Hypersensitivity and Allergy

Hypersensitivity reactions are classified by the Gell and Coombs system, formalized by British immunologists Philip Gell and Robin Coombs in their 1963 textbook Clinical Aspects of Immunology. The scheme sorts immunopathology into four types based on which immune effector mechanism causes the damage: Type I uses immunoglobulin E (IgE) bound to mast cells and basophils; Type II uses IgG or IgM antibodies directed against antigens fixed to cell surfaces or extracellular matrix; Type III uses soluble antigen-antibody immune complexes that deposit in tissues; and Type IV uses antigen-specific T lymphocytes acting without a central antibody contribution. Types I–III are antibody-mediated and can occur within minutes to hours (hence "immediate hypersensitivity" for Type I); Type IV is cell-mediated and characteristically takes 24–72 hours to develop (hence "delayed-type hypersensitivity," DTH).

Allergy is the clinical term for Type I hypersensitivity to environmental antigens — now called allergens — that are otherwise harmless to most people: pollen, dust-mite feces, animal dander, food proteins, insect venom, and drugs. The word "allergy" was coined in 1906 by Austrian pediatrician Clemens von Pirquet from Greek allos (other) + ergon (work/reaction), meaning an altered reactivity to a substance the first time was ordinarily tolerated. Crucially, a hypersensitivity reaction requires prior sensitization: the immune system must first encounter the antigen, generate memory (B cells with class-switched IgE, or effector/memory T cells), and only on re-exposure does the destructive reaction occur. This sensitization requirement links hypersensitivity mechanistically to The Humoral Response (for antibody-mediated Types I–III) and to Helper and Cytotoxic T Cells (for Type IV, and for T-cell help driving IgE class switching). A key conceptual distinction threading through all four types is that the antigen itself is rarely intrinsically dangerous — pollen grains, transfused red cells, and self-basement-membrane collagen do not damage tissue directly. Damage arises from the immune system's own effector chemistry: histamine-induced vasodilation and smooth muscle contraction, complement membrane attack complexes, neutrophil-released proteases, and cytotoxic T-cell perforin/granzyme. This is why hypersensitivity is often described as "the price of having an immune system" — the very mechanisms that clear intracellular bacteria or neutralize toxins become the mechanisms of self-inflicted injury when mistargeted.

Type I: IgE-mediated immediate hypersensitivity

Sensitization phase. On first exposure to an allergen (e.g., a peanut protein, Ara h 2), dendritic cells present allergen-derived peptides on MHC class II to naive CD4+ T cells. In genetically and environmentally predisposed individuals, this differentiates the T cell into a Th2 subset, which secretes interleukin-4 (IL-4) and IL-13. These cytokines drive B cells specific for the allergen to class-switch their immunoglobulin heavy chain from IgM to IgE. Secreted IgE then binds, via its Fc region, to the high-affinity IgE receptor FcεRI on the surface of tissue mast cells and circulating basophils. A single mast cell can display 100,000–500,000 FcεRI receptors, each loaded with an IgE molecule of a particular allergen specificity — the cell is now "armed" and primed, though no reaction has yet occurred.

Elicitation phase. On re-exposure, allergen molecules — which are typically multivalent, presenting several identical epitopes — bind and cross-link adjacent IgE-FcεRI complexes on the mast cell surface. This cross-linking, not simple binding, is the trigger: it clusters receptor cytoplasmic tails, activates Lyn and Syk tyrosine kinases, and triggers a calcium-dependent signaling cascade that causes: 1. Immediate degranulation (seconds to minutes): preformed granules release histamine, tryptase, and heparin. Histamine acts on H1 receptors to cause vasodilation, increased vascular permeability, and smooth muscle contraction — producing the classic wheal-and-flare skin reaction, bronchoconstriction, and gut cramping. 2. Lipid mediator synthesis (minutes): membrane phospholipids are converted via phospholipase A2 and 5-lipoxygenase into leukotrienes (LTC4, LTD4, LTE4 — collectively the "slow-reacting substance of anaphylaxis") and via cyclooxygenase into prostaglandin D2. Leukotrienes are roughly 1,000-fold more potent than histamine at causing bronchoconstriction and account for the sustained bronchospasm of asthma. 3. Cytokine transcription (hours): TNF-α, IL-4, IL-5, IL-13 are newly synthesized, recruiting eosinophils and amplifying the late-phase reaction 4–8 hours after exposure — the reason asthma and allergic reactions often have a biphasic course. Systemically, massive mast cell/basophil activation produces anaphylaxis: widespread vasodilation and vascular leak drop blood pressure (distributive shock), airway edema and bronchospasm compromise breathing, and death can occur within minutes without treatment — which is why epinephrine (an α1-agonist that vasoconstricts and a β2-agonist that bronchodilates, also stabilizing mast cells) is first-line emergency therapy, not antihistamines, which act too slowly and address only the histamine component.

