The Concept of Hypersensitivity
Hypersensitivity refers to an inappropriately strong immune response capable of causing damage to the body's own tissues. Normally, the immune system's response to a foreign agent is proportionate to the stimulus. In hypersensitivity, this proportionality is disrupted: a harmless antigen (such as peanut protein) provokes a severe reaction, up to and including angioedema.
Classically, four types of hypersensitivity reactions are distinguished, to which modern classification has added a fifth — the receptor-mediated type, separated from the second type. Thus, the current nomenclature features five types:
- Type I — reaginic (anaphylactic), immediate-type hypersensitivity;
- Type II — cytotoxic;
- Type III — immune complex;
- Type IV — cell-mediated, delayed-type hypersensitivity;
- Type V — receptor-mediated.
Type I — Reaginic (Anaphylactic)
The underlying mechanism is the production of class E immunoglobulins (IgE) in response to an antigen. Upon initial contact with an antigen, the resulting IgE molecules bind to the surface of mast cells and basophils. Upon re-exposure to the same antigen, it directly binds to the pre-existing IgE on these cells, triggering their degranulation.
Histamine, serotonin, and other biologically active substances are released from the granules; simultaneously, the de novo synthesis of inflammatory mediators is initiated.
Stages of the reaction:
- Immunological stage — primary contact with the antigen and IgE production;
- Pathochemical stage — re-exposure, degranulation, and mediator formation;
- Pathophysiological stage — the effect of mediators on tissues.
Clinical manifestations: allergic urticaria, atopic dermatitis, bronchial asthma, angioedema, allergic conjunctivitis, seasonal rhinitis, and anaphylactic shock in severe cases.
Type II — Cytotoxic
Antigens become fixed on the surface of the body's own cells (e.g., erythrocytes). The resulting antibodies (IgG, IgM) recognize these cells as foreign and mediate their destruction.
Mechanisms of target cell lysis:
- Complement-dependent lysis — antibody binding recruits the complement system with the formation of the membrane attack complex;
- Phagocytosis of opsonized cells by macrophages;
- Antibody-dependent cellular cytotoxicity (ADCC) — destruction of the target cell by cytotoxic T cells and NK cells.
Typical examples: drug allergy with hemolysis, hemolytic disease of the newborn due to Rhesus incompatibility between mother and fetus. With timely diagnosis, Rhesus incompatibility is managed, and the child is born healthy.
Type III — Immune Complex
Circulating immune complexes — combinations of free antigens with antibodies — play a key role. The resulting complexes deposit on the vascular endothelium, in renal glomeruli, and synovial membranes.
Sequence of events: antigen enters the bloodstream → B lymphocyte recognizes it and differentiates into a plasma cell → antibody production → formation of an immune complex → its deposition on the endothelium. Neutrophils are recruited to the deposited complexes and the complement system is activated; neutrophil degranulation and the membrane attack complex locally damage the endothelium, producing the clinical picture of vasculitis, glomerulonephritis, or serum sickness.
Type IV — Cell-Mediated (Delayed)
The reaction is mediated not by antibodies, but by T lymphocytes. A hapten binds to a carrier protein, forming a complete antigen. It is captured by an antigen-presenting cell (APC), processed, and presented in the context of MHC molecules to T helper cells and macrophages.
Upon re-exposure to the antigen, a sensitized T helper cell initiates inflammation by activating macrophages and cytotoxic T cells, which damage tissues in the area where the antigen is present. All the steps — capture, processing, presentation, and activation of effector cells — take 24–48 hours, which is why the reaction is termed delayed. Contact dermatitis, the tuberculin skin test, and graft rejection develop via this mechanism.
Type V — Receptor-Mediated
Separated from Type II. Antibodies bind not to a random antigen on the cell, but directly to receptors on the cell membrane. Two variants are possible:
- Stimulating — the antibody mimics the ligand and activates the receptor. Example: antibodies against the TSH receptor in Graves' disease cause thyrocytes to synthesize thyroid hormones;
- Blocking — the antibody occupies the receptor and blocks the true ligand from binding. Example: antibodies against acetylcholine receptors in myasthenia gravis, preventing acetylcholine binding.
Key to Memorization
All five types differ in the localization of antigen and antibody:
- Type I — antibodies (IgE) on mast cells and basophils;
- Type II — antigen on the body's own cell, antibodies cause its lysis (cytotoxicity);
- Type III — antigen and antibody meet freely in the blood, forming immune complexes;
- Type IV — many cells (APCs, T helpers, macrophages), no antibodies — cell-mediated;
- Type V — antibodies on cell receptors.
Key points
- Hypersensitivity is an inappropriately strong immune response that damages the body's own tissues.
- Type I is mediated by IgE on mast cells and basophils, manifesting as anaphylaxis, asthma, and urticaria.
- Type II is cytotoxic: antibodies destroy cells with fixed antigen via complement, phagocytosis, and ADCC.
- Type III is mediated by circulating immune complexes that deposit on the endothelium and in the kidneys.
- Type IV is cell-mediated, developing over 24–48 hours with the involvement of T helper cells and macrophages.
- Type V is receptor-mediated: antibodies stimulate (Graves' disease) or block (myasthenia gravis) receptors.
- The key to classification is the localization of the antigen and antibody in each mechanism.