positive → Type IV).
Diagnostic tests: Use skin prick tests or allergen-specific IgE levels for suspected Type I (immediate) allergies; direct/indirect Coombs tests for antibody-mediated cytotoxic reactions (Type II); check complement levels, immune complex assays, or tissue biopsy (immunofluorescence) for immune complex disease (Type III); and perform patch testing for contact (Type IV) allergies.
Mechanistic clues: Type II reactions tend to be localized to specific tissues (e.g. one organ system affected), whereas Type III often cause multisystem or vasculitic manifestations due to complexes circulating. Recognize patterns like linear vs granular deposition on immunofluorescence (linear in anti-GBM disease = Type II vs granular in immune complex GN = Type III) to distinguish mechanisms.
Condition
Distinguishing Feature
Non-IgE (anaphylactoid) reaction
Clinically similar to anaphylaxis but due to direct mast cell activation (no IgE); e.g. contrast dye, opioids.
Hereditary angioedema
Recurrent angioedema without urticaria, caused by C1 inhibitor deficiency (bradykinin-mediated); not an IgE allergy.
Stevens–Johnson syndrome
Severe delayed drug reaction with mucosal involvement and skin necrosis (often T-cell mediated Type IV), distinct from immediate IgE-mediated hives.
Irritant contact dermatitis
Skin inflammation from chemical irritation (non-immune); lacks the sensitization and T-cell mediation of allergic contact dermatitis.
Type I (Immediate): Ensure airway; give epinephrine IM promptly for anaphylaxis. Adjuncts include antihistamines for urticaria, bronchodilators for bronchospasm, and corticosteroids to reduce late-phase inflammation. Long-term, emphasize allergen avoidance and consider desensitization immunotherapy for severe recurrent allergies.
Type II (Cytotoxic): Remove or treat the offending agent (e.g. stop the drug, treat infection). Immunosuppressive therapy is mainstay – typically high-dose glucocorticoids to reduce antibody production and inflammation. In severe cases, add IVIG (to neutralize pathogenic antibodies) or perform plasmapheresis to directly remove antibodies (e.g. in Goodpasture syndrome). Preventive measure: for hemolytic disease of newborn (Rh incompatibility), give RhoGAM to Rh– mothers.
Type III (Immune complex): Address underlying cause (treat infection, discontinue offending drug) and use immunosuppressants to dampen ongoing inflammation. Corticosteroids are often used (e.g. for lupus nephritis or serum sickness) to reduce immune complex deposition damage. For chronic immune complex diseases like lupus or rheumatoid arthritis, steroid-sparing agents (DMARDs such as methotrexate, cyclophosphamide, or biologics like TNF inhibitors) are employed.
Type IV (Delayed):Avoid the trigger allergen or antigen when possible (e.g. known contact allergens). For allergic contact dermatitis, use topical corticosteroids to reduce inflammation; more severe reactions may require systemic steroids with a taper. In severe T-cell mediated reactions like Stevens–Johnson syndrome, hospitalize for supportive care (fluid/electrolyte management, wound care). Chronic Type IV conditions (e.g. transplant rejection, autoimmune) may need potent immunosuppressants (cyclosporine, tacrolimus, etc.).
Types I, II, III are all antibody-mediated (Type I involves IgE; II and III involve IgG/IgM), whereas Type IV is the only one mediated by T cells (no antibodies involved).
Type II can cause cell destruction (via complement/phagocytes, e.g. hemolysis) or cellular dysfunction without cell death (antibodies acting as agonist or blocker, e.g. Graves disease or myasthenia gravis). USMLE classifies both as Type II hypersensitivity.
Type III reactions often consume complement (e.g. low C3/C4 in lupus or serum sickness) due to widespread immune complex activation of the complement cascade. Think immune complexes → vasculitis and neutrophils (e.g. post-strep GN, serum sickness).
Any signs of anaphylaxis (airway swelling, stridor, hypotension) → immediately administer epinephrine and secure airway. Do *not* delay, as this is life-threatening.
Painful rash with mucosal lesions after a new drug (suspected SJS/TEN) → stop the offending drug and provide urgent hospital care (burn unit or ICU for fluids, wound management).
Exposure to potential allergen → Assess reaction timing and severity (immediate vs delayed; mild vs anaphylaxis).
If anaphylaxis suspected (rapid onset, hypotension, respiratory distress) → IM epinephrine *first*, plus airway management and IV fluids as needed.
If not an acute emergency → Determine likely type: gather history of timing (minutes vs hours vs days) and perform targeted tests (e.g. skin prick test for IgE, antibody assays or biopsy for immune complexes, patch test for contact).
Classify as Type I, II, III, or IV and treat accordingly: e.g. antihistamines/steroids for Type I allergies, immunosuppression or plasmapheresis for antibody-mediated Type II/III, and avoidance + steroids for Type IV. Ensure removal of or avoidance of the triggering antigen in all cases.
Stung by a bee, within minutes develops wheezing, hives, and hypotension → Anaphylaxis (Type I hypersensitivity).
Young adult with hemoptysis and hematuria; renal biopsy shows *linear* IgG deposits along basement membranes → Goodpasture syndrome (Type II hypersensitivity).
Patient started on an antithymocyte serum 10 days ago now has fever, urticarial rash, arthralgias, and proteinuria → Serum sickness (Type III immune complex reaction).
48 hours after hiking, a patient develops a pruritic blistering rash in streaks on the legs (contact with poison ivy) → Allergic contact dermatitis (Type IV delayed hypersensitivity).
Case 1
A 24‑year‑old man is stung by a wasp while hiking and within minutes develops diffuse hives, wheezing, abdominal cramps, and lightheadedness.
Case 2
A blood transfusion is started in a patient with anemia, but within an hour he develops fever, flank pain, chest tightness, and oozing from his IV sites. His urine turns red.
Case 3
Ten days after receiving antivenom for a snake bite, a 30‑year‑old develops fever, a diffuse urticarial rash, arthralgias, and enlarged lymph nodes. Labs show low C3 complement levels and proteinuria.
Case 4
A 35‑year‑old female presents with an intensely itchy, blistering rash on her hands and neck. She started using a new nickel-containing jewelry 3 days ago. Patch testing on the skin is positive for nickel.
Diagram of the four types of hypersensitivity: Type I (IgE-mediated mast cell degranulation), Type II (IgG/IgM autoantibodies with complement/ADCC), Type III (immune complex deposition with neutrophil activation), and Type IV (T-cell mediated delayed inflammation).
