Premed · Premed · Immunology
Lecture 24: Hypersensitivity Reactions: Types I-IV
Immunology
Learning Objectives
By the end of this lecture, students will be able to:
- Define hypersensitivity and classify the four types (Gell and Coombs classification)
- Describe the mechanism, mediators, and clinical examples of Type I (immediate) hypersensitivity
- Explain Type II (antibody-mediated cytotoxic) hypersensitivity and its clinical manifestations
- Describe Type III (immune complex-mediated) hypersensitivity and its pathogenesis
- Explain Type IV (delayed-type) hypersensitivity and its subtypes
Lecture Content
I. Overview of Hypersensitivity
Hypersensitivity refers to exaggerated or inappropriate immune responses that cause tissue damage. Under normal circumstances, immune mechanisms are protective, but they become pathological when directed against harmless environmental antigens (allergens), causing allergy; against self-antigens, causing autoimmunity; against alloantigens, leading to transplant rejection and transfusion reactions; or against infectious agents when the response is excessive, resulting in immunopathology.
The Gell and Coombs classification organizes hypersensitivity reactions into four types based on their underlying mechanism. Type I is IgE-mediated immediate hypersensitivity. Type II involves IgG or IgM antibody-mediated cytotoxic reactions. Type III is driven by immune complex deposition. Type IV is T cell-mediated delayed-type hypersensitivity. An important distinction is that Types I through III are antibody-mediated (humoral), while Type IV is cell-mediated. It is also worth noting that many diseases involve more than one type of hypersensitivity simultaneously.
II. Type I Hypersensitivity (Immediate/Anaphylactic)
Type I hypersensitivity is mediated by IgE-dependent mast cell and basophil degranulation. It occurs within minutes of antigen exposure during the immediate phase, with a possible late phase at 4 to 8 hours. The reaction unfolds in distinct steps.
During the sensitization phase upon first exposure, allergen is taken up by dendritic cells and presented to CD4+ Th2 cells. These Th2 cells produce IL-4 and IL-13, which drive B cell class switching to IgE. The IgE then binds to high-affinity FcepsilonRI receptors on mast cells and basophils, completing sensitization. No symptoms occur during this initial phase.
The effector phase occurs upon re-exposure. The allergen cross-links IgE molecules on the mast cell surface, bridging at least two FcepsilonRI receptors. This triggers FcepsilonRI signaling and mast cell degranulation. Preformed mediators are released immediately, including histamine, which causes vasodilation, increased vascular permeability, bronchoconstriction, and pruritus, along with proteases such as tryptase and chymase, and heparin. Within minutes, newly synthesized lipid mediators are produced, including prostaglandin D2, which causes vasodilation and bronchoconstriction, and leukotrienes C4, D4, and E4 (historically known as slow-reacting substance of anaphylaxis), which are 1000 times more potent than histamine at inducing bronchoconstriction, mucus secretion, and increased vascular permeability. Over the following hours, cytokines including TNF-alpha, IL-4, IL-5, and IL-13 are produced, which recruit eosinophils and promote ongoing inflammation.
The late-phase reaction develops 4 to 8 hours after allergen exposure and is characterized by eosinophil and neutrophil infiltration. Sustained inflammation mediated by leukotrienes and cytokines contributes to chronic allergic inflammation.
The clinical manifestations of Type I hypersensitivity can be local or systemic. Local reactions include allergic rhinitis affecting the nasal mucosa, asthma affecting the bronchi, food allergy in the GI tract, urticaria and eczema on the skin, and allergic conjunctivitis in the eyes. Systemic anaphylaxis results from widespread mast cell degranulation, producing massive vasodilation, hypotension, laryngeal edema, bronchospasm, and cardiovascular collapse, which can be life-threatening. Common triggers include insect stings, penicillin, peanuts, shellfish, and latex. The immediate treatment is epinephrine, followed by antihistamines, corticosteroids, and IV fluids.