Type II: Antibody-mediated cytotoxic hypersensitivity

IgG or IgM antibodies bind antigens that are fixed to the surface of a cell or embedded in extracellular matrix — as opposed to Type III's soluble, circulating antigen. Once bound, three effector mechanisms can be triggered:

• Complement-dependent cytotoxicity: antibody Fc regions recruit C1q, activating the classical complement cascade, culminating in the membrane attack complex (C5b-9) that lyses the target cell. This underlies ABO-mismatched transfusion reactions, where pre-existing IgM antibodies against foreign ABO blood-group antigens trigger intravascular hemolysis within minutes.
• Antibody-dependent cellular cytotoxicity (ADCC): NK cells and macrophages bear Fc receptors that engage antibody-coated cells and kill them via perforin/granzyme or phagocytosis, without complement.
• Antibody-mediated cellular dysfunction (a variant without cell killing): antibodies against cell-surface receptors can block or stimulate signaling. In myasthenia gravis, antibodies against the acetylcholine receptor block neuromuscular transmission; in Graves disease, stimulating antibodies against the TSH receptor cause hyperthyroidism — these are sometimes classified as "Type V" but conventionally folded into Type II.

Classic examples: hemolytic disease of the newborn (maternal anti-Rh IgG crosses the placenta and destroys fetal Rh+ red cells), Goodpasture syndrome (autoantibodies against type IV collagen in glomerular and alveolar basement membrane cause kidney and lung damage), and autoimmune hemolytic anemia.

Type III: Immune-complex-mediated hypersensitivity

Here antibody (usually IgG) binds a soluble antigen circulating in blood, forming immune complexes. Small complexes formed in modest antigen excess are poorly cleared by phagocytes and deposit passively in the basement membranes of small vessels, joints, and renal glomeruli — sites of high blood flow and pressure filtration. Once lodged, they activate complement (C3a and C5a act as anaphylatoxins/chemoattractants), recruiting neutrophils whose released lysosomal enzymes and reactive oxygen species damage the surrounding vessel wall — a picture of vasculitis. The paradigm is serum sickness: historically caused by injecting patients with horse-derived antiserum (e.g., diphtheria antitoxin), where the patient mounts antibodies against the foreign horse serum proteins 1–2 weeks later; circulating immune complexes then deposit systemically, causing fever, urticarial rash, arthralgia, and glomerulonephritis roughly 7–10 days after exposure — the delay corresponding exactly to the time needed to generate antibody. The Arthus reaction is the localized cutaneous version, seen when antigen is injected into an already-sensitized (antibody-rich) individual, producing local vasculitis and edema within hours at the injection site. Systemic lupus erythematosus, post-streptococcal glomerulonephritis, and serum-sickness-like drug reactions (e.g., to some antibiotics) all follow this mechanism.

Type IV: T-cell-mediated (delayed-type) hypersensitivity

Unlike Types I–III, Type IV requires no antibody. Sensitized Th1 CD4+ T cells (or, in some cases, cytotoxic CD8+ T cells) recognize antigen presented on MHC by local antigen-presenting cells and, upon re-exposure, secrete interferon-gamma (IFN-γ), which activates macrophages into a highly inflammatory state — increased phagocytic and microbicidal activity, but also tissue-damaging protease and reactive-oxygen release. Because this requires antigen presentation, T-cell trafficking to the tissue, and cytokine-driven macrophage activation — a multi-cellular relay rather than a preformed granule release — the reaction takes 24–72 hours to peak, hence "delayed." Three classic manifestations:

• Contact hypersensitivity: small lipid-soluble haptens (poison ivy urushiol, nickel, chromate) penetrate skin, covalently modify self-proteins, and are presented by Langerhans cells to hapten-specific T cells — producing the itchy, vesicular rash of contact dermatitis 1–3 days after re-exposure.
• Tuberculin-type reaction: the basis of the PPD (Mantoux) skin test for tuberculosis exposure — intradermal injection of Mycobacterium tuberculosis protein derivative in a previously sensitized (or infected) person produces a firm, red induration peaking at 48–72 hours, reflecting recruited T cells and macrophages.
• Granulomatous hypersensitivity: when antigen cannot be cleared (e.g., intracellular M. tuberculosis, or an implanted foreign body), chronic macrophage activation forms granulomas — organized aggregates of epithelioid macrophages, multinucleated giant cells, and a surrounding T-cell cuff, often with central caseous necrosis in TB — a mechanism directly continuous with normal cell-mediated immunity against intracellular pathogens taught alongside Helper and Cytotoxic T Cells.

