Hypersensitivity Reactions I–IV
ACID - four ways the immune system turns on the host
The ACID framework
Four ways to injure the host. Hypersensitivity reactions are immune responses that damage the body's own tissues. The ACID mnemonic sorts them by effector: type I Anaphylactic/atopic (IgE), type II antibody-mediated Cytotoxic, type III Immune complex, and type IV Delayed (T cell). Types I–III are antibody-driven and can be transferred with serum; type IV is cell-mediated, uses no antibody, and transfers only with sensitized T cells.
| Feature | Type I | Type II | Type III | Type IV |
|---|---|---|---|---|
| Effector | IgE on mast cells and basophils | IgG/IgM against a fixed cell or matrix antigen | IgG–antigen complexes | Sensitized CD4 and CD8 T cells |
| Timing | Minutes; late phase hours | Variable (hemolytic transfusion: minutes to hours) | Hours (Arthus) to 5–10 days (serum sickness) | Delayed; peaks 48–72 hours |
| Complement | Not required | Often (MAC, opsonization) | Consumed: low C3/C4 | Not involved |
| Prototypes | Anaphylaxis, asthma | Hemolytic anemias, Goodpasture | SLE, serum sickness, PSGN | PPD, contact dermatitis |
| Test | Skin test, specific IgE, tryptase | Coombs | Low complement, granular deposits | PPD, patch test |
Type I: immediate, IgE-mediated
Sensitization. On first exposure, Th2 help (IL-4) switches allergen-specific B cells to IgE, which binds high-affinity Fc receptors on mast cells and basophils. This first exposure is silent; the second exposure is the dangerous one.
- First exposureIgE is made and coats mast cells and basophils
- Re-exposureMultivalent antigen cross-links adjacent IgE
- DegranulationHistamine and tryptase released within minutes
- Late phaseHours later: eosinophils and chemokines sustain inflammation
Immediate vs late phase. Preformed mediators (histamine, tryptase) cause vasodilation, vascular leak, bronchoconstriction, and itch within minutes. Over the next hours, newly synthesized mediators (leukotrienes, prostaglandins) and chemokines recruit eosinophils and other leukocytes, producing the late-phase reaction.
Clinical spectrum and testing. Examples include anaphylaxis (bee sting, peanut, penicillin), allergic rhinitis, asthma, atopic dermatitis, and urticaria. Serum tryptase, a mast-cell-specific protease, rises in anaphylaxis. Scratch/skin-prick testing and allergen-specific serum IgE (RAST) confirm sensitization by detecting preformed, cross-linkable IgE. Anaphylaxis is treated first with intramuscular epinephrine. Patients with selective IgA deficiency may carry anti-IgA antibodies and react anaphylactically to IgA-containing blood products.
Type II: antibody against a fixed antigen
Three routes of injury. IgG or IgM binds antigen on a cell surface or in extracellular matrix, then damages it by:
- Opsonization and phagocytosis: antibody- and C3b-coated cells are cleared by splenic macrophages (autoimmune hemolytic anemia, ITP).
- Complement activation: assembly of the membrane attack complex and neutrophil recruitment (ABO-mismatched transfusion, Goodpasture).
- Antibody-dependent cellular cytotoxicity: NK cells bind the Fc portion of IgG and kill the coated cell.
Function without lysis. Some antibodies alter receptor function instead of destroying the cell: stimulating anti-TSH receptor antibodies in Graves disease, blocking anti-acetylcholine receptor antibodies in myasthenia gravis.
| Feature | Direct Coombs | Indirect Coombs |
|---|---|---|
| Detects | Antibody (or complement) already ON the patient's RBCs | Free anti-RBC antibody IN the patient's serum |
| Method | Add anti-human globulin to patient RBCs; look for agglutination | Mix patient serum with test RBCs, then add anti-human globulin |
| Uses | Autoimmune and drug-induced hemolysis, hemolytic disease of the newborn | Pre-transfusion antibody screen, Rh screen in pregnancy |
Type II roster (with targets).
- Autoimmune and drug-induced hemolytic anemia; ITP (anti-GPIIb/IIIa on platelets).
- Hemolytic disease of the newborn: maternal anti-Rh(D) IgG crosses the placenta and coats fetal RBCs.
- Acute hemolytic transfusion reaction: preformed anti-A/anti-B against mismatched donor RBCs.
- Goodpasture syndrome: anti-GBM (type IV collagen), linear immunofluorescence.
- Acute rheumatic fever: anti-M protein antibodies cross-react with cardiac myosin.
- Pemphigus vulgaris (anti-desmoglein), Graves disease, myasthenia gravis, pernicious anemia (anti-intrinsic factor/parietal cell).
- Also classic: bullous pemphigoid (anti-hemidesmosome) and hyperacute transplant rejection (preformed anti-donor antibodies).
Type III: immune complex disease
Mechanism. Antigen–IgG complexes form in the circulation, most pathogenically when antigen is in slight excess, and deposit in vessel walls, glomeruli, and joints. There they fix complement; C5a recruits neutrophils, which release lysosomal enzymes and cause vasculitis (fibrinoid necrosis) and glomerulonephritis. Complement is consumed, so serum C3 and C4 fall. Prototypes: SLE, polyarteritis nodosa (PAN), and poststreptococcal glomerulonephritis (PSGN).
| Feature | Serum sickness | Arthus reaction |
|---|---|---|
| Extent | Systemic (prototypic type III) | Local, at the injection site |
| Trigger | Foreign protein (e.g., equine antivenom, antithymocyte globulin) or a drug acting as a hapten | Intradermal antigen in a presensitized person with preformed IgG (e.g., tetanus or other vaccine booster) |
| Timing | 5–10 days (time needed to make antibody) | Within hours |
| Findings | Fever, urticaria, arthralgias, lymphadenopathy, glomerulonephritis/proteinuria; low C3/C4 | Edema, necrosis, and vasculitis in the skin |
Type IV: delayed, T-cell mediated
Mechanism. Previously sensitized T cells respond over hours to days. CD4 Th1 cells release cytokines (notably IFN-γ) that activate macrophages, producing granulomatous inflammation; CD8 cytotoxic T cells kill antigen-bearing cells directly. No antibody or complement is involved, so type IV is the only type not transferable by serum. Memory hook, the 4 T's: T cells, Transplant rejection, TB skin test, Touching (contact dermatitis).
- Tuberculin (PPD) test: induration read at 48–72 hours; measure induration, not redness.
- Contact dermatitis: poison ivy, nickel, chemicals in latex gloves; confirmed by patch testing.
- Graft rejection and graft-versus-host disease.
- Granulomatous disease, such as tuberculosis.
- Autoimmune: multiple sclerosis and type 1 diabetes. Guillain-Barré has a T-cell component but is now usually listed as type II (anti-ganglioside antibodies).
Latex splits by mechanism: glove contact dermatitis is type IV, but latex urticaria, bronchospasm, or anaphylaxis is IgE-mediated type I.
High-yield contrasts
Same trigger, different type. Group A streptococcal infection produces two sequelae by different mechanisms: rheumatic fever is type II (molecular mimicry between M protein and myosin), whereas PSGN is type III (immune complexes with low C3).
Linear vs lumpy-bumpy. Goodpasture (type II) shows smooth linear IgG along the GBM because antibody binds antigen distributed evenly in the membrane. PSGN (type III) shows granular "lumpy-bumpy" deposits because complexes lodge in discrete clumps.
Timing is the fastest discriminator: minutes after exposure → type I; 5–10 days after a new drug or foreign protein with low complement → type III; induration at 48–72 hours → type IV.