<image>A step-by-step diagram of Type I hypersensitivity. Panel 1 (Sensitization): An allergen (e.g., pollen grain) is shown being captured by a dendritic cell, which presents allergen peptide on MHC II to a naive CD4+ T cell, polarizing it toward Th2. The Th2 cell produces IL-4 and IL-13 (shown with arrows), which act on a B cell to induce class switching to IgE. IgE molecules bind FcεRI on a mast cell surface (shown as Y-shaped antibodies anchored to the mast cell). Panel 2 (Re-exposure and degranulation): The same allergen returns and cross-links two IgE molecules on the mast cell surface. FcεRI signaling cascade is triggered. The mast cell degranulates, releasing granules containing histamine, tryptase, and heparin. Newly synthesized mediators are shown: prostaglandin D2 and leukotrienes (LTC4/D4/E4) from membrane phospholipids via the arachidonic acid pathway. Effects are labeled: vasodilation, increased vascular permeability, bronchoconstriction, mucus secretion. Panel 3 (Late phase): Cytokines (TNF-alpha, IL-5, IL-13) recruit eosinophils and neutrophils, causing sustained tissue inflammation.</image>
III. Type II Hypersensitivity (Antibody-Mediated Cytotoxic)
Type II hypersensitivity involves IgG or IgM antibodies directed against antigens on cell surfaces or in the extracellular matrix, resulting in cell destruction or functional alteration. These reactions develop over hours to days and operate through three distinct sub-mechanisms.
Opsonization and phagocytosis or complement-mediated lysis occurs when antibody binds a cell-surface antigen, leading to Fc receptor-mediated phagocytosis and/or complement activation with membrane attack complex formation and cell lysis. Clinical examples include autoimmune hemolytic anemia, where anti-RBC antibodies destroy red blood cells; autoimmune thrombocytopenic purpura (ITP), where anti-platelet antibodies cause platelet destruction; hemolytic disease of the newborn (HDN), where maternal anti-Rh IgG crosses the placenta and attacks fetal red blood cells; transfusion reactions, where ABO-incompatible blood triggers anti-A or anti-B IgM, complement activation, and intravascular hemolysis; and Goodpasture syndrome, where anti-glomerular basement membrane antibodies activate complement, causing glomerulonephritis and pulmonary hemorrhage.
Antibody-dependent cellular cytotoxicity (ADCC) represents the second mechanism, in which IgG-coated target cells are killed by NK cells through their CD16 (FcgammaRIIIA) receptor, as well as by eosinophils, macrophages, and neutrophils.
The third mechanism, antibody-mediated cellular dysfunction, is non-cytotoxic. Here, antibodies alter cell function by binding to receptors, either stimulating or blocking them. In Graves' disease, anti-TSH receptor antibodies (thyroid-stimulating immunoglobulins) mimic TSH and drive hyperthyroidism. In myasthenia gravis, anti-acetylcholine receptor antibodies block neuromuscular transmission, causing muscle weakness. In pernicious anemia, anti-intrinsic factor antibodies block vitamin B12 absorption.
IV. Type III Hypersensitivity (Immune Complex-Mediated)
Type III hypersensitivity occurs when antigen-antibody (IgG) immune complexes deposit in tissues, activate complement, and trigger inflammation that damages surrounding tissue. The timeline ranges from hours (in the Arthus reaction) to days or weeks (in serum sickness).
The pathogenesis follows a predictable sequence. Antigen-antibody complexes form either in the circulation or locally within tissues. Small-to-intermediate-sized complexes are the most pathogenic because they are not efficiently cleared by the reticuloendothelial system. These complexes deposit preferentially in vessel walls, glomeruli, joints, and skin, particularly in sites where blood is filtered or flow is turbulent. Once deposited, the complexes activate complement, generating anaphylatoxins C3a and C5a that recruit neutrophils. The neutrophils release lysosomal enzymes and reactive oxygen species, causing tissue damage in the form of vasculitis and glomerulonephritis. Fc receptor-bearing cells also contribute to the inflammatory response.
Clinical examples of Type III hypersensitivity include serum sickness, a systemic immune complex disease historically caused by injection of foreign serum and now more commonly drug-induced, which presents with fever, arthralgia, vasculitis, and glomerulonephritis 7 to 10 days after exposure. The Arthus reaction is a localized immune complex reaction at the site of antigen injection in a previously sensitized individual, producing local vasculitis, edema, and necrosis. SLE nephritis results from deposition of anti-dsDNA immune complexes in the glomeruli. Post-streptococcal glomerulonephritis occurs when streptococcal antigen-antibody complexes deposit in the kidneys. Polyarteritis nodosa involves hepatitis B immune complex-driven vasculitis. Farmer's lung and other forms of hypersensitivity pneumonitis result from inhalation of antigens such as mold spores or bird proteins, with subsequent immune complex deposition in the lungs.
<image>A comparison diagram of the four types of hypersensitivity reactions. Four columns, each representing one type. Type I (Immediate): Shows mast cell with IgE bound to FcεRI, allergen cross-linking IgE, degranulation releasing histamine. Timeline: minutes. Examples listed: anaphylaxis, allergic rhinitis, asthma. Type II (Antibody-mediated cytotoxic): Shows IgG bound to antigens on a cell surface (e.g., red blood cell), with three outcomes: complement activation → MAC → cell lysis; Fc receptor-mediated phagocytosis by a macrophage; and receptor stimulation/blocking (Graves'/myasthenia gravis). Timeline: hours. Examples listed: hemolytic anemia, HDN, Goodpasture. Type III (Immune complex): Shows antigen-antibody complexes circulating in blood, depositing in a glomerular capillary wall, activating complement (C3a, C5a), recruiting neutrophils that release enzymes causing tissue damage. Timeline: hours to weeks. Examples: SLE, serum sickness, Arthus reaction. Type IV (Delayed-type): Shows a sensitized Th1 cell recognizing antigen on an APC, releasing IFN-gamma and TNF, activating macrophages that cause tissue damage; also a CD8+ T cell killing a target. Timeline: 24-72 hours. Examples: contact dermatitis, tuberculin test, granulomas.</image>
V. Type IV Hypersensitivity (Delayed-Type/Cell-Mediated)
Type IV hypersensitivity is mediated entirely by T cells, with no antibody involvement. The characteristic feature is the delayed onset of 24 to 72 hours after antigen exposure, which gives this category its name. Type IV is subdivided into several subtypes based on the effector cells involved.
Type IVa represents classic delayed-type hypersensitivity (DTH), mediated by CD4+ Th1 cells. When sensitized Th1 cells encounter antigen presented by macrophages or dendritic cells, they release IFN-gamma and TNF. IFN-gamma activates macrophages, enhancing their killing capacity and production of inflammatory mediators, which ultimately causes tissue damage. In chronic DTH, macrophages differentiate into epithelioid cells and fuse into multinucleated giant cells, forming granulomas, which are organized aggregates surrounded by T cells. Classic examples include the tuberculin test (PPD/Mantoux test), in which intradermal injection of tuberculin produces induration at 48 to 72 hours in previously sensitized individuals. Granulomatous diseases such as tuberculosis, leprosy, sarcoidosis, and Crohn's disease exemplify chronic DTH. Contact dermatitis occurs when a hapten such as poison ivy urushiol or nickel modifies self-proteins, triggering a Th1 response against hapten-modified peptides.
Type IVb involves T cell-mediated eosinophilic inflammation driven by Th2 cells. IL-5 recruits eosinophils, while IL-4 and IL-13 promote IgE production and mucus secretion. Chronic allergic asthma, which overlaps with Type I, is the prime example.
Type IVc involves direct cytotoxicity mediated by CD8+ CTLs, which kill target cells through the perforin/granzyme pathway or Fas-FasL interactions. Examples include the CD8 component of contact dermatitis, cellular graft rejection, and Stevens-Johnson syndrome/toxic epidermal necrolysis caused by drug-reactive CTLs.
Type IVd is characterized by neutrophilic inflammation mediated by T cells that produce IL-8/CXCL8 and GM-CSF, leading to neutrophil recruitment and activation. Acute generalized exanthematous pustulosis (AGEP), a drug reaction, is a representative example.
VI. Summary and Clinical Integration
In clinical practice, hypersensitivity types frequently overlap within a single disease. Rheumatoid arthritis combines Type III reactions (immune complexes in joints) with Type IV responses (T cell-mediated synovial inflammation). SLE involves both Type III hypersensitivity (immune complexes) and Type II (anti-RBC antibodies causing hemolytic anemia). Allergic asthma combines Type I (IgE-mediated) with Type IVb (Th2-driven chronic inflammation).
Understanding the mechanism of hypersensitivity in a given disease directly guides therapy. Type I reactions are managed with antihistamines, leukotriene inhibitors, epinephrine, and anti-IgE (omalizumab). Type II reactions may require plasmapheresis, immunosuppression, or receptor-blocking antibodies depending on the specific mechanism. Type III reactions are treated with immunosuppression and anti-inflammatory agents. Type IV reactions respond to corticosteroids, calcineurin inhibitors (cyclosporine, tacrolimus), and T cell-directed therapies.