Allograft (transplant) rejection uses overlapping machinery: CD8+ T cells directly kill graft cells bearing foreign MHC, while CD4+ T cells orchestrate delayed-type inflammation — a hybrid of Type II (antibody against graft vasculature in hyperacute rejection) and Type IV (cellular rejection).

The Prausnitz–Küstner reaction (1921). German physicians Carl Prausnitz and Heinz Küstner provided the founding proof that immediate hypersensitivity is transferred by a soluble serum factor, not by cells. Küstner was allergic to cooked fish; Prausnitz was not. Prausnitz injected a small volume of Küstner's serum into his own forearm skin. Twenty-four hours later, Prausnitz injected fish extract into that same skin site — and a wheal-and-flare reaction erupted within minutes, exactly reproducing Küstner's allergy in a person who had never been exposed to fish allergen. Injecting fish extract into untreated skin, or serum alone, produced no reaction; the combination of pre-sensitized serum plus later antigen challenge at that site was necessary and sufficient. This proved that a transferable serum factor — later called "reagin" — conferred immediate hypersensitivity, decades before its molecular identity was known. The reaction is now recognized as an ethically unrepeatable but historically pivotal experiment (deliberately transferring blood-borne factors between people is no longer done for this purpose, given later-recognized risks of blood-borne pathogens).

Identification of IgE (Ishizaka and Ishizaka, 1966–67). Kimishige Ishizaka and Teruko Ishizaka, working in Denver, set out to identify the molecular nature of "reagin." Existing antibody classes (IgG, IgA, IgM) were known, but reagin activity in allergic patients' serum did not co-purify with any of them by the standard biochemical fractionation and did not react with antisera against known immunoglobulin classes. The Ishizakas raised antisera in rabbits against ragweed-sensitive patients' serum, then absorbed out all reactivity to known immunoglobulin classes; the remaining antiserum still blocked Prausnitz–Küstner-type reactivity, revealing a novel immunoglobulin class, which they named IgE (for erythema, the skin reaction it caused). Independently, Swedish researchers S.G.O. Johansson and Hans Bennich identified an unusual myeloma protein (IgND) that turned out to be the same new class. The two groups' findings converged and were confirmed as identical in 1968 by the World Health Organization, officially designating IgE as the fifth immunoglobulin class. This resolved the fifty-year mystery from Prausnitz–Küstner: reagin is IgE.

Landsteiner's hapten-carrier experiments (1930s). Karl Landsteiner (who earlier discovered the ABO blood groups, foundational to Type II hypersensitivity in transfusion reactions) established that small chemical groups — haptens — are not immunogenic alone but become targets of antibody or T-cell response once covalently coupled to a larger carrier protein. This work, using synthetic aryl-diazonium haptens conjugated to proteins, defined the exquisite chemical specificity of antibodies (distinguishing ortho-, meta-, and para-substituted benzene rings) and directly explains the molecular basis of contact hypersensitivity (Type IV): small molecules like urushiol or nickel ions act as haptens that modify self-proteins in skin, creating new antigenic determinants recognized by T cells.

Serum sickness models (Clemens von Pirquet and Béla Schick, 1905; and later quantitative studies by Frank Dixon in the 1950s–60s). Von Pirquet and Schick, observing children treated with horse-derived diphtheria antitoxin, documented the delayed onset (typically 8–12 days) of fever, rash, and joint pain — coining the term "serum sickness" and correctly inferring that the reaction depended on the patient's own antibody response against the foreign horse protein, not on the antitoxin's direct toxicity. Decades later, Frank Dixon and colleagues used radiolabeled foreign protein (bovine serum albumin) injected into rabbits to track antigen and antibody levels quantitatively over time, showing three phases: an early phase with free antigen circulating, a phase of immune-complex formation coinciding with the onset of glomerulonephritis and vasculitis, and a final phase of antibody excess with clearance and resolution — directly demonstrating that pathogenic immune complexes form preferentially in modest antigen excess and are deposited in glomerular capillaries, establishing the mechanistic basis of Type III hypersensitivity.

Example 1 — Interpreting a penicillin reaction timeline. A 34-year-old patient receives intravenous penicillin for the first time in her life for a wound infection, with no prior known penicillin exposure. Twelve minutes into the infusion she develops urticaria, wheezing, and a blood pressure of 78/40 mmHg (baseline 122/76). She is treated with intramuscular epinephrine and recovers. Question: is this consistent with Type I hypersensitivity if she reports "no prior use" of penicillin? Reasoning: true Type I anaphylaxis requires prior sensitization — an initial exposure that generates allergen-specific IgE bound to mast cells — before a reaction can occur on re-exposure. A reaction within minutes of a first reported dose strongly suggests either (a) unrecognized prior exposure (penicillin and related β-lactams are common trace contaminants in food from livestock treatment, or she may have had a prior undocumented course), or (b) cross-reactivity: her IgE was raised against a structurally similar β-lactam antigenic determinant (the penicilloyl group forms after penicillin's β-lactam ring opens and covalently attaches to serum proteins — itself a hapten-carrier mechanism directly descended from Landsteiner's work), from a related drug she has taken before. The clinical timeline (minutes, hypotension, wheeze, urticaria — classic anaphylaxis) is diagnostic of Type I regardless of the exact sensitizing exposure; the biology requires that sensitization occurred at some prior time, even if not consciously recalled or reported.

Example 2 — A Rh-incompatible pregnancy, quantified. An Rh-negative mother (genotype dd) is pregnant with her second Rh-positive child (father genotype DD, so all offspring are Dd, Rh-positive). Her first Rh-positive delivery caused a small fetal-maternal hemorrhage of Rh+ red cells into her circulation, which — unless prevented — sensitizes her B cells to make anti-D IgG. Question: mechanistically, why does the first Rh+ pregnancy usually produce a healthy baby while the second risks severe hemolytic disease of the newborn (HDN), and how does prophylaxis intervene? Reasoning: this is Type II hypersensitivity. During the first pregnancy, fetal Rh+ cells cross the placenta (most substantially at delivery), and the mother's immune system, encountering the foreign D antigen for the first time, undergoes primary sensitization — generating memory B cells over subsequent weeks, too late to affect the first child. In a second Rh+ pregnancy, if her anti-D memory B cells were not neutralized, a much smaller fetal-maternal hemorrhage triggers a rapid secondary (anamnestic) antibody response, dominated by IgG (able to cross the placenta, unlike IgM). This maternal IgG binds fetal Rh+ red cell surface antigen, activating complement-mediated lysis and Fc-receptor-mediated splenic destruction (Type II ADCC/complement mechanism) — producing fetal anemia, hydrops, and jaundice from bilirubin release. Prophylaxis — anti-D immunoglobulin (RhoGAM) given to the Rh-negative mother at ~28 weeks and after delivery — works by binding and clearing any fetal Rh+ cells in the maternal circulation before her own B cells recognize and become sensitized to the D antigen, preventing primary sensitization altogether. This is passive antibody blocking active immunization — a direct application of the mechanism to prevention.

Allergen immunotherapy ("allergy shots" or sublingual tablets) works by repeatedly administering escalating doses of allergen to gradually shift the immune response away from Th2/IgE and toward a Th1/regulatory T-cell profile with blocking IgG4 antibodies — a direct clinical application of the sensitization mechanism run in reverse. Anti-IgE biologics (omalizumab) bind free serum IgE, preventing it from occupying FcεRI on mast cells, and are used in severe allergic asthma and chronic urticaria — a therapy made possible only because the Ishizakas identified the target molecule. Epinephrine auto-injectors are carried by millions of food- and venom-allergic patients worldwide as first-line anaphylaxis rescue therapy, grounded directly in Type I mechanism. Blood typing and crossmatching before transfusion, and Rh-immunoglobulin prophylaxis in pregnancy, are routine preventive medicine built on Type II mechanisms and Landsteiner's foundational blood-group work. Complement inhibitors (eculizumab and related agents) are now used to blunt Type II/III complement-mediated tissue injury in diseases from atypical hemolytic uremic syndrome to antibody-mediated transplant rejection. Tuberculin skin testing and interferon-gamma release assays for latent TB screening in public health programs are direct clinical uses of Type IV delayed hypersensitivity. And immunosuppressive regimens for solid organ transplantation are designed explicitly to blunt the Type II (antibody-mediated) and Type IV (T-cell-mediated) rejection pathways described here — the same principles extend, as the next conceptual step, into Autoimmunity, where these four mechanistic types turn against the body's own antigens rather than transplanted or environmental ones.

Ask the tutor: How does the same Type II and Type III machinery described here reappear when the immune system loses tolerance to self-antigens in autoimmune disease